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ADRIAMYCIN AND LONGITUDINAL PIGMENTED BANDING OF FINGERNAILS
1337 correct timing of of A.F.P. values.
amniocentesis and prevent misinterpretation
(ii) Confirmation of fetal life (amniocentesis is contraindicated when there is fetal death because of the increased risk of infection) and the detection of other abnormalities such as hydatidiform mole in which amniocentesis is ill advised. (iii) Early diagnosis of multiple pregnancy; ultrasound will usually permit amniocentesis to be performed on each sac. This is of importance as witnessed by a patient of ours at present under study who has raised A.F.P. values in one sac and normal values in the other. (iv) The safe performance of amniocentesis which when carried out immediately following ultrasonic examination or through a biopsy transducer will reduce the hazard of direct injury to the fetus, reduce the incidence of fetomaternal transfusion and almost eliminate the occurrence of significant fetal blood contamination of the amniotic fluid. We agree with Mrs Kitau and her colleagues and with Dr Goldie and Dr Monk that fetal blood contamination can result in a significant rise in amniotic-fluid A.F.P. levels, and that a loss of approximately 10 ml. of fetal blood into the amniotic fluid would have produced a level of 110 t-tg. per ml. at 17 1/2 weeks menstrual age. It is unlikely that this was the reason for the raised A.F.P. levels in case 3 for two reasons. Firstly, the amniotic fluid was submitted to microscopy before analysis and only anuclear red cells were seen which we believed excluded a fetal loss as large as 10 ml. Secondly, an acute loss of 10 ml. at 17 weeks represents between 35% and 50% of the fetal blood volume, which is unlikely to be compatible with fetal survival. Furthermore, it should be pointed out that a sharp fall in amniotic-fluid A.F.P. levels can often occur in the presence of severe neural-tube abnormality, as exemplified by case 2. We would agree with Dr Goldie and Dr Monk that the Kleihauer acid-elution test should be performed on all samples of bloodstained amniotic fluid and that the results should be considered unreliable if a significant number of fetal cells is found to be present. The importance of having an alternative method of making the diagnosis of spina bifida in these cases is self evident.
confirmed by other workers, but we believe that there is no strong, consistent, and confirmed evidence that any other form of risk-factor intervention will influence the prognosis of patients who survive a coronary attack. Indeed, apart from the routine treatment of complications such as cardiac failure or arrhythmias, there is no evidence that exercise programmes, or measures such as drugs or surgical treatment, will improve prognosis. If we are to deal rationally with such patients we should have a clear picture of the scientific basis of our treatment measures. We would support Dr Opie’s plea for physical fitness and a full secondary prevention approach because they are plausible, if not proven, methods of reducing morbidity and mortality from coronary disease and stroke. Secondary prevention measures may also reduce morbidity and mortality from other non-coronary causes, and such measures are psychologically beneficial because they will appeal to the patient’s sense of logic and they will encourage him to return to a normal and active life. St. Vincent’s Hospital, Elm Park, Dublin 4, and
University College, Dublin.
RISTEARD MULCAHY NOEL HICKEY.
ADRIAMYCIN AND LONGITUDINAL PIGMENTED BANDING OF FINGERNAILS SiR,—We wish to’ report that three patients receiving cytotoxic therapy at this hospital have developed longitudinal pigmented banding of their fingernails. All three patients are women with locally recurrent or metastatic breast cancer. Their ages are 34, 51, and 56 years. Although they have had a variety of treatments, the only drugs common to all three are adriamycin and cyclophosphamide. One patient had
STUART CAMPBELL
J. PRYSE-DAVIES Queen Charlotte’s Maternity Hospital, Goldhawk Road, London W6 0XG.
T. M. COLTART MARY SELLER J. D. SINGER.
RISK FACTORS AFTER CORONARY THROMBOSIS
SIR,-Dr Opie (May 17, p. 1142) is uncertain about the efficacy of risk-factor intervention in the management of patients with established coronary heart-disease. He states that the simplest and best-proven measure is to stop smoking, and he cites one paper1 which supports the value of stopping smoking after a heart-attack. Lest his letter should leave doubts about the significance of cigarette smoking in
patients
with established coronary heart-disease, it should be stated that there are at least two other papers which show a significant reduction in mortality amongst patients who stop smoking after a coronary attacks In fact both the Gothenberg and Dublin experiences 2,3 show that mortality in those who stop smoking is about half that of those who fail to reduce smoking. To the best of our knowledge there is no report of a similar study which denies these results. It remains to be seen whether these reports will be 1. Wilhelmsson, C., Vedin, J. A., sen, L. Lancet, 1975, i, 415.
