- Email: [email protected]
Human herpesvirus 6 (variant A) in Kaposi's sarcoma
1288
PREDICTION OF INCREASE OF AIDS IN ADULTS IN NEW YORK CITY
*From registrations and AIDS Surveillance .5 tCalculated from regression of incidence (y) over time units (x), expressed as annual aggregate of monthly averages from 1982 to 1989 giving equation for prediction y= -845+827x.
contact, infectivity and susceptibility are uniformly high, but I have been ensure9 about its applicability in more complex infections where exposure and susceptibility depend mainly on where people are and what they do, what are their haplotypes, and what else is going on besides infection1o with a particular virus such as HIV. His model predicts an exponential growth rate proportional to transmission of HIV and this could be why he over-estimated the incidence of AIDS. With respect to dates, a report of correct predictions by the regression model, based on unselective data4,5 to 1989, was submitted in 1990 to the Royal Society, and is still being considered by them. I also sent a draft to the Chairman of the Advisory Committee on Dangerous Pathogens, who sent it to the epidemiology committee of the Medical Research Council. I then sent an updated draft to the Chief Medical Officer because, by contrast with the official predictions and pronouncements which remained uncorrected, the estimates from regression were demonstrably accurate, excluded any spread in the general population by heterosexual transmission, and had immediate implications for the control of and budgeting for AIDS. I do not share Anderson’s pessimism about AIDS because, on present trends and the presumption of a continuing disinclination towards risk behaviour in the general population, it cannot undergo rapid general spread in developed countries even though it remains lethal in risk groups and third parties they put at risk. Lastly, I made an error in numbering the reference in the table as 8 instead of 3.should have cited a reference to prediction by linear regression in another paperb which the Communicable Diseases (Scotland) Weekly Report published in 1990.
daily postoperatively. She had had herpes simplex virus (type I) infections throughout much of her life, with severe "cold sores" at least annually. In March, 1993, she inadvertently omitted her tamoxifen for 3 days, towards the end of which she noticed the onset of characteristic early herpetic lesions. Within 24 hours of resuming tamoxifen, the patient noticed that the lesions were not developing into a full-blown herpetic rash, but were regressing. After a further 24 hours, the lesions had resolved. The patient had never previously had such rapid remission. We speculate whether tamoxifen was responsible not only for the resolution of these early lesions but may also have kept previous flare-ups at bay. Tumour viruses (eg, human papillomavirus) may induce malignant transformation via production of oncoproteins, such as E7, which have an affinity for and combine with the retinoblastoma suppressor gene product pRB, thereby promoting cell cycling. The negative transforming growth factor, TGFp, which is induced in vivo by tamoxifen in breast cancer patients,2 can interact with this system by maintaining pRB in an active form, thus favouring cell-cycle arrest.3 An antiviral effect of tamoxifen may be mediated by inducing growth factors that modify the ratio of T-suppressor to T-helper cells, or by inducing interferon or other viral inhibitors, in a manner analogous to induction of growth factors. Although a pathophysiological explanation for an antiviral action is elusive, such an effect may have significance in relation to the 20 mg
familiar antitumour effects of tamoxifen. Metastases may by subcellular transmission of genetic information, in addition to the classical model of cellular events.’ Metastatic foci could arise from transfection of differentiated host cells by "lethal packets" of genetic material which are derived from death by apoptosis of existing cancer cells. Perhaps tamoxifen inhibits the transmission of such putative virus-like particles in breast cancer patients, precluding transfection of host cells, and hence establishment of this type of metastasis.
more
occur
Royal Marsden Hospital,
J. R. BENSON
London SW3 6JJ, UK
M. BAUM
1. Vennin PH, Gougeon E, Azab M. Anti-viral response to tamoxifen. Lancet 1992; 340: 798. 2. Butta A, Maclennan K, Flanders KC, et al. Induction of transforming growth factor beta, in human breast cancer in vivo following tamoxifen treatment. Cancer Res
1992; 52: 4261-64. 3. Laiho M, De Caprio C, Ludlow JW, Livingston DM, Massague J. Growth inhibition by TGF&bgr; linked to suppression of retinoblastoma protein phosphorylation. Cell 1990; 62: 175-85. 4. Baum M. Breast cancer 2000 BC to 2000 AD—time for a paradigm shift. Acta Oncologica 1993; 32: 3-8.
