114
You suggest that the protocol of the trial of screening in women 40-41 in Britain may need modification in the light of the Canadian results. The only lesson to be learnt is the overriding importance of continual quality control.
aged
MRC Biostatistics Unit, UK
Cambridge CB2 2BW,
NICHOLAS E. DAY STEPHEN W. DUFFY
1. Baines
CJ, Miller AB, Kopans DB, et al. Canadian breast screening study: assessment of technical quality by external review. Am J Roentgenol 1990; 155: 743-47. 2. Miller AB, Baines CJ, To T, Wall C. The Canadian National Breast Screening Study. In: Miller AB, Chamberlain J, Day NE, Hakama M, Prorok PC, eds. Cancer screening. Cambridge: Cambridge University Press (in press). 3. Day NE. Screening for breast cancer. Br Med Bull 1991; 47: 400-15.
Tamoxifen to prevent breast cancer S!R,—The participation of premenopausal women in a trial of tamoxifen for the prevention of breast cancer is questioned by Dr Spicer and colleagues (June 8, p 1414) because of the risk of induction of ovarian cancer. Although we agree that caution is needed in asking well women to take part in such a study, especially those in the younger age group, there does not seem to be any clinical evidence to suggest that the postulated biological actions on the ovary cause serious difficulties. Worldwide, over 8500 premenopausal women (in fact those aged under 50) have been randomised to trials of adjuvant tamoxifen after treatment for primary breast cancer and of these about one-third did not receive any adjuvant chemotherapy. At the overview analysis by the Early Breast Cancer Trialist Collaborative group at its meeting in Oxford in September, 1990, there was no evidence of an increased risk of non-breast cancers for the tamoxifen-treated group, although this was not looked at in great detail. In the CRC Adjuvant Breast Trial, which randomised 676 premenopausal women between tamoxifen (353) and control (323), no excess ovarian cancers have been reported. Half the patients received postoperative cyclophosphamide 5 mg/kg daily for six days and tamoxifen was scheduled for two years at 20 mg daily. With a median follow-up of almost eight years only three ovarian tumours have been reported and all these are in the non-tamoxifen treated patients. To ensure that we are not missing information on these events a detailed questionnaire on medical conditions developing subsequent to the breast cancer is being completed by clinicians on all patients who are alive and breast-cancer free at the current time. This should enable us to determine whether any increased risk is evident in this group of patients. CRC Clinical Trials Centre, King’s College School of Medicine and Dentistry,
that conventional treatments are not suitable for or are less useful in older patients. In general fitness-especially mental, psychological,
and physiological-elderly patients are better than in former decades in Europe, so that more elderly patients with cancer will now be suitable for optimum cancer therapy. As part of the evaluation of cancer treatments in older patients, quality-of-life measures should be routine. Early diagnosis is just as important in the old as in younger groups, especially for cancers of the breast and colon. Elderly people are seldom the target of campaigns and tend to be excluded from screening projects but the biology of tumours in the elderly is no different, and certainly no less aggressive, than that in younger
patients. There are few data on chemotherapy and radiotherapy in elderly patients, and this area of clinical research should be improved. Surgery should always be considered as first-line therapy for solid tumours in elderly patients as in younger ones. In some diseases such as non-Hodgkin lymphoma and acute leukaemia, specific regimens have been developed, not with the intention of undertreating elderly patients but to provide adequate and acceptable therapy for patients for whom aggressive chemotherapy is likely to be unsafe. A major focus of research should be the establishment of a scale of
frailty so that treatments can be selected for different stages. The three major issues raised in this consensus were: (1) Chronological age should not be used to exclude patients from early diagnosis programmes, screening projects, or trials of treatment
Centro di Riferimento
Rayne Institute,
JOAN HOUGHTON
London SE5 9NU, UK
DIANA RILEY
Oncologico,
(PN), Italy
U. TIRELLI
Hôpital Cantonal Universitaire, Geneva
M. AAPRO
33081 Aviano
Kantonsspital, Basel
R. OBRIST
Katholieke Universiteit, Nijmegen
J. FESTEN
Centre Antoine Laccassagne, Nice
M. SCHEIDER
Guy’s Hospital,
I. FENTIMAN
London
Centro di Riferimento
1. Fentiman
MICHAEL BAUM
for cancer.