Elmfeldt, D., Tibblin, G., Wilhem-
Matzdorff, E., Lippert, A., Schmidt, A., Schmidt, K. Dt. med. Wschr. 1973, 98, 2183. 3. Mulcahy, R., Hickey, N., Graham, I., McKenzie, G. Br. Heart J. 1975, 37, 158.
2.
Pigmented right thumbnail and normal left thumbnail of patient on adriamycin therapy been treated with cyclophosphamide at an earlier stage in her disease and had noted no abnormality of the nails at that time. It is therefore presumed that adriamycin is the cause. Banding was noted 3, 4, and 6 months after starting adriamycin, and it extended from the matrix to the tip, the pigment being grey, brown, and black, respectively. Bands appeared on one or two nails only. The pigment seems to be in the nail plate and is presumably melanin. The anatomical distribution suggests that the band is due to the activity of a single melanocyte in the matrix.
Pigmented bands have been reported with a number of drugs1 but not previously with a cytotoxic agent. There was no history of trauma. Pigmented banding has been noted after adrenalectomy, but no patient in the series had this operation, although it is interesting to speculate on a possible selective hormone-suppressive action of adria1. 2.
Caron, G. A. Lancet, 1962, i, 508. Bondy, P. K., Harwick, H. J. New Engl. J. Med. 1969, 281, 1056.
1338
mycin which might allow an excess of melanocyte-stimulating hormone to be released from the pituitary. Velindre
Hospital, Whitchurch,
T. J. PRIESTMAN KEITH W. JAMES.
Cardiff CF4 7XL.
CYTOGENETIC EVIDENCE OF IN-VIVO LEUKÆMIC TRANSFORMATION OF ENGRAFTED MARROW CELLS SiR,—Chromosomal abnormalities found in acute leukaemia disappear when remission is induced by antileuksemic therapy. The abnormalities reappear when the disease relapses. This suggests either that the mutant malignant cells were not completely gone or that the carcinogenic factor which produced the original mutant cells was not removed by the antileukaemic agents.l Cytogenetic studies suggest that the internal environment is very important in allowing mutant cells to become established, proliferate, and be expressed as clinical cancer or leukaemia.22 Fialkow et al. and Thomas et al. both reported a case of a girl with acute lymphoblastic leukaemia treated with 1000 rads total-body irradiation followed by bone-marrow infusion from the patient’s HL-A-match brother. Successful engraftment was achieved in both, as evidenced by sexchromosomal3 and sex-chromosomal and fluorescent-Ybody studies.44. Leukaemia recurred in both patients.3,4 Because these cases might provide evidence for or against leukaemic transformation of engrafted marrow cells, it was suggested that further studies should be carried out in one of these patients.II Such studies were carried out in the second casebut no chromosomal abnormality was found in ’117 metaphases analysed from direct bone-marrow preparations, including some after the recurrence of leukaemia. Cytogenetic studies have been carried out in a 4-year-old girl with acute leukaemia who was treated with cyclophosphamide and bone-marrow transplantation from her HL-Aidentical, mixed-lymphocyte-culture non-reactive brother.6
/
Goh, K. O. D.M. April, 1965, p. 43. Goh, K. O. Radiat. Res. (in the press). Fialkow, P. J., Thomas, E. D., Bryant, J. I., Neiman, P. E. Lancet, 1971, i, 251. 4. Thomas, E. D., Bryant, J. I., Buckner, C. D., Clift, R. A., Fefer, A., Johnson, F. L., Neiman, P., Ramberg, R. E., Storb, R. ibid. 1972, i, 1310. 5. Goh, K. O. ibid. 1971, ii, 101. 6. Klemperer, M. R., Lee, H., Segal, G. B., Goh, K. O., May, A. Pediat. Res. 1973, 7, 123. 1. 2. 3.