Human
herpesvirus 6 (variant A) in Kaposi’s sarcoma
Glenavon, Clifton Down, Bristol BS8 3HT, UK
GORDON T. STEWART
SiR,-Human herpesvirus 6 (HHV-6) isolates are divided into variants, A and B, which can be differentiated by molecular, biological, and immunological properties. At least in the Western population, variant B is detected more often, and only variant B is isolated from patients with exanthema subitum, except in rare cases with both variants.2 Hodgkin’s lymphomas contain variant B sequences in 31 % of cases, whereas A occurs in only 3% of biopsy specimens. Analysis of lymphocytes from the healthy population shows the predominance of variant B, present in 15% of cases compared with 3% for A (data not shown). Whether the lower frequency of variant A reflects a different facility with which viruses of the two variants can be detected or differences in the pathogenetic two
1. Cox DR, Anderson RM, Hillier HC, eds. Epidemiological and statistical aspects of the AIDS epidemic. Phil Trans R Soc London (B) 1989; 325: 37-187. 2. Department of Health and the Welsh Office. Short-term prediction of HIV and AIDS: Report of a working group (Chairman: Sir David Cox), London: HM Stationery Office, 1988. 3. Day N. Letter to the Sunday Times, news review. May 2nd, 1993. 4. AIDS-HIV Quarterly Surveillance Tables, no 18, to end December, 1992. London: Public Health Laboratory Service, AIDS Centre, and the Communicable Disease (Scotland) Unit, 1993. 5. New York City, Department of Health. AIDS surveillance updates, 1982-92. New York: NY DOH, 1991. 6. Stewart GT. Acquired immune difidency syndrome: differences within the United Kingdom. Comm Dis (Scotland) Wkly Rep 1990; 33 (AIDS suppl): 1-3. 7. Anderson RM, May RM. Directly-transmitted infectious diseases: control by vaccination. Science 1992; 215: 1053-60. 8. Anderson RM, May RM. Transmission dynamics of HIV infection. Nature 1987; 326: 137-42. 9. Stewart GT. Age-specific immunisation schedules. Lancet 1982; i: 806-07. 10. Stewart GT. Limitations of the Germ Theory. Lancet 1968; i: 1077-81.
Antiviral effect of tamoxifen SIR,-An antiviral effect oftamoxifen has been alluded to. We report another serendipitous
case.
55-year-old woman underwent locoregional treatment for "early" breast cancer in April, 1992, and started adjuvant tamoxifen A
role is debatable. We analysed DNA from 20 Kaposi’s sarcoma biopsies for the presence of HHV-6 DNA by polymerase chain reaction.3 HHV-6 was present in 7 of 20 (35%) samples. The frequency was similar in endemic (4/12, 33%) and classic (2/7, 28%) forms (the other specimen was from an AIDS patient). Characterisation by restriction site analysis of the amplified product showed that 6 isolates belonged to variant A and 1 was B (endemic Kaposi’s sarcoma). Geographical differences in the distribution of HHV-6 variants seem unlikely, because the frequency of HHV-6 variant A is similar in endemic (African) and classic (European) Kaposi’s sarcoma.
1289
The higher occurrence of variant A in Kaposi’s sarcoma biopsy specimens (6/20, 30%) compared with the lower detection rate in the general population (3%) could reflect a preferential tropism for endothelial tissue, but viral reactivation due to immunosuppression cannot
be
excluded.
Infectious
agents,
such
as
human
cytomegalovirus, may have a role in the pathogenesis of Kaposi’s sarcoma, but
a
causal relation has
not
been established. The
detection of HHV-6 variant A in Kaposi’s sarcoma biopsy samples suggests the opportunity to investigate possible contributions of the virus to the pathogenesis of this disease.