(2) All treatment modalities should be offered to elderly patients. (3) Great effort should be made to establish quality-of-life measures in elderly patients.
S. MONFARDINI
Oncologico, Aviano
I, Tirelli U, Monfardini S, elderly? Lancet 1990; 335: 1020-22.
et
al.
Why
Adverse reactions with Cancer treatment and old
people
SiR,—In April, 1990, we discussed in The Lancet problems related to the management of cancer in the elderly/ and announced a joint EORTC/National Cancer Institute meeting. This was held last October at San Servolo Island, Venice. A European Community Working Party on Neoplasia in the Elderly was appointed on Oct 16. This was sponsored by Directorate General XII of the EC as part of the programme Europe against Cancer. What follows is that working-party’s consensus on a strategy for cancer treatment in the elderly. Epidemiological data point to a significant increase in cancer patients over the age of 70 years in Europe in the 1990s. Better diagnostic techniques and treatments for elderly patients are needed urgently because cancer-related survival of these patients is lower than it is in younger patients with malignant disease. In the management of elderly patients there should be no discrimination based on age alone. Education programmes should be addressed to general practitioners and specialists to convince them that surgery, radiotherapy, and chemotherapy should be considered when necessary in all cancer patients irrespective of age. In EC countries the referral rate of elderly patients to cancer centres tends to be lower than that for younger patients because most physicians feel
is
cancer so
badly treated in the
anistreplase
SIR,-Anisoylated human plasminogen streptokinase activator complex (APSAC, anistreplase) reduces mortality in patients with acute myocardial infarction. However, the value of this thrombolytic agent as a treatment for acute massive pulmonary embolism (AMPE) is not yet fully established.2 We have recently taken part in a European open pilot study on the effects of 30 U anistreplase given intravenously as a 5 min infusion in patients with AMPE. The trial was stopped after 9 patients were treated because 3 had episodes of severe hypotension. No patient had pre-existing cardiopulmonary disease, and none had previously received a thrombolytic drug or had any contraindication to such therapy. Case 1-A 35-year-old woman was admitted with AMPE. Mean pulmonary artery pressure (PAP) was 43 mm Hg, cardiac index (CI) 3111 solidus min per m2, and total pulmonary vascular resistance (TPVR) 14 IU/mZ. 4 min after anistreplase infusion, she complained of malaise and sweating. Tachycardia was followed by bradycardia (heart rate 40/min) and a seizure. She was successfully resuscitated and 19 h after thrombolysis mean PAP and TPVR were 15 mm Hg and 4 IU/m2, respectively. Case 2-A 69-year-old-woman presented with AMPE. She had moderate increases in mean PAP (19 mm Hg) and TPVR (8 IU 1m2). 5 min after the end of anistreplase infusion, she felt faint, and her blood pressure fell from 127/80 to 83/53 mm Hg, but
115
spontaneously rose 2 min later to 148/93 mm Hg. Her subsequent course was
uneventful, and at
18 h
mean
PAP and TPVR were 12
Hg and 4-8 IU 1m2, respectively. Case 3-A 51-year-old man with AMPE (mean PAP 14 mm Hg, TPVR 4 ID/m2) had an episode of hypotension (systolic arterial pressure fell from 120 to 60 mm Hg) with bronchospasm tachypnoea, and cyanosis. PAP had increased to 24 mm Hg. Treatment with intravenous aminophylline, dexamethasone, and nasal oxygen led to recovery after 30 min. 19 h later mean PAP and TPVR were 14 mm Hg and 2-1IU/m2, respectively. 