59
normal after a few days and mesenteric ischaemia was thought be merely a possibility. The presence of birefringent cholesterol crystals within the vascular lumen of a distal subdermal vessel on skin biopsy confirmed the diagnosis of CES. The clinical evolution was marked by progressive deterioration of renal function which required haemodialysis, and necrosis of several toes which were amputated. Coronary angiography was not done in the absence of recurrent chest pain. CES is poorly recognised after embolisation of cholesterol crystals from atherosclerotic plaques of major arteries into small distal arteries. It has been mainly described after angiographic procedures,’,5 vascular surgery, and treatment with vitamin K antagonists. Skin, skeletal muscle, kidneys, spleen, and intestine are the most frequently affected organs. Diagnosis is established by microscopic examination of affected tissue. Mortality is high (up to 81%). There have been only four reports of CES, in which it occurred 22 h, 36 h, 1 week, and 15 days after intravenous thrombolytic therapy for myocardial infarction.1-3 Coronary arteriography preceded CES in 2 of these patients.’ Streptokinase was implicated in 3 patients,1.2 and tissue plasminogen sctivator in 1.3 It is noteworthy that in 3 patients warfarin’ or heparin’-3 were given before CES occurred. As far as we are aware, this is the earliest occurrence of CES after intravenous thrombolytic therapy for myocardial infarction without previous catheterisation or anticoagulation treatment. Although cholesterol embolisation may be spontaneous, the temporal relation . between the embolic event in our patient and the onset of thrombolysis makes this improbable. The mechanism of CES is assumed to be through streptokinase lysing thrombi, including those covering atherosclerotic plaques, which might thus release cholesterol debris into the blood stream. Since thrombolytic therapy is routine in early acute myocardial infarction, this rare but potentially fatal complication should not be ignored in severely atherosclerotic patients. was
to
Department of Cardiology N3, Centre Hospitaller Leon Binet, 77160 Provins, France
Hôpital
Henri Mondor,
Creteil
G. POCHMALICKI L. FELDMAN P. MEUNIER C. ROUGEOT J. WESCHLER F. JAN
Theoretical growth of two metastatic tumours, starting from different sizes and with growth rates in inverse proportion to size. . =volume
doubling time 7 days, A =doubling time 40 days
in diameter. This is equivalent to 30 volume doublings single cell. At 40 volume doublings the terminal phase is near so that three-quarters of the life span of metastases is unseen. The figure illustrates how a rapidly growing tumour that has by very good treatment been reduced to one cell may appear to have fared worse than a slowly growing tumour with a large residuum consequent on poor treatment. Time to relapse or survival from an arbitrary date of entry into a trial is an inappropriate measure of treatment efficacy. Since the startingpoint is unknown in terms of quantity of tumour present and growth rate, how can an endpoint be measured? Most trials fail to reveal differences between treatments because large numbers conceal the range of tumour behaviour. If the numbers are increased by an overview,4 amalgamating many trials, then a significant result can be obtained. However, this answer applies to a mythical average patient and is of no benefit to the next individual. Patients prefer to be treated as individuals: that is where the Bristol Centre came in. metastases up to 1 cm
1 Schwartz MN, McDonald GB. Cholesterol embolization syndrome occurence after intravenous streptokinase therapy for myocardial infarction. JAMA 1987; 258: 1934-35. 2. Pirson Y, Honhon B, Cosyns JP, Van Ypersele C Cholesterol embolism in a renal graft after treatment with streptokinase. Br Med J 1988; 296: 394-95. 3 Shapiro LS. Cholesterol embolization after treatment with tissue plasminogen activator. N Engl J Med 1989; 321: 1270 4 Games PA, Cumberland DC, Kennedy A, Welsh CL, Moorhead P, Rutley MS. Cholesterol embolisation. a lethal complication of vascular catheterisation Lancet
1988, i. 168-70 5. Tomson CRV Cholesterol embolisation after angiography. Lancet
1988; i: 643-44.
Growth rates of breast tumours SIR,-Further correspondence on the Bristol Cancer Help Centre study (Nov 30, p 1401) highlights disagreement over the relation between menopausal status and growth rate in breast tumour. We and others1,2 have found that breast cancers tend to grow more quickly in younger, premenopausal women. Unfortunately, breast cancer studies often fail to define the most important prognostic factors influencing survival. These are: amount of metastatic disease present at the end of definitive treatment; site(s) of metastasis; and the rate of growth of individual tumours. These variables are not defmed in the TNM classification or in clinical staging but they must be allowed for in any controlled
study. Growth rate can be estimated from histopathological features (unpublished data from this centre), and work on tumour cell properties important in metastasis3 may lead to a clearer definition of those tumours most likely to metastasise. There is at present no satisfactory diagnostic technique for identifying breast cancer
from
a
Breast Study Centre, Mount Vernion Hospital, Northwood HA6 2RN, UK
1. Kusama
ANN E.