PASQUALINA BOVENZI PRISCO MIRANDOLA PAOLA SECCHIERO RENATA STRUMIA ENZO CASSAI DARIO DI LUCA
Institute of Microbiology and Department of Dermatology, Univesity of Ferrara, 44100 Ferrara, Italy
DV, Balachandian N, Josephs SF, et al. Genomic polymorphism, growth properties and immunologic variations in human herpesvirus-6 isolates. Virology
myeloid leukaemia developing in patients previously treated with mitomycin for various primary malignancies.3-6 There are no reports of such blood dyscrasias after mitomycin for breast carcinoma. Neither methotrexate nor mitoxantrone have been associated with an increased frequency of myeloid malignancy; in 1038 reports to the UK Committee for Safety of Medicines of adverse effects with mitoxantrone, only 1 case of acute myeloblastic leukaemia was found. Similarly, only two cases of acute myeloblastic leukaemia after methotrexate were listed in a total of 1316 adverse event reports. Because MMM is widely used (in some centres as first line chemotherapy with or without involved-field radiotherapy) in the treatment of breast carcinoma, close surveillance for further cases of secondary leukaemia is indicated. acute
Division of Haematology, St George’s Hospital Medical School, London SW17 0RE, UK
N. J. PHILPOTT D. H. BEVAN E. C. GORDON-SMITH
1. Ablashi
1991; 184: 545-53. 2. Pruksananonda P, Breese Hall C, Insel RA,
et al. Primary human herpesvirus 6 infection in young children. N Engl J Med 1992; 326: 145-50. 3. Aubin JT, Collandre H, Candotti D, et al. Several groups among herpesvirus 6 strains can be distinguished by Southern blotting and polymerase chain reaction. J Clin Microbiol 1991; 29: 367-72.
Secondary leukaemia after MMM combined modality therapy for breast carcinoma SIR,-Melphalan and cyclophosphamide in the treatment of breast carcinoma are associated with an increased risk of secondary myelodysplastic syndromes and acute myeloid leukaemia. The cumulative frequency of such blood dyscrasias is 0-7%, with new cases developing up to 9 years post-chemotherapy.l The relative risk is greater after melphalan (31 4) than cyclophosphamide (3 -1 ). We report two women with breast carcinomas treated with mitoxantrone, methotrexate, and mitomycin (MMM) who developed secondary acute myeloid leukaemia. Case 1 (56, presented in 1990 with poorly differentiated carcinoma of right breast and lymph-node metastases)--she was treated with eight cycles of MMM (mitoxantrone 7 mg/m2 and methotrexate 30 mg/m2, 3 weekly; and mitomycin 7 mg/m2, 6 weekly), immediately received local radiotherapy (total dose 70 Gy to breast and 50 Gy to axilla and supraclavicular fossa), and started tamoxifen 20 mg daily. She was disease-free for 18 months but then presented with progressive pancytopenia (haemoglobin [Hb] 10.11 g/dL, white cells 1-7 x 109/L, neutrophils < 0- x 109/L, occasional myeloblasts, platelets 5 x 109/L). Bone marrow was inaspirable and trephine biopsy revealed striking hypoplasia, dysplastic features, and increased fibrosis, but no metastatic carcinoma. Hypoplastic myelodysplastic syndrome was diagnosed. She was treated with two courses of subcutaneous cytarabine (10 mg/m2 daily for 14 days each month) and granulocyte colony-stimulating factor (300 (ig daily for 14 days after each course of chemotherapy) without response. 6 months after presentation, the peripheral blood blast count began to rise (Hb 12g/dL, white cells 66 x 109/L, blasts 62%, platelets 24 x 109/L). The blasts showed early myeloid phenotype (CD34 +, CD 13+, CD33 +, HLA-DR +). Case 2 (39, presented in September, 1991, with poorly differentiated breast carcinoma and lymph-node metastases)—she was treated with eight cycles of MMM and local radiotherapy (total dose 50 Gy to the breast) immediately after chemotherapy. In April, 1992, she developed progressive pancytopenia. By October, 1992, her blood
showed Hb 80 g/dL, white cells 17 x 109/L, 109/L, occasional blasts, and platelets 11 x 1012/L. aspirate was hypercellular with dysplastic features,
count
neutrophils 06
x
Bone marrow 32% myeloid
blasts;
Immunophenotyping
no
megakaryocytes
were
seen.
