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SECULAR TRENDS IN LEUKÆMIA MORTALITY
720 TABLE I-AVERAGE ANNUAL AGE-SPECIFIC LEUKAEMIA DEATH-RATES PER
MILLION
AMONG
WHITE
CHILDREN, AGES 0-19 YEARS,
OHIO, 1953-72
Mitotic indices of granulopoietic precursor cells in bone-marrow of 9 Ph-positive and 3 Ph’-negative patients at diagnosis of C.M.L.
TABLE II-AVERAGE ANNUAL LEUKMIA DEATH-RATES PER MILLION IN WHITE CHILDREN BY CELL TYPE, SEX, AND AGE, OHIO, 1968-72
I
_
I
_
I
-
-
.
I
-
years) with white counts of 28,000-350,000 had the PhI in 100% of their bone-marrow cells. 3 male patients aged 74-78 years with white counts of 29,000-350,000 Detailed karyotype data are reported were PhI-negative. elsewhere.1O A mitotic index of the granulopoietic precursor cells (myeloblasts -I-promyelocytes +myelocytes) was determined through examination of an average 4500 such cells in bone-marrow smears stained with May-GrunwaldGiemsa. In the Phl-negative group the mitotic indices proved to be lower than in the Ph-positive patients (P=0-01 Mann-Whitney U test) (see accompanying figure). Since the time of survival in Phl-negative C.M.L. is known to be shorter than in Phl-positive cases,6-8 the results support the view5 that an accumulation of precursor cells with a low mitotic activity has a serious prognostic implication in C.M.L. The mechanisms bringing about a more aggressive clinical course in patients with a low mitotic activity of the precursors remain to be clarified. L. BRANDT Department of Internal Medicine, F. MITELMAN University Hospital, P. G. NILSSON S-221 85 Lund, U. SJÖGREN. Sweden.
SECULAR TRENDS IN LEUKÆMIA MORTALITY
SIR,-In 1967 Fraumeni and Miller reported a decline in leukaemia mortality-rates among the U.S. White population.l The largest reduction was in children under 5 years. Possible explanations for the decline have included a decrease in incidence related perhaps to a more conservative use of medical X-rays 11 or a reduction in exposure to unknown environmental leukaemogens, or an increase in survival time consequent to improvements in leukaemia therapy. Two years later, Miller 12 suggested that the reduction in childhood mortality-rate may have been a reflection of a reduction in the occurrence of the disease. Compared with previous years, Leck et al.13 observed an increase in the incidence of childhood leukaemia in 1971-72 10. Mitelman, F., Brandt, L., Nilsson, P. G. Hereditas (in the press). 11. Fraumeni, J. F., Jr., Miller, R. W. Science, 1967, 155, 1126. 12. Miller, R. W. Lancet, 1969, ii, 1189. 13. Leck, I., Morris-Jones, P., Steward, J. K., Evans, D. I. K., Marsden, H. B. ibid. 1973, ii, 509.
among children of Manchester. Falk et al.,14 however, presented data from the Atlanta, Georgia, and Houston, Texas, registries which showed a decline in leukaemia between 1958-62 and 1963-68-findings in agreement with the mortality trends reported previously for U.S. children.", 12 They also observed a levelling off in 1968-72 and suggested that the increased incidence in Manchester children 13 may have been due to random variation. To determine whether the trend in childhood leukaemia mortality-rates among Ohio White children in the period 1968-72 indicated an increase, as may be suggested by the observations of Leck et al.,13or had levelled off 14 or had continued to decline, data from Ohio death certificates for the twenty years 1953-72 were analysed. The data in table i show age-specific mortality-rates by sex for four consecutive 5-year periods. For the years 1958-62 compared with the previous 5-year period, the rates for boys showed no improvement, whereas the rates for girls declined slightly at most ages. With sexes combined, for children of all ages, 0-19 years, the rates declined through 1968-72. The decline was most prominent between 1958-62 and 1963-67. Only a slight decline, however, was observed between the latter two 5-year periods (1963-67 v. 1968-72). In both boys and girls for the period 1968-72, age-groups 5-9 showed a slight increase in mortality-rates. This may be a reflection of postponement in leukaemia mortality for younger-aged children. The age-specific data for boys and girls com14. Falk, H., Heath, C.
p. 862.