JOHNSON
S, Spratt JS Jr, Donegan WL, Watson FR, Cunningham C The gross rates of growth of human mammary cancer. Cancer 1972; 30: 594-99. 2. Cheung CWD, Johnson AE. Carcinoma of the breast: measurement and the management of treatment II. the regression of tumours. Br J Radiol 1991; 64: 121-32 3. Nicolson GL. Cancer metastasis, tumor cell and host organ properties important m metastasis to specific secondary sites. Biochim Biophys Acta 1988; 948: 175-224. 4. Early Breast Cancer Trialists’ Collaborative Group Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. N Engl J Med 1988; 319: 1681-92
normal after a few days and mesenteric ischaemia was thought be merely a possibility. The presence of birefringent cholesterol crystals within the vascular lumen of a distal subdermal vessel on skin biopsy confirmed the diagnosis of CES. The clinical evolution was marked by progressive deterioration of renal function which required haemodialysis, and necrosis of several toes which were amputated. Coronary angiography was not done in the absence of recurrent chest pain. CES is poorly recognised after embolisation of cholesterol crystals from atherosclerotic plaques of major arteries into small distal arteries. It has been mainly described after angiographic procedures,’,5 vascular surgery, and treatment with vitamin K antagonists. Skin, skeletal muscle, kidneys, spleen, and intestine are the most frequently affected organs. Diagnosis is established by microscopic examination of affected tissue. Mortality is high (up to 81%). There have been only four reports of CES, in which it occurred 22 h, 36 h, 1 week, and 15 days after intravenous thrombolytic therapy for myocardial infarction.1-3 Coronary arteriography preceded CES in 2 of these patients.’ Streptokinase was implicated in 3 patients,1.2 and tissue plasminogen sctivator in 1.3 It is noteworthy that in 3 patients warfarin’ or heparin’-3 were given before CES occurred. As far as we are aware, this is the earliest occurrence of CES after intravenous thrombolytic therapy for myocardial infarction without previous catheterisation or anticoagulation treatment. Although cholesterol embolisation may be spontaneous, the temporal relation . between the embolic event in our patient and the onset of thrombolysis makes this improbable. The mechanism of CES is assumed to be through streptokinase lysing thrombi, including those covering atherosclerotic plaques, which might thus release cholesterol debris into the blood stream. Since thrombolytic therapy is routine in early acute myocardial infarction, this rare but potentially fatal complication should not be ignored in severely atherosclerotic patients. was
to
Department of Cardiology N3, Centre Hospitaller Leon Binet, 77160 Provins, France
Hôpital
Henri Mondor,
Creteil
G. POCHMALICKI L. FELDMAN P. MEUNIER C. ROUGEOT J. WESCHLER F. JAN
Theoretical growth of two metastatic tumours, starting from different sizes and with growth rates in inverse proportion to size. . =volume
doubling time 7 days, A =doubling time 40 days
in diameter. This is equivalent to 30 volume doublings single cell. At 40 volume doublings the terminal phase is near so that three-quarters of the life span of metastases is unseen. The figure illustrates how a rapidly growing tumour that has by very good treatment been reduced to one cell may appear to have fared worse than a slowly growing tumour with a large residuum consequent on poor treatment. Time to relapse or survival from an arbitrary date of entry into a trial is an inappropriate measure of treatment efficacy. Since the startingpoint is unknown in terms of quantity of tumour present and growth rate, how can an endpoint be measured? Most trials fail to reveal differences between treatments because large numbers conceal the range of tumour behaviour. If the numbers are increased by an overview,4 amalgamating many trials, then a significant result can be obtained. However, this answer applies to a mythical average patient and is of no benefit to the next individual. Patients prefer to be treated as individuals: that is where the Bristol Centre came in. metastases up to 1 cm
1 Schwartz MN, McDonald GB. Cholesterol embolization syndrome occurence after intravenous streptokinase therapy for myocardial infarction. JAMA 1987; 258: 1934-35. 2. Pirson Y, Honhon B, Cosyns JP, Van Ypersele C Cholesterol embolism in a renal graft after treatment with streptokinase. Br Med J 1988; 296: 394-95. 3 Shapiro LS. Cholesterol embolization after treatment with tissue plasminogen activator. N Engl J Med 1989; 321: 1270 4 Games PA, Cumberland DC, Kennedy A, Welsh CL, Moorhead P, Rutley MS. Cholesterol embolisation. a lethal complication of vascular catheterisation Lancet
1988, i. 168-70 5. Tomson CRV Cholesterol embolisation after angiography. Lancet
1988; i: 643-44.
Growth rates of breast tumours SIR,-Further correspondence on the Bristol Cancer Help Centre study (Nov 30, p 1401) highlights disagreement over the relation between menopausal status and growth rate in breast tumour. We and others1,2 have found that breast cancers tend to grow more quickly in younger, premenopausal women. Unfortunately, breast cancer studies often fail to define the most important prognostic factors influencing survival. These are: amount of metastatic disease present at the end of definitive treatment; site(s) of metastasis; and the rate of growth of individual tumours. These variables are not defmed in the TNM classification or in clinical staging but they must be allowed for in any controlled
study. Growth rate can be estimated from histopathological features (unpublished data from this centre), and work on tumour cell properties important in metastasis3 may lead to a clearer definition of those tumours most likely to metastasise. There is at present no satisfactory diagnostic technique for identifying breast cancer
from
a
Breast Study Centre, Mount Vernion Hospital, Northwood HA6 2RN, UK
1. Kusama
ANN E.
JOHNSON
S, Spratt JS Jr, Donegan WL, Watson FR, Cunningham C The gross rates of growth of human mammary cancer. Cancer 1972; 30: 594-99. 2. Cheung CWD, Johnson AE. Carcinoma of the breast: measurement and the management of treatment II. the regression of tumours. Br J Radiol 1991; 64: 121-32 3. Nicolson GL. Cancer metastasis, tumor cell and host organ properties important m metastasis to specific secondary sites. Biochim Biophys Acta 1988; 948: 175-224. 4. Early Breast Cancer Trialists’ Collaborative Group Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. N Engl J Med 1988; 319: 1681-92