showed CD34+, CD13+, CD33+, CD14 +, HLA-DR +, CD7 +, and CD2 +. Cytogenetic analysis showed a small unidentified marker chromosome. These two patients developed CD34 + secondary myeloid leukaemias presenting as peripheral blood pancytopenia early (18 months and 6 months) after primary treatment for breast carcinoma with combined modality therapy, including mitomycin and radiotherapy. There are six cases of myelodysplastic syndrome and
RE, Boice JD, Moloney WC, et al. Leukaemia following chemotherapy for breast cancer. Cancer Res 1990; 50: 2741-56. 2. Curtis RE, Boice JD, Storal M, et al. Risk of leukaemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med 1992; 326: 1745-51. 3. Bouillet T, Lepage E, Gisselbrecht C, Boiron M. Acute non-lymphocytic leukaemia following FAM combination adjuvant chemotherapy for gastric and lung adenocarcinoma. Now Rev Fr Hematol 1990; 32: 207-09. 4. Sonneveld P, Kurth KH, Hagemeyer A, Abels J. Secondary haematologic neoplasm after intravesical chemotherapy for superficial bladder carcinoma. Cancer 1990; 65: 23-25. 5. Advani SH, Doval DC, Gopal R, et al. Therapy-related leukaemia. Oncology 1983; 40: 268-72. 6. Burde B, Haim N, Gez E, Polliack A. Acute myeloblastic leukaemia following treatment with mitomycin C: a case report. Cancer Chem Pharmacol 1989; 24: 71. 1. Curtis
Loss of heterozygosity on chromosome 7q31 in breast cancer et all reported that loss of heterozygosity at the proto-oncogene locus on chromosome 7q31 was correlated with decreased survival in patients with primary breast cancer. 49 out of 121 patients had lost heterozygosity at 7q31 in tumour DNA compared with blood DNA. However, this finding disagrees with others/,3 although these two reports were of smaller numbers. We examined blood and tumour DNA from 111patients with primary breast cancer with the c-met probe. In blood DNA samples, 52 patients were heterozygous for the TaqI RFLP of 7-5 and 40 kb, with 36 being homozygous for the larger allele and 23 homozygous for the smaller allele. Thus the overall frequency for the rarer allele was 44% which is similar to the 42% found by Bieche et al. When tumour DNA from the 52 heterozygous patients was tested with the c-met probe after digestion with TaqI, only 2 patients showed loss of heterozygosity. We cannot confirm the high level of loss of heterozygosity at 7q31.1
SIR,-Bieche
c-met
Duncan Guthrie Institute of Medical Genetics,
Yorkhill,
Glasgow G3 8SJ, UK
Department of Surgery, Infirmary, Glasgow
Western
A. COOKE Y. T. KIM T. I. HARVEY J. M. CONNOR
J. NAGY W. D. GEORGE
I, Champeme MH, Matifas F, Hacene K, Callahan R, Lidereau R. Loss of heterozygosity on chromosome 7q and aggressive primary breast cancer. Lancet
1. Bieche
1992; 339: 139-43. 2. Devilee P, Van Vliet M, Van Sloun P, et al. Allelotype of human breast carcinoma: a second major site for loss of heterozygosity is on chromosome 6q. Oncogene 1991; 6: 1705-11. 3. Larsson C, Bystrom C, Skoog L, Rotstein S, Nordenskjold M. Genomic alterations in human breast carcinomas. Genes Chrom Cancer 1990; 2: 191-97.