Fig. 1-Pereentage of XY (male) metaphases in the patient** bone-marrow aspirates at various intervals after the transplantation. -
Fig. 1 shows the frequency of male donor metaphases in the recipient’s bone-marrow aspirates at various intervals during follow-up. The last specimen was obtained post mortem. No chromosomal abnormality was found in the donor’s bonemarrow before transplantation, except for occasional variation in the size of the homologous chromosomes. 65 weeks after transplantation 37 % of the bone-marrow interphases had a Y body. Detailed karyotypes of the metaphases obtained from the post-mortem bone-marrow aspirate indicated acute leukaemia, with many pseudodiploid and aneuploid metaphases having either XX or XY sex-chromosomal patterns. In addition, three XY metaphases with 47 chromosomes had an extra chromosome in group F (fig. 2). One or more extra F chromosomes are sometimes seen in patients with acute leukaemia, whether the acute process is preceded by chronic myelocytic leukaemia 7-9 or not. to The findings reported here provide, for the first time, cytogenetic evidence that mutations developed in vivo in the engrafted male marrow cells. This strongly suggests that a leukaemic stimulus existing in the patient transformed the engrafted male cells. Further studies of karyotypes at various intervals and 7. 8. 9. 10.
Goh, K. O. Archs intern. Med. 1967, 120, 315. Goh, K. O. Am. J. med. Sci. 1974, 267, 229. Hossfeld, D. K. Humangenetik, 1974, 23, 111. Goh, K. O. Unpublished.
Fig. 2-One of three 47,XY-chromosome metaphases (right) and its karyotype (left) obtained from the patient’s bone-marrow post mortem.
The F
(19-20) chromosomes
are
pointed with black
arrows
and the G (21-22) and the Y chromosomes with white
arrows.
amniocentesis and prevent misinterpretation
(ii) Confirmation of fetal life (amniocentesis is contraindicated when there is fetal death because of the increased risk of infection) and the detection of other abnormalities such as hydatidiform mole in which amniocentesis is ill advised. (iii) Early diagnosis of multiple pregnancy; ultrasound will usually permit amniocentesis to be performed on each sac. This is of importance as witnessed by a patient of ours at present under study who has raised A.F.P. values in one sac and normal values in the other. (iv) The safe performance of amniocentesis which when carried out immediately following ultrasonic examination or through a biopsy transducer will reduce the hazard of direct injury to the fetus, reduce the incidence of fetomaternal transfusion and almost eliminate the occurrence of significant fetal blood contamination of the amniotic fluid. We agree with Mrs Kitau and her colleagues and with Dr Goldie and Dr Monk that fetal blood contamination can result in a significant rise in amniotic-fluid A.F.P. levels, and that a loss of approximately 10 ml. of fetal blood into the amniotic fluid would have produced a level of 110 t-tg. per ml. at 17 1/2 weeks menstrual age. It is unlikely that this was the reason for the raised A.F.P. levels in case 3 for two reasons. Firstly, the amniotic fluid was submitted to microscopy before analysis and only anuclear red cells were seen which we believed excluded a fetal loss as large as 10 ml. Secondly, an acute loss of 10 ml. at 17 weeks represents between 35% and 50% of the fetal blood volume, which is unlikely to be compatible with fetal survival. Furthermore, it should be pointed out that a sharp fall in amniotic-fluid A.F.P. levels can often occur in the presence of severe neural-tube abnormality, as exemplified by case 2. We would agree with Dr Goldie and Dr Monk that the Kleihauer acid-elution test should be performed on all samples of bloodstained amniotic fluid and that the results should be considered unreliable if a significant number of fetal cells is found to be present. The importance of having an alternative method of making the diagnosis of spina bifida in these cases is self evident.