W., Jr., Fernbach,
D.
J., Falletta, J. M. ibid
721 in table i. The distribution for 1963-67, with the two previous 5-year periods, suggests compared that the reductions in mortality-rates in 1963-67 were mostly the result of decreased incidence; the peak for the 1-4-year age-groups is much lower than in previous periods, without a subsequent increase in rates in the older age-groups. In the latter two 5-year periods, however, the mode of the distribution appears to be shifting from the 1-4 to the 5-9 age-group. This shift in the peak mortality-rate suggests a postponement in leukxmia mortality, which may be the result of improved cancer therapy,16 Thus, the slight decline in leukaemia mortality in the last 5-year period may have been the result of an increased survival time, whereas the much greater decline in rates between 1958-62 and 1963-68 appears to have Miller 12 has been the result of a decreased incidence. shown that the decrease in leukaemia mortality for 1960-66 compared with previous years was the result of decreased occurrence of the disease, and others have shown that the incidence has levelled off for 1968-72 compared with 1963-67. These data also show that the incidence may be levelling off and that the slight decrease in overall mortality-rates in the last 5-year period may be the resul1 of a postponement in mortality. Table II shows rates for leukaemia mortality by cell type for 1968-72. Data before this period were not coded by cell type. In both sexes, the peak rates for acute lymphocytic leukaemia were in the 5-9 age-group; in girls, however, this may have been at the expense of the other and unspecified category. Compared with previous reports,!7,!! this finding does suggest a tendency for a shift in the, peat mortality-rate of acute lymphocytic leukxmia to a later age, which may be the result of lag in mortality. If medical radiation has contributed to the occurrence of childhood leukaemia, as suggested by Miller,12 the decline in mortality-rates would be expected to become less steep as restriction in radiation exposure approaches its limit. These data for Ohio children seem to be consistent with such hypotheses.
bined
are
given
Ohio Department of Health, 450 East Town Street, Post Office Box 118, Columbus, Ohio 43216, U.S.A.
P. F. INFANTE
J. H. ACKERMAN A. L. MACKENZIE.
TINIDAZOLE IN TREATMENT OF GIARDIASIS SIR,—Dr Thompson
and his
colleagues (April o, p. 614)
recommend the use of metronidazole (’ Flagyl ’) or mepacrine for the treatment of Giardia lamblia infection; you make no mention of the use of tinidazole (‘ Fasigyn ’). Similarly, in a leading article19 elsewhere on giardiasis the And yet the first use of tinidazole was not discussed. clinical trial on the successful use of this drug in the treatment of G. lamblia infection was published over two years ago.20 Metronidazole and mepacrine may cause nausea and may cause an unpleasant yellow discolouration of the skin. An alternative drug for the treatment of this common infection is therefore to be
vomiting,
and
mepacrine
welcomed. For the past six months we have successfully treated with tinidazole 23 patients admitted to our wards with G. lamblia infection. Only patients heavily infected were selected for treatment (3 consecutive stool specimens containing cysts or trophozoites). All the patients were males, the youngest was 6 years and the eldest 50. 10 patients received daily a dose of 900 mg. for 10 days; and 13 were treated with a 15.