Retinoic acid syndrome SiR,—We report two cases of a new syndrome that can occur when all-trans retinoic acid is used to induce remission in promyelocytic leukaemia. The first case was a 22-year-old woman with acute promyelocytic (French-American-British m3) leukaemia treated with all-trans retinoic acid with a view to standard chemotherapy at the stage of minimal residual disease. The initial white cell count was
PREDICTION OF INCREASE OF AIDS IN ADULTS IN NEW YORK CITY
*From registrations and AIDS Surveillance .5 tCalculated from regression of incidence (y) over time units (x), expressed as annual aggregate of monthly averages from 1982 to 1989 giving equation for prediction y= -845+827x.
contact, infectivity and susceptibility are uniformly high, but I have been ensure9 about its applicability in more complex infections where exposure and susceptibility depend mainly on where people are and what they do, what are their haplotypes, and what else is going on besides infection1o with a particular virus such as HIV. His model predicts an exponential growth rate proportional to transmission of HIV and this could be why he over-estimated the incidence of AIDS. With respect to dates, a report of correct predictions by the regression model, based on unselective data4,5 to 1989, was submitted in 1990 to the Royal Society, and is still being considered by them. I also sent a draft to the Chairman of the Advisory Committee on Dangerous Pathogens, who sent it to the epidemiology committee of the Medical Research Council. I then sent an updated draft to the Chief Medical Officer because, by contrast with the official predictions and pronouncements which remained uncorrected, the estimates from regression were demonstrably accurate, excluded any spread in the general population by heterosexual transmission, and had immediate implications for the control of and budgeting for AIDS. I do not share Anderson’s pessimism about AIDS because, on present trends and the presumption of a continuing disinclination towards risk behaviour in the general population, it cannot undergo rapid general spread in developed countries even though it remains lethal in risk groups and third parties they put at risk. Lastly, I made an error in numbering the reference in the table as 8 instead of 3.should have cited a reference to prediction by linear regression in another paperb which the Communicable Diseases (Scotland) Weekly Report published in 1990.
daily postoperatively. She had had herpes simplex virus (type I) infections throughout much of her life, with severe "cold sores" at least annually. In March, 1993, she inadvertently omitted her tamoxifen for 3 days, towards the end of which she noticed the onset of characteristic early herpetic lesions. Within 24 hours of resuming tamoxifen, the patient noticed that the lesions were not developing into a full-blown herpetic rash, but were regressing. After a further 24 hours, the lesions had resolved. The patient had never previously had such rapid remission. We speculate whether tamoxifen was responsible not only for the resolution of these early lesions but may also have kept previous flare-ups at bay. Tumour viruses (eg, human papillomavirus) may induce malignant transformation via production of oncoproteins, such as E7, which have an affinity for and combine with the retinoblastoma suppressor gene product pRB, thereby promoting cell cycling. The negative transforming growth factor, TGFp, which is induced in vivo by tamoxifen in breast cancer patients,2 can interact with this system by maintaining pRB in an active form, thus favouring cell-cycle arrest.3 An antiviral effect of tamoxifen may be mediated by inducing growth factors that modify the ratio of T-suppressor to T-helper cells, or by inducing interferon or other viral inhibitors, in a manner analogous to induction of growth factors. Although a pathophysiological explanation for an antiviral action is elusive, such an effect may have significance in relation to the 20 mg
familiar antitumour effects of tamoxifen. Metastases may by subcellular transmission of genetic information, in addition to the classical model of cellular events.’ Metastatic foci could arise from transfection of differentiated host cells by "lethal packets" of genetic material which are derived from death by apoptosis of existing cancer cells. Perhaps tamoxifen inhibits the transmission of such putative virus-like particles in breast cancer patients, precluding transfection of host cells, and hence establishment of this type of metastasis.
more
occur
Royal Marsden Hospital,
J. R. BENSON
London SW3 6JJ, UK
M. BAUM
1. Vennin PH, Gougeon E, Azab M. Anti-viral response to tamoxifen. Lancet 1992; 340: 798. 2. Butta A, Maclennan K, Flanders KC, et al. Induction of transforming growth factor beta, in human breast cancer in vivo following tamoxifen treatment. Cancer Res
1992; 52: 4261-64. 3. Laiho M, De Caprio C, Ludlow JW, Livingston DM, Massague J. Growth inhibition by TGF&bgr; linked to suppression of retinoblastoma protein phosphorylation. Cell 1990; 62: 175-85. 4. Baum M. Breast cancer 2000 BC to 2000 AD—time for a paradigm shift. Acta Oncologica 1993; 32: 3-8.