2 further patients experienced slight and brief clinical deterioration immediately after anistreplase infusion, with acute but transient increases in PAP. Subsequently, a 60-year-old man with AMPE was given a lower dose of anistreplase (10 U intravenous infusion over 5 min), which has been reported safe and effective in cases of pulmonary embolism.2 Close monitoring ofhaemodynamic status showed an acute, transient rise in PAP (20 to 28 mm Hg) after 2 min, with a fall in CI (3-5 to 2-91/min per m2). After 10 min, PAP and CI had nearly returned to pretreatment values. Early moderate and transient systemic hypotension has been reported after fibrinolysis with both streptokinase and anistreplase in patients with acute myocardial infarction.3 Our observations of an acute but transient rise in PAP, which leads to a sudden increase in right ventricular afterload, point to a potential life-threatening complication in patients with AMPE. The course of this reaction is unclear. Early recurrence of pulmonary embolism seems unlikely because of the angiographic improvement shortly after therapy. Acute release of a vasoactive mediator, such as bradykinin, may be involved. Acute release of bradykinin has been shown with streptokinase4 but not with anistreplase.5 In our opinion, the rate of haemodynamic adverse events observed in our patients is too high, and precludes a 30 U 5 min intravenous infusion of anistreplase in AMPE. mm
F. BRENOT G. PACOURET G. MEYER H. SORS B. CHARBONNIER G. SIMONNEAU
Department of Respiratory Medicine, Hôpital Antoine Béclère, 92141 Clamart, France;
Department of Cardiology, Hôpital Trousseau, Tours, and Department of Respiratory Medicine, Hôpital Laennec, Paris
PH, Koon KT, Salim Y. Effects of tissue-type plasminogen activator and anisoylated plasminogen streptokinase activator complex on mortality in acute myocardial infarction. Circulation 1990; 82: 1668-74. 2. Vander Sande J, Bossaert L, Brochier M, et al. Thrombolytic treatment of pulmonary embolism with APSAC. Eur Respir J 1988; 1: 721-25 3. Hogg KJ, Gemmill JD, Burns JMA, et al. Angiographic patency study of anistreplase versus streptokinase in acute myocardial infarction. Lancet 1990; 335: 254-58. 4. Migne J, Verdrine Y, Conard J, et al. Activation comparée des kinines par la 1. Held
Steptokinase
et
al l’Urokinase "m vitro"
et
au
cours
des
traitements
thrombolytiques. Path Biol 1977; 254 (suppl): 42-47. 5. Green J, Dupe RJ, Smith GS, et al. Comparison of the hypotensive effects of streptokinase—human plasmin activator complex and BRL 26921 (p-anisoylated streptokinase-plasminogen activator complex) in the dog after high dose, bolus administration. Thromb Res 1984; 36: 26-36.
Hyperreactive malarious splenomegaly SIR,-Dr Bates and her colleagues (March 2, p 505) report on Ig gene rearrangements in hyperreactive malarious splenomegaly (HMS). There is a tendency to diagnose HMS on inadequate grounds. The original definition of tropical splenomegaly syndrome/ the establishment of diagnostic criteria2 or the attempt to eliminate confusion by renaming the condition HMS3 has not prevented overdiagnosis. HMS is an abberrant response to malaria in which the dominant abnormality is overproduction of IgM.’ Two essential diagnostic features are a serum IgM level at least 2 SD above the local mean and a decrease in spleen size after prolonged antimalarial prophylaxis.s Both are at issue in the study
by Bates et al. Serum IgM
was
measured in
only
a
"small number" of
individuals. How many, and how were they selected; what was the
sample size and selection method for the local mean; and were IgM levels for the two patients cited more than 2 SD above that mean? Did proguanil reduce total serum IgM, especially malaria-specific immunoglobulin? Patients were classified into three groups
according to response to proguanil, but for how long was the malarial chemotherapy continued; and if 3 months is too short what is acceptable? On the basis of response to antimalarials, the splenomegaly in group 1 patients was due to malaria but the diagnosis of HMS has not been established. The initial, yet unsustained, splenic response to proguanil in those patients from group 2 without gene rearrangements may have been due to the emergence of proguanilresistant parasites,6 possibly as a result of individual variation in the ability to convert proguanil to the active metabolite cycloguanil (N. A. Helsby, personal communication). Other explanations are "slow response" HMS or a non-malarious splenomegaly. Department of Haematology, London Hospital Medical College, London E1 2AD, UK
CHRISTINE A. FACER
Division of Haematology, Concord Repatriation General Hospital, Concord, NSW, Australia
G. G. CRANE
1.