Pavlovsky, S. Pædiatrician, 1972-73, 1, 209. Cutler, S. J., Axtell,L., Heise, H.J. natn. Cancer Inst. 1967, 39, 993. 17. Court-Brown, W. M., Doll, R. Br. med. J. 1961, i, 981. 18. Lee, J. A. H. ibid. p. 988. 19. Br. med. J. 1974, ii, 347. 20. Andersson, T., Forssell, J., Sterner, G. ibid. 1972, ii, 449. 16.
dose of 2 g. (four 0-5 g. tablets). All 23 patients cured (at least 10 stool specimens were examined for each patient for 3-5 weeks after completing therapy). The drug was very well tolerated and there were no sideeffects. It is certainly time that tinidazole be mentioned as an alternative drug to metronidazole and mepacrine for the treatment of G. lamblia infection.
single oral were
U.S. Naval Medical Research Unit No. 3; and Abbassia Fever Hospital, Ministry of Public Health,
Cairo, Egypt.
Z. FARID N. A. EL-MASRY W. F. MINER ANWAR HASSAN.
OXOLINIC ACID IN URINARY INFECTIONS
SIR,— The urinary disinfectant, oxolinic acid (’Prodoxol’) is now available on the U.K. market. Oxolinic acid may be thought of as being superior to nalidixic acid, to which it is closely related, being more active weight for weight against nalidixic-acid-sensitive bacteria, and effective against some of the bacterial species which are resistant to nalidixic acid. The former claim is quite well documented for many gram-negative urinary pathogens, the minimum inhibitory concentration (M.LC.) of nalidixic acid being times greater than that of oxolinic acid for Escherichia coli, Proteus spp., and Klebsiella spp.1 The broader antibacterial spectrum claimed for oxolinic acid includes the gram-positive organism, Staphylococcus aureus, which is completely resistant to nalidixic acid. The M.l.c. of oxolinic acid for this organism, although some tenfold higher than for Escherichia coli, seems to be within the therapeutic range of the drug in the urinary tract. Staph. aureus is an unusual urinary pathogen, however, being completely overshadowed in this respect by the coagulase-negative Staph. epidermidis and Micrococcus spp., the biotype 3 of the latter being the second most common bacterial pathogen of the urinary tract of young It therefore seemed important to establish women. 2,3 whether the sensitivity of urinary strains of these organisms to oxolinic acid differs from that of Staph. aureus, and also to confirm that the other major gram-positive urinary pathogen, the faecal-type streptococcus, is resistant to the drug. To this end, 25 strains of Micrococcus biotype 3 and ten or more
25 Staph. epidermidis, separated by novobiocin sensitivity a and according to Baird-Parker’s criteria,5,6 together with 8 fxcal-type streptococci, all of which had been isolated in significant numbers from the urine of patients with urinarytract infections, were tested by the diffusion method on , Wellcotest’ agar (Wellcome Reagents Ltd.) against a disc containing 2 jj.g. of oxolinic acid. None of the Micrococcus sp. or faecal-type streptococci showed any zone of inhibition, while Staph. epidermidis gave zones of inhibition ranging from nil to 5 mm., measured radially from the edge of the
disc.
The Oxford strain of Staph. aureus (NCTC 6571) of inhibition of 4 mm. under the same conditions. The M.l.c.s of 7 of the micrococci, of 7 of the staphylococci selected to cover the range of zones found by disc diffusion, and of 4 of the faecal-type streptococci were estimated by the agar dilution technique using Wellcotest agar, under conditions which gave an M.l.c. for the Oxford staphylococcus of 6-25 (.Lg. per ml. All the micrococci had M.l.c.s of 25 (.Lg. per ml., while the M.l.c.s of the 7 staphylococci varied between 6-25 (4 strains) and gave
1.
a zone
Atlas, E., Clark, H., Silverblatt, F., Turck,
M. Ann. intern. Med.
1969, 70, 713. 2. Meers, P. D. J. Hyg., Camb. 1974, 72, 229. 3. Maskell,R. Lancet, 1974, i, 1155. 4. Mitchell,R. G., Baird-Parker, A. C. J. appl. Bact. 1967, 30, 251. 5. Baird-Parker, A. C. J. gen. Microbiol. 1965, 38, 363. 6. Baird-Parker, A. C. in The Staphylococci (edited by J. O. Cohen); p. 1. New York, 1972.