confirmed by other workers, but we believe that there is no strong, consistent, and confirmed evidence that any other form of risk-factor intervention will influence the prognosis of patients who survive a coronary attack. Indeed, apart from the routine treatment of complications such as cardiac failure or arrhythmias, there is no evidence that exercise programmes, or measures such as drugs or surgical treatment, will improve prognosis. If we are to deal rationally with such patients we should have a clear picture of the scientific basis of our treatment measures. We would support Dr Opie’s plea for physical fitness and a full secondary prevention approach because they are plausible, if not proven, methods of reducing morbidity and mortality from coronary disease and stroke. Secondary prevention measures may also reduce morbidity and mortality from other non-coronary causes, and such measures are psychologically beneficial because they will appeal to the patient’s sense of logic and they will encourage him to return to a normal and active life. St. Vincent’s Hospital, Elm Park, Dublin 4, and
University College, Dublin.
RISTEARD MULCAHY NOEL HICKEY.
ADRIAMYCIN AND LONGITUDINAL PIGMENTED BANDING OF FINGERNAILS SiR,—We wish to’ report that three patients receiving cytotoxic therapy at this hospital have developed longitudinal pigmented banding of their fingernails. All three patients are women with locally recurrent or metastatic breast cancer. Their ages are 34, 51, and 56 years. Although they have had a variety of treatments, the only drugs common to all three are adriamycin and cyclophosphamide. One patient had
STUART CAMPBELL
J. PRYSE-DAVIES Queen Charlotte’s Maternity Hospital, Goldhawk Road, London W6 0XG.
T. M. COLTART MARY SELLER J. D. SINGER.
RISK FACTORS AFTER CORONARY THROMBOSIS
SIR,-Dr Opie (May 17, p. 1142) is uncertain about the efficacy of risk-factor intervention in the management of patients with established coronary heart-disease. He states that the simplest and best-proven measure is to stop smoking, and he cites one paper1 which supports the value of stopping smoking after a heart-attack. Lest his letter should leave doubts about the significance of cigarette smoking in
patients
with established coronary heart-disease, it should be stated that there are at least two other papers which show a significant reduction in mortality amongst patients who stop smoking after a coronary attacks In fact both the Gothenberg and Dublin experiences 2,3 show that mortality in those who stop smoking is about half that of those who fail to reduce smoking. To the best of our knowledge there is no report of a similar study which denies these results. It remains to be seen whether these reports will be 1. Wilhelmsson, C., Vedin, J. A., sen, L. Lancet, 1975, i, 415.
Elmfeldt, D., Tibblin, G., Wilhem-
Matzdorff, E., Lippert, A., Schmidt, A., Schmidt, K. Dt. med. Wschr. 1973, 98, 2183. 3. Mulcahy, R., Hickey, N., Graham, I., McKenzie, G. Br. Heart J. 1975, 37, 158.
2.
Pigmented right thumbnail and normal left thumbnail of patient on adriamycin therapy been treated with cyclophosphamide at an earlier stage in her disease and had noted no abnormality of the nails at that time. It is therefore presumed that adriamycin is the cause. Banding was noted 3, 4, and 6 months after starting adriamycin, and it extended from the matrix to the tip, the pigment being grey, brown, and black, respectively. Bands appeared on one or two nails only. The pigment seems to be in the nail plate and is presumably melanin. The anatomical distribution suggests that the band is due to the activity of a single melanocyte in the matrix.
Pigmented bands have been reported with a number of drugs1 but not previously with a cytotoxic agent. There was no history of trauma. Pigmented banding has been noted after adrenalectomy, but no patient in the series had this operation, although it is interesting to speculate on a possible selective hormone-suppressive action of adria1. 2.
Caron, G. A. Lancet, 1962, i, 508. Bondy, P. K., Harwick, H. J. New Engl. J. Med. 1969, 281, 1056.
1338
mycin which might allow an excess of melanocyte-stimulating hormone to be released from the pituitary. Velindre
Hospital, Whitchurch,
T. J. PRIESTMAN KEITH W. JAMES.
Cardiff CF4 7XL.