Trans R Soc Trop Med Hyg 1968; 62: 717-28. 2. Greenwood BM, Fakunle YM. The tropical splenomegaly syndrome: a review of its pathogenesis. In: The role of the spleen m the immunology of parasitic diseases. Basel: Schwabe, 1979: 229-43. 3. Bryceson A, Fakunle YM, Fleming AF, et al. Malaria and splenomegaly. Trans R Soc Trop Med Hyg 1983; 77: 879. 4. Crane GG. Hyperreactive malarious splenomegaly. Parasitol Today 1986; 2: 4-9. 5. Fakunle YM. Tropical splenomegaly I: tropical Africa. Clin Haematol 1981; 10: 963-75. 6 Wilson T, Edeson JFB. Cross resistance between daraprim and proguanil. Br Med J
Pitney WR. The tropical splenomegaly syndrome.
1953; 1: 731.
*** This letter has been shown - red. L.
to
Dr
Bates, whose reply follows.
SIR,-We agree that IgM concentrations in HMS may be more than 2 SD above the local, normal mean but African HMS patients can have normal IgM values. DeCock et all looked specifically at the IgM criterion by comparing two groups of Kenyan patients with HMS. They found no clinical difference between those with IgM concentrations 2 SD above the normal mean and the rest and concluded that it was "unreasonable" to consider this degree of IgM increase as essential for the diagnosis. Studies from Malawi and Uganda23have also found that HMS is underdiagnosed if the 2 SD IgM criterion is a prerequisite. The main aim of our study was to differentiate between HMS and lymphoma, and for this purpose stringent analysis of response to proguanil is a more biologically relevant discriminator than IgM values which may be normal or high in both HMS and lymphoma .4 ’ For these reasons, and because IgM levels were not locally available, we did not use a very high IgM value as a criterion for the diagnosis of HMS nor did we use a fall in IgM as an indicator of therapeutic response. Our local mean IgM (1 -9 g/1), measured in 22 healthy controls, was comparable to that from Nigeria (1 -89 g/1)6 which is close to Ghana. IgM concentrations, measured in 7/13 patients from group 1, 3/6 group 2 patients, and 2/3 group 3 patients, were (g/1):1-6-8-9 (mean 3-9), 2-8,3-0, and 7-0, and 2-5 and 9-2, respectively.
Proguanil therapy in HMS begins to produce splenic shrinkage by 3 months and the effect is greatest by 10-12 months. In some patients the spleen may never become impalpable. Ideally therapy should be continued for life (the disorder recurs if treatment is stopped) but long-term follow-up in the tropics is difficult. We therefore judged that a sustained splenic reduction of 40% on treatment constituted a good response and reductions of less than this were taken as moderate (15-30%) or no response. Group 1 patients had good responses to proguanil and had no other observable cause for their splenomegaly. We therefore confidently diagnosed HMS. The study defines an interesting group of patients who have transient responses to proguanil. Some of them have circulating monoclonal lymphocytes, which is direct evidence for a malignant process. Although the lack of response in patients with polyclonal lymphocytes may have been due to proguanil-resistant malaria we found no evidence for acute malaria in the blood films of any of the pateints, and a lack of demonstrable malaria parasites is characteristic of HMS.7 Our preferred
You suggest that the protocol of the trial of screening in women 40-41 in Britain may need modification in the light of the Canadian results. The only lesson to be learnt is the overriding importance of continual quality control.