MILLION
AMONG
WHITE
CHILDREN, AGES 0-19 YEARS,
OHIO, 1953-72
Mitotic indices of granulopoietic precursor cells in bone-marrow of 9 Ph-positive and 3 Ph’-negative patients at diagnosis of C.M.L.
TABLE II-AVERAGE ANNUAL LEUKMIA DEATH-RATES PER MILLION IN WHITE CHILDREN BY CELL TYPE, SEX, AND AGE, OHIO, 1968-72
I
_
I
_
I
-
-
.
I
-
years) with white counts of 28,000-350,000 had the PhI in 100% of their bone-marrow cells. 3 male patients aged 74-78 years with white counts of 29,000-350,000 Detailed karyotype data are reported were PhI-negative. elsewhere.1O A mitotic index of the granulopoietic precursor cells (myeloblasts -I-promyelocytes +myelocytes) was determined through examination of an average 4500 such cells in bone-marrow smears stained with May-GrunwaldGiemsa. In the Phl-negative group the mitotic indices proved to be lower than in the Ph-positive patients (P=0-01 Mann-Whitney U test) (see accompanying figure). Since the time of survival in Phl-negative C.M.L. is known to be shorter than in Phl-positive cases,6-8 the results support the view5 that an accumulation of precursor cells with a low mitotic activity has a serious prognostic implication in C.M.L. The mechanisms bringing about a more aggressive clinical course in patients with a low mitotic activity of the precursors remain to be clarified. L. BRANDT Department of Internal Medicine, F. MITELMAN University Hospital, P. G. NILSSON S-221 85 Lund, U. SJÖGREN. Sweden.
SECULAR TRENDS IN LEUKÆMIA MORTALITY
SIR,-In 1967 Fraumeni and Miller reported a decline in leukaemia mortality-rates among the U.S. White population.l The largest reduction was in children under 5 years. Possible explanations for the decline have included a decrease in incidence related perhaps to a more conservative use of medical X-rays 11 or a reduction in exposure to unknown environmental leukaemogens, or an increase in survival time consequent to improvements in leukaemia therapy. Two years later, Miller 12 suggested that the reduction in childhood mortality-rate may have been a reflection of a reduction in the occurrence of the disease. Compared with previous years, Leck et al.13 observed an increase in the incidence of childhood leukaemia in 1971-72 10. Mitelman, F., Brandt, L., Nilsson, P. G. Hereditas (in the press). 11. Fraumeni, J. F., Jr., Miller, R. W. Science, 1967, 155, 1126. 12. Miller, R. W. Lancet, 1969, ii, 1189. 13. Leck, I., Morris-Jones, P., Steward, J. K., Evans, D. I. K., Marsden, H. B. ibid. 1973, ii, 509.
among children of Manchester. Falk et al.,14 however, presented data from the Atlanta, Georgia, and Houston, Texas, registries which showed a decline in leukaemia between 1958-62 and 1963-68-findings in agreement with the mortality trends reported previously for U.S. children.", 12 They also observed a levelling off in 1968-72 and suggested that the increased incidence in Manchester children 13 may have been due to random variation. To determine whether the trend in childhood leukaemia mortality-rates among Ohio White children in the period 1968-72 indicated an increase, as may be suggested by the observations of Leck et al.,13or had levelled off 14 or had continued to decline, data from Ohio death certificates for the twenty years 1953-72 were analysed. The data in table i show age-specific mortality-rates by sex for four consecutive 5-year periods. For the years 1958-62 compared with the previous 5-year period, the rates for boys showed no improvement, whereas the rates for girls declined slightly at most ages. With sexes combined, for children of all ages, 0-19 years, the rates declined through 1968-72. The decline was most prominent between 1958-62 and 1963-67. Only a slight decline, however, was observed between the latter two 5-year periods (1963-67 v. 1968-72). In both boys and girls for the period 1968-72, age-groups 5-9 showed a slight increase in mortality-rates. This may be a reflection of postponement in leukaemia mortality for younger-aged children. The age-specific data for boys and girls com14. Falk, H., Heath, C.
p. 862.