Human
herpesvirus 6 (variant A) in Kaposi’s sarcoma
Glenavon, Clifton Down, Bristol BS8 3HT, UK
GORDON T. STEWART
SiR,-Human herpesvirus 6 (HHV-6) isolates are divided into variants, A and B, which can be differentiated by molecular, biological, and immunological properties. At least in the Western population, variant B is detected more often, and only variant B is isolated from patients with exanthema subitum, except in rare cases with both variants.2 Hodgkin’s lymphomas contain variant B sequences in 31 % of cases, whereas A occurs in only 3% of biopsy specimens. Analysis of lymphocytes from the healthy population shows the predominance of variant B, present in 15% of cases compared with 3% for A (data not shown). Whether the lower frequency of variant A reflects a different facility with which viruses of the two variants can be detected or differences in the pathogenetic two
1. Cox DR, Anderson RM, Hillier HC, eds. Epidemiological and statistical aspects of the AIDS epidemic. Phil Trans R Soc London (B) 1989; 325: 37-187. 2. Department of Health and the Welsh Office. Short-term prediction of HIV and AIDS: Report of a working group (Chairman: Sir David Cox), London: HM Stationery Office, 1988. 3. Day N. Letter to the Sunday Times, news review. May 2nd, 1993. 4. AIDS-HIV Quarterly Surveillance Tables, no 18, to end December, 1992. London: Public Health Laboratory Service, AIDS Centre, and the Communicable Disease (Scotland) Unit, 1993. 5. New York City, Department of Health. AIDS surveillance updates, 1982-92. New York: NY DOH, 1991. 6. Stewart GT. Acquired immune difidency syndrome: differences within the United Kingdom. Comm Dis (Scotland) Wkly Rep 1990; 33 (AIDS suppl): 1-3. 7. Anderson RM, May RM. Directly-transmitted infectious diseases: control by vaccination. Science 1992; 215: 1053-60. 8. Anderson RM, May RM. Transmission dynamics of HIV infection. Nature 1987; 326: 137-42. 9. Stewart GT. Age-specific immunisation schedules. Lancet 1982; i: 806-07. 10. Stewart GT. Limitations of the Germ Theory. Lancet 1968; i: 1077-81.
Antiviral effect of tamoxifen SIR,-An antiviral effect oftamoxifen has been alluded to. We report another serendipitous
case.
55-year-old woman underwent locoregional treatment for "early" breast cancer in April, 1992, and started adjuvant tamoxifen A
role is debatable. We analysed DNA from 20 Kaposi’s sarcoma biopsies for the presence of HHV-6 DNA by polymerase chain reaction.3 HHV-6 was present in 7 of 20 (35%) samples. The frequency was similar in endemic (4/12, 33%) and classic (2/7, 28%) forms (the other specimen was from an AIDS patient). Characterisation by restriction site analysis of the amplified product showed that 6 isolates belonged to variant A and 1 was B (endemic Kaposi’s sarcoma). Geographical differences in the distribution of HHV-6 variants seem unlikely, because the frequency of HHV-6 variant A is similar in endemic (African) and classic (European) Kaposi’s sarcoma.
1289
The higher occurrence of variant A in Kaposi’s sarcoma biopsy specimens (6/20, 30%) compared with the lower detection rate in the general population (3%) could reflect a preferential tropism for endothelial tissue, but viral reactivation due to immunosuppression cannot
be
excluded.