aged
MRC Biostatistics Unit, UK
Cambridge CB2 2BW,
NICHOLAS E. DAY STEPHEN W. DUFFY
1. Baines
CJ, Miller AB, Kopans DB, et al. Canadian breast screening study: assessment of technical quality by external review. Am J Roentgenol 1990; 155: 743-47. 2. Miller AB, Baines CJ, To T, Wall C. The Canadian National Breast Screening Study. In: Miller AB, Chamberlain J, Day NE, Hakama M, Prorok PC, eds. Cancer screening. Cambridge: Cambridge University Press (in press). 3. Day NE. Screening for breast cancer. Br Med Bull 1991; 47: 400-15.
Tamoxifen to prevent breast cancer S!R,—The participation of premenopausal women in a trial of tamoxifen for the prevention of breast cancer is questioned by Dr Spicer and colleagues (June 8, p 1414) because of the risk of induction of ovarian cancer. Although we agree that caution is needed in asking well women to take part in such a study, especially those in the younger age group, there does not seem to be any clinical evidence to suggest that the postulated biological actions on the ovary cause serious difficulties. Worldwide, over 8500 premenopausal women (in fact those aged under 50) have been randomised to trials of adjuvant tamoxifen after treatment for primary breast cancer and of these about one-third did not receive any adjuvant chemotherapy. At the overview analysis by the Early Breast Cancer Trialist Collaborative group at its meeting in Oxford in September, 1990, there was no evidence of an increased risk of non-breast cancers for the tamoxifen-treated group, although this was not looked at in great detail. In the CRC Adjuvant Breast Trial, which randomised 676 premenopausal women between tamoxifen (353) and control (323), no excess ovarian cancers have been reported. Half the patients received postoperative cyclophosphamide 5 mg/kg daily for six days and tamoxifen was scheduled for two years at 20 mg daily. With a median follow-up of almost eight years only three ovarian tumours have been reported and all these are in the non-tamoxifen treated patients. To ensure that we are not missing information on these events a detailed questionnaire on medical conditions developing subsequent to the breast cancer is being completed by clinicians on all patients who are alive and breast-cancer free at the current time. This should enable us to determine whether any increased risk is evident in this group of patients. CRC Clinical Trials Centre, King’s College School of Medicine and Dentistry,
that conventional treatments are not suitable for or are less useful in older patients. In general fitness-especially mental, psychological,
and physiological-elderly patients are better than in former decades in Europe, so that more elderly patients with cancer will now be suitable for optimum cancer therapy. As part of the evaluation of cancer treatments in older patients, quality-of-life measures should be routine. Early diagnosis is just as important in the old as in younger groups, especially for cancers of the breast and colon. Elderly people are seldom the target of campaigns and tend to be excluded from screening projects but the biology of tumours in the elderly is no different, and certainly no less aggressive, than that in younger
patients. There are few data on chemotherapy and radiotherapy in elderly patients, and this area of clinical research should be improved. Surgery should always be considered as first-line therapy for solid tumours in elderly patients as in younger ones. In some diseases such as non-Hodgkin lymphoma and acute leukaemia, specific regimens have been developed, not with the intention of undertreating elderly patients but to provide adequate and acceptable therapy for patients for whom aggressive chemotherapy is likely to be unsafe. A major focus of research should be the establishment of a scale of
frailty so that treatments can be selected for different stages. The three major issues raised in this consensus were: (1) Chronological age should not be used to exclude patients from early diagnosis programmes, screening projects, or trials of treatment
Centro di Riferimento
Rayne Institute,
JOAN HOUGHTON
London SE5 9NU, UK
DIANA RILEY
Oncologico,
(PN), Italy
U. TIRELLI
Hôpital Cantonal Universitaire, Geneva
M. AAPRO
33081 Aviano
Kantonsspital, Basel
R. OBRIST
Katholieke Universiteit, Nijmegen
J. FESTEN
Centre Antoine Laccassagne, Nice
M. SCHEIDER
Guy’s Hospital,
I. FENTIMAN
London
Centro di Riferimento
1. Fentiman
MICHAEL BAUM
for cancer.