W., Jr., Fernbach,
D.
J., Falletta, J. M. ibid
721 in table i. The distribution for 1963-67, with the two previous 5-year periods, suggests compared that the reductions in mortality-rates in 1963-67 were mostly the result of decreased incidence; the peak for the 1-4-year age-groups is much lower than in previous periods, without a subsequent increase in rates in the older age-groups. In the latter two 5-year periods, however, the mode of the distribution appears to be shifting from the 1-4 to the 5-9 age-group. This shift in the peak mortality-rate suggests a postponement in leukxmia mortality, which may be the result of improved cancer therapy,16 Thus, the slight decline in leukaemia mortality in the last 5-year period may have been the result of an increased survival time, whereas the much greater decline in rates between 1958-62 and 1963-68 appears to have Miller 12 has been the result of a decreased incidence. shown that the decrease in leukaemia mortality for 1960-66 compared with previous years was the result of decreased occurrence of the disease, and others have shown that the incidence has levelled off for 1968-72 compared with 1963-67. These data also show that the incidence may be levelling off and that the slight decrease in overall mortality-rates in the last 5-year period may be the resul1 of a postponement in mortality. Table II shows rates for leukaemia mortality by cell type for 1968-72. Data before this period were not coded by cell type. In both sexes, the peak rates for acute lymphocytic leukaemia were in the 5-9 age-group; in girls, however, this may have been at the expense of the other and unspecified category. Compared with previous reports,!7,!! this finding does suggest a tendency for a shift in the, peat mortality-rate of acute lymphocytic leukxmia to a later age, which may be the result of lag in mortality. If medical radiation has contributed to the occurrence of childhood leukaemia, as suggested by Miller,12 the decline in mortality-rates would be expected to become less steep as restriction in radiation exposure approaches its limit. These data for Ohio children seem to be consistent with such hypotheses.
bined
are
given
Ohio Department of Health, 450 East Town Street, Post Office Box 118, Columbus, Ohio 43216, U.S.A.
P. F. INFANTE
J. H. ACKERMAN A. L. MACKENZIE.
TINIDAZOLE IN TREATMENT OF GIARDIASIS SIR,—Dr Thompson
and his
colleagues (April o, p. 614)
recommend the use of metronidazole (’ Flagyl ’) or mepacrine for the treatment of Giardia lamblia infection; you make no mention of the use of tinidazole (‘ Fasigyn ’). Similarly, in a leading article19 elsewhere on giardiasis the And yet the first use of tinidazole was not discussed. clinical trial on the successful use of this drug in the treatment of G. lamblia infection was published over two years ago.20 Metronidazole and mepacrine may cause nausea and may cause an unpleasant yellow discolouration of the skin. An alternative drug for the treatment of this common infection is therefore to be
vomiting,
and
mepacrine
welcomed. For the past six months we have successfully treated with tinidazole 23 patients admitted to our wards with G. lamblia infection. Only patients heavily infected were selected for treatment (3 consecutive stool specimens containing cysts or trophozoites). All the patients were males, the youngest was 6 years and the eldest 50. 10 patients received daily a dose of 900 mg. for 10 days; and 13 were treated with a 15.