CYTOGENETIC EVIDENCE OF IN-VIVO LEUKÆMIC TRANSFORMATION OF ENGRAFTED MARROW CELLS SiR,—Chromosomal abnormalities found in acute leukaemia disappear when remission is induced by antileuksemic therapy. The abnormalities reappear when the disease relapses. This suggests either that the mutant malignant cells were not completely gone or that the carcinogenic factor which produced the original mutant cells was not removed by the antileukaemic agents.l Cytogenetic studies suggest that the internal environment is very important in allowing mutant cells to become established, proliferate, and be expressed as clinical cancer or leukaemia.22 Fialkow et al. and Thomas et al. both reported a case of a girl with acute lymphoblastic leukaemia treated with 1000 rads total-body irradiation followed by bone-marrow infusion from the patient’s HL-A-match brother. Successful engraftment was achieved in both, as evidenced by sexchromosomal3 and sex-chromosomal and fluorescent-Ybody studies.44. Leukaemia recurred in both patients.3,4 Because these cases might provide evidence for or against leukaemic transformation of engrafted marrow cells, it was suggested that further studies should be carried out in one of these patients.II Such studies were carried out in the second casebut no chromosomal abnormality was found in ’117 metaphases analysed from direct bone-marrow preparations, including some after the recurrence of leukaemia. Cytogenetic studies have been carried out in a 4-year-old girl with acute leukaemia who was treated with cyclophosphamide and bone-marrow transplantation from her HL-Aidentical, mixed-lymphocyte-culture non-reactive brother.6
/
Goh, K. O. D.M. April, 1965, p. 43. Goh, K. O. Radiat. Res. (in the press). Fialkow, P. J., Thomas, E. D., Bryant, J. I., Neiman, P. E. Lancet, 1971, i, 251. 4. Thomas, E. D., Bryant, J. I., Buckner, C. D., Clift, R. A., Fefer, A., Johnson, F. L., Neiman, P., Ramberg, R. E., Storb, R. ibid. 1972, i, 1310. 5. Goh, K. O. ibid. 1971, ii, 101. 6. Klemperer, M. R., Lee, H., Segal, G. B., Goh, K. O., May, A. Pediat. Res. 1973, 7, 123. 1. 2. 3.
Fig. 1-Pereentage of XY (male) metaphases in the patient** bone-marrow aspirates at various intervals after the transplantation. -
Fig. 1 shows the frequency of male donor metaphases in the recipient’s bone-marrow aspirates at various intervals during follow-up. The last specimen was obtained post mortem. No chromosomal abnormality was found in the donor’s bonemarrow before transplantation, except for occasional variation in the size of the homologous chromosomes. 65 weeks after transplantation 37 % of the bone-marrow interphases had a Y body. Detailed karyotypes of the metaphases obtained from the post-mortem bone-marrow aspirate indicated acute leukaemia, with many pseudodiploid and aneuploid metaphases having either XX or XY sex-chromosomal patterns. In addition, three XY metaphases with 47 chromosomes had an extra chromosome in group F (fig. 2). One or more extra F chromosomes are sometimes seen in patients with acute leukaemia, whether the acute process is preceded by chronic myelocytic leukaemia 7-9 or not. to The findings reported here provide, for the first time, cytogenetic evidence that mutations developed in vivo in the engrafted male marrow cells. This strongly suggests that a leukaemic stimulus existing in the patient transformed the engrafted male cells. Further studies of karyotypes at various intervals and 7. 8. 9. 10.
Goh, K. O. Archs intern. Med. 1967, 120, 315. Goh, K. O. Am. J. med. Sci. 1974, 267, 229. Hossfeld, D. K. Humangenetik, 1974, 23, 111. Goh, K. O. Unpublished.
Fig. 2-One of three 47,XY-chromosome metaphases (right) and its karyotype (left) obtained from the patient’s bone-marrow post mortem.
The F
(19-20) chromosomes
are
pointed with black
arrows
and the G (21-22) and the Y chromosomes with white
arrows.