(2) All treatment modalities should be offered to elderly patients. (3) Great effort should be made to establish quality-of-life measures in elderly patients.
S. MONFARDINI
Oncologico, Aviano
I, Tirelli U, Monfardini S, elderly? Lancet 1990; 335: 1020-22.
et
al.
Why
Adverse reactions with Cancer treatment and old
people
SiR,—In April, 1990, we discussed in The Lancet problems related to the management of cancer in the elderly/ and announced a joint EORTC/National Cancer Institute meeting. This was held last October at San Servolo Island, Venice. A European Community Working Party on Neoplasia in the Elderly was appointed on Oct 16. This was sponsored by Directorate General XII of the EC as part of the programme Europe against Cancer. What follows is that working-party’s consensus on a strategy for cancer treatment in the elderly. Epidemiological data point to a significant increase in cancer patients over the age of 70 years in Europe in the 1990s. Better diagnostic techniques and treatments for elderly patients are needed urgently because cancer-related survival of these patients is lower than it is in younger patients with malignant disease. In the management of elderly patients there should be no discrimination based on age alone. Education programmes should be addressed to general practitioners and specialists to convince them that surgery, radiotherapy, and chemotherapy should be considered when necessary in all cancer patients irrespective of age. In EC countries the referral rate of elderly patients to cancer centres tends to be lower than that for younger patients because most physicians feel
is
cancer so
badly treated in the
anistreplase
SIR,-Anisoylated human plasminogen streptokinase activator complex (APSAC, anistreplase) reduces mortality in patients with acute myocardial infarction. However, the value of this thrombolytic agent as a treatment for acute massive pulmonary embolism (AMPE) is not yet fully established.2 We have recently taken part in a European open pilot study on the effects of 30 U anistreplase given intravenously as a 5 min infusion in patients with AMPE. The trial was stopped after 9 patients were treated because 3 had episodes of severe hypotension. No patient had pre-existing cardiopulmonary disease, and none had previously received a thrombolytic drug or had any contraindication to such therapy. Case 1-A 35-year-old woman was admitted with AMPE. Mean pulmonary artery pressure (PAP) was 43 mm Hg, cardiac index (CI) 3111 solidus min per m2, and total pulmonary vascular resistance (TPVR) 14 IU/mZ. 4 min after anistreplase infusion, she complained of malaise and sweating. Tachycardia was followed by bradycardia (heart rate 40/min) and a seizure. She was successfully resuscitated and 19 h after thrombolysis mean PAP and TPVR were 15 mm Hg and 4 IU/m2, respectively. Case 2-A 69-year-old-woman presented with AMPE. She had moderate increases in mean PAP (19 mm Hg) and TPVR (8 IU 1m2). 5 min after the end of anistreplase infusion, she felt faint, and her blood pressure fell from 127/80 to 83/53 mm Hg, but
115
spontaneously rose 2 min later to 148/93 mm Hg. Her subsequent course was
uneventful, and at
18 h
mean
PAP and TPVR were 12
Hg and 4-8 IU 1m2, respectively. Case 3-A 51-year-old man with AMPE (mean PAP 14 mm Hg, TPVR 4 ID/m2) had an episode of hypotension (systolic arterial pressure fell from 120 to 60 mm Hg) with bronchospasm tachypnoea, and cyanosis. PAP had increased to 24 mm Hg. Treatment with intravenous aminophylline, dexamethasone, and nasal oxygen led to recovery after 30 min. 19 h later mean PAP and TPVR were 14 mm Hg and 2-1IU/m2, respectively. 