Pavlovsky, S. Pædiatrician, 1972-73, 1, 209. Cutler, S. J., Axtell,L., Heise, H.J. natn. Cancer Inst. 1967, 39, 993. 17. Court-Brown, W. M., Doll, R. Br. med. J. 1961, i, 981. 18. Lee, J. A. H. ibid. p. 988. 19. Br. med. J. 1974, ii, 347. 20. Andersson, T., Forssell, J., Sterner, G. ibid. 1972, ii, 449. 16.
dose of 2 g. (four 0-5 g. tablets). All 23 patients cured (at least 10 stool specimens were examined for each patient for 3-5 weeks after completing therapy). The drug was very well tolerated and there were no sideeffects. It is certainly time that tinidazole be mentioned as an alternative drug to metronidazole and mepacrine for the treatment of G. lamblia infection.
single oral were
U.S. Naval Medical Research Unit No. 3; and Abbassia Fever Hospital, Ministry of Public Health,
Cairo, Egypt.
Z. FARID N. A. EL-MASRY W. F. MINER ANWAR HASSAN.
OXOLINIC ACID IN URINARY INFECTIONS
SIR,— The urinary disinfectant, oxolinic acid (’Prodoxol’) is now available on the U.K. market. Oxolinic acid may be thought of as being superior to nalidixic acid, to which it is closely related, being more active weight for weight against nalidixic-acid-sensitive bacteria, and effective against some of the bacterial species which are resistant to nalidixic acid. The former claim is quite well documented for many gram-negative urinary pathogens, the minimum inhibitory concentration (M.LC.) of nalidixic acid being times greater than that of oxolinic acid for Escherichia coli, Proteus spp., and Klebsiella spp.1 The broader antibacterial spectrum claimed for oxolinic acid includes the gram-positive organism, Staphylococcus aureus, which is completely resistant to nalidixic acid. The M.l.c. of oxolinic acid for this organism, although some tenfold higher than for Escherichia coli, seems to be within the therapeutic range of the drug in the urinary tract. Staph. aureus is an unusual urinary pathogen, however, being completely overshadowed in this respect by the coagulase-negative Staph. epidermidis and Micrococcus spp., the biotype 3 of the latter being the second most common bacterial pathogen of the urinary tract of young It therefore seemed important to establish women. 2,3 whether the sensitivity of urinary strains of these organisms to oxolinic acid differs from that of Staph. aureus, and also to confirm that the other major gram-positive urinary pathogen, the faecal-type streptococcus, is resistant to the drug. To this end, 25 strains of Micrococcus biotype 3 and ten or more
25 Staph. epidermidis, separated by novobiocin sensitivity a and according to Baird-Parker’s criteria,5,6 together with 8 fxcal-type streptococci, all of which had been isolated in significant numbers from the urine of patients with urinarytract infections, were tested by the diffusion method on , Wellcotest’ agar (Wellcome Reagents Ltd.) against a disc containing 2 jj.g. of oxolinic acid. None of the Micrococcus sp. or faecal-type streptococci showed any zone of inhibition, while Staph. epidermidis gave zones of inhibition ranging from nil to 5 mm., measured radially from the edge of the
disc.
The Oxford strain of Staph. aureus (NCTC 6571) of inhibition of 4 mm. under the same conditions. The M.l.c.s of 7 of the micrococci, of 7 of the staphylococci selected to cover the range of zones found by disc diffusion, and of 4 of the faecal-type streptococci were estimated by the agar dilution technique using Wellcotest agar, under conditions which gave an M.l.c. for the Oxford staphylococcus of 6-25 (.Lg. per ml. All the micrococci had M.l.c.s of 25 (.Lg. per ml., while the M.l.c.s of the 7 staphylococci varied between 6-25 (4 strains) and gave
1.
a zone
Atlas, E., Clark, H., Silverblatt, F., Turck,
M. Ann. intern. Med.
1969, 70, 713. 2. Meers, P. D. J. Hyg., Camb. 1974, 72, 229. 3. Maskell,R. Lancet, 1974, i, 1155. 4. Mitchell,R. G., Baird-Parker, A. C. J. appl. Bact. 1967, 30, 251. 5. Baird-Parker, A. C. J. gen. Microbiol. 1965, 38, 363. 6. Baird-Parker, A. C. in The Staphylococci (edited by J. O. Cohen); p. 1. New York, 1972.