2 further patients experienced slight and brief clinical deterioration immediately after anistreplase infusion, with acute but transient increases in PAP. Subsequently, a 60-year-old man with AMPE was given a lower dose of anistreplase (10 U intravenous infusion over 5 min), which has been reported safe and effective in cases of pulmonary embolism.2 Close monitoring ofhaemodynamic status showed an acute, transient rise in PAP (20 to 28 mm Hg) after 2 min, with a fall in CI (3-5 to 2-91/min per m2). After 10 min, PAP and CI had nearly returned to pretreatment values. Early moderate and transient systemic hypotension has been reported after fibrinolysis with both streptokinase and anistreplase in patients with acute myocardial infarction.3 Our observations of an acute but transient rise in PAP, which leads to a sudden increase in right ventricular afterload, point to a potential life-threatening complication in patients with AMPE. The course of this reaction is unclear. Early recurrence of pulmonary embolism seems unlikely because of the angiographic improvement shortly after therapy. Acute release of a vasoactive mediator, such as bradykinin, may be involved. Acute release of bradykinin has been shown with streptokinase4 but not with anistreplase.5 In our opinion, the rate of haemodynamic adverse events observed in our patients is too high, and precludes a 30 U 5 min intravenous infusion of anistreplase in AMPE. mm
F. BRENOT G. PACOURET G. MEYER H. SORS B. CHARBONNIER G. SIMONNEAU
Department of Respiratory Medicine, Hôpital Antoine Béclère, 92141 Clamart, France;
Department of Cardiology, Hôpital Trousseau, Tours, and Department of Respiratory Medicine, Hôpital Laennec, Paris
PH, Koon KT, Salim Y. Effects of tissue-type plasminogen activator and anisoylated plasminogen streptokinase activator complex on mortality in acute myocardial infarction. Circulation 1990; 82: 1668-74. 2. Vander Sande J, Bossaert L, Brochier M, et al. Thrombolytic treatment of pulmonary embolism with APSAC. Eur Respir J 1988; 1: 721-25 3. Hogg KJ, Gemmill JD, Burns JMA, et al. Angiographic patency study of anistreplase versus streptokinase in acute myocardial infarction. Lancet 1990; 335: 254-58. 4. Migne J, Verdrine Y, Conard J, et al. Activation comparée des kinines par la 1. Held
Steptokinase
et
al l’Urokinase "m vitro"
et
au
cours
des
traitements
thrombolytiques. Path Biol 1977; 254 (suppl): 42-47. 5. Green J, Dupe RJ, Smith GS, et al. Comparison of the hypotensive effects of streptokinase—human plasmin activator complex and BRL 26921 (p-anisoylated streptokinase-plasminogen activator complex) in the dog after high dose, bolus administration. Thromb Res 1984; 36: 26-36.
Hyperreactive malarious splenomegaly SIR,-Dr Bates and her colleagues (March 2, p 505) report on Ig gene rearrangements in hyperreactive malarious splenomegaly (HMS). There is a tendency to diagnose HMS on inadequate grounds. The original definition of tropical splenomegaly syndrome/ the establishment of diagnostic criteria2 or the attempt to eliminate confusion by renaming the condition HMS3 has not prevented overdiagnosis. HMS is an abberrant response to malaria in which the dominant abnormality is overproduction of IgM.’ Two essential diagnostic features are a serum IgM level at least 2 SD above the local mean and a decrease in spleen size after prolonged antimalarial prophylaxis.s Both are at issue in the study
by Bates et al. Serum IgM
was
measured in
only
a
"small number" of
individuals. How many, and how were they selected; what was the
sample size and selection method for the local mean; and were IgM levels for the two patients cited more than 2 SD above that mean? Did proguanil reduce total serum IgM, especially malaria-specific immunoglobulin? Patients were classified into three groups
according to response to proguanil, but for how long was the malarial chemotherapy continued; and if 3 months is too short what is acceptable? On the basis of response to antimalarials, the splenomegaly in group 1 patients was due to malaria but the diagnosis of HMS has not been established. The initial, yet unsustained, splenic response to proguanil in those patients from group 2 without gene rearrangements may have been due to the emergence of proguanilresistant parasites,6 possibly as a result of individual variation in the ability to convert proguanil to the active metabolite cycloguanil (N. A. Helsby, personal communication). Other explanations are "slow response" HMS or a non-malarious splenomegaly. Department of Haematology, London Hospital Medical College, London E1 2AD, UK
CHRISTINE A. FACER
Division of Haematology, Concord Repatriation General Hospital, Concord, NSW, Australia
G. G. CRANE
1.
Trans R Soc Trop Med Hyg 1968; 62: 717-28. 2. Greenwood BM, Fakunle YM. The tropical splenomegaly syndrome: a review of its pathogenesis. In: The role of the spleen m the immunology of parasitic diseases. Basel: Schwabe, 1979: 229-43. 3. Bryceson A, Fakunle YM, Fleming AF, et al. Malaria and splenomegaly. Trans R Soc Trop Med Hyg 1983; 77: 879. 4. Crane GG. Hyperreactive malarious splenomegaly. Parasitol Today 1986; 2: 4-9. 5. Fakunle YM. Tropical splenomegaly I: tropical Africa. Clin Haematol 1981; 10: 963-75. 6 Wilson T, Edeson JFB. Cross resistance between daraprim and proguanil. Br Med J
Pitney WR. The tropical splenomegaly syndrome.
1953; 1: 731.
*** This letter has been shown - red. L.
to
Dr
Bates, whose reply follows.
SIR,-We agree that IgM concentrations in HMS may be more than 2 SD above the local, normal mean but African HMS patients can have normal IgM values. DeCock et all looked specifically at the IgM criterion by comparing two groups of Kenyan patients with HMS. They found no clinical difference between those with IgM concentrations 2 SD above the normal mean and the rest and concluded that it was "unreasonable" to consider this degree of IgM increase as essential for the diagnosis. Studies from Malawi and Uganda23have also found that HMS is underdiagnosed if the 2 SD IgM criterion is a prerequisite. The main aim of our study was to differentiate between HMS and lymphoma, and for this purpose stringent analysis of response to proguanil is a more biologically relevant discriminator than IgM values which may be normal or high in both HMS and lymphoma .4 ’ For these reasons, and because IgM levels were not locally available, we did not use a very high IgM value as a criterion for the diagnosis of HMS nor did we use a fall in IgM as an indicator of therapeutic response. Our local mean IgM (1 -9 g/1), measured in 22 healthy controls, was comparable to that from Nigeria (1 -89 g/1)6 which is close to Ghana. IgM concentrations, measured in 7/13 patients from group 1, 3/6 group 2 patients, and 2/3 group 3 patients, were (g/1):1-6-8-9 (mean 3-9), 2-8,3-0, and 7-0, and 2-5 and 9-2, respectively.
Proguanil therapy in HMS begins to produce splenic shrinkage by 3 months and the effect is greatest by 10-12 months. In some patients the spleen may never become impalpable. Ideally therapy should be continued for life (the disorder recurs if treatment is stopped) but long-term follow-up in the tropics is difficult. We therefore judged that a sustained splenic reduction of 40% on treatment constituted a good response and reductions of less than this were taken as moderate (15-30%) or no response. Group 1 patients had good responses to proguanil and had no other observable cause for their splenomegaly. We therefore confidently diagnosed HMS. The study defines an interesting group of patients who have transient responses to proguanil. Some of them have circulating monoclonal lymphocytes, which is direct evidence for a malignant process. Although the lack of response in patients with polyclonal lymphocytes may have been due to proguanil-resistant malaria we found no evidence for acute malaria in the blood films of any of the pateints, and a lack of demonstrable malaria parasites is characteristic of HMS.7 Our preferred