Infectious
agents,
such
as
human
cytomegalovirus, may have a role in the pathogenesis of Kaposi’s sarcoma, but
a
causal relation has
not
been established. The
detection of HHV-6 variant A in Kaposi’s sarcoma biopsy samples suggests the opportunity to investigate possible contributions of the virus to the pathogenesis of this disease.
PASQUALINA BOVENZI PRISCO MIRANDOLA PAOLA SECCHIERO RENATA STRUMIA ENZO CASSAI DARIO DI LUCA
Institute of Microbiology and Department of Dermatology, Univesity of Ferrara, 44100 Ferrara, Italy
DV, Balachandian N, Josephs SF, et al. Genomic polymorphism, growth properties and immunologic variations in human herpesvirus-6 isolates. Virology
myeloid leukaemia developing in patients previously treated with mitomycin for various primary malignancies.3-6 There are no reports of such blood dyscrasias after mitomycin for breast carcinoma. Neither methotrexate nor mitoxantrone have been associated with an increased frequency of myeloid malignancy; in 1038 reports to the UK Committee for Safety of Medicines of adverse effects with mitoxantrone, only 1 case of acute myeloblastic leukaemia was found. Similarly, only two cases of acute myeloblastic leukaemia after methotrexate were listed in a total of 1316 adverse event reports. Because MMM is widely used (in some centres as first line chemotherapy with or without involved-field radiotherapy) in the treatment of breast carcinoma, close surveillance for further cases of secondary leukaemia is indicated. acute
Division of Haematology, St George’s Hospital Medical School, London SW17 0RE, UK
N. J. PHILPOTT D. H. BEVAN E. C. GORDON-SMITH
1. Ablashi
1991; 184: 545-53. 2. Pruksananonda P, Breese Hall C, Insel RA,
et al. Primary human herpesvirus 6 infection in young children. N Engl J Med 1992; 326: 145-50. 3. Aubin JT, Collandre H, Candotti D, et al. Several groups among herpesvirus 6 strains can be distinguished by Southern blotting and polymerase chain reaction. J Clin Microbiol 1991; 29: 367-72.
Secondary leukaemia after MMM combined modality therapy for breast carcinoma SIR,-Melphalan and cyclophosphamide in the treatment of breast carcinoma are associated with an increased risk of secondary myelodysplastic syndromes and acute myeloid leukaemia. The cumulative frequency of such blood dyscrasias is 0-7%, with new cases developing up to 9 years post-chemotherapy.l The relative risk is greater after melphalan (31 4) than cyclophosphamide (3 -1 ). We report two women with breast carcinomas treated with mitoxantrone, methotrexate, and mitomycin (MMM) who developed secondary acute myeloid leukaemia. Case 1 (56, presented in 1990 with poorly differentiated carcinoma of right breast and lymph-node metastases)--she was treated with eight cycles of MMM (mitoxantrone 7 mg/m2 and methotrexate 30 mg/m2, 3 weekly; and mitomycin 7 mg/m2, 6 weekly), immediately received local radiotherapy (total dose 70 Gy to breast and 50 Gy to axilla and supraclavicular fossa), and started tamoxifen 20 mg daily. She was disease-free for 18 months but then presented with progressive pancytopenia (haemoglobin [Hb] 10.11 g/dL, white cells 1-7 x 109/L, neutrophils < 0- x 109/L, occasional myeloblasts, platelets 5 x 109/L). Bone marrow was inaspirable and trephine biopsy revealed striking hypoplasia, dysplastic features, and increased fibrosis, but no metastatic carcinoma. Hypoplastic myelodysplastic syndrome was diagnosed. She was treated with two courses of subcutaneous cytarabine (10 mg/m2 daily for 14 days each month) and granulocyte colony-stimulating factor (300 (ig daily for 14 days after each course of chemotherapy) without response. 6 months after presentation, the peripheral blood blast count began to rise (Hb 12g/dL, white cells 66 x 109/L, blasts 62%, platelets 24 x 109/L). The blasts showed early myeloid phenotype (CD34 +, CD 13+, CD33 +, HLA-DR +). Case 2 (39, presented in September, 1991, with poorly differentiated breast carcinoma and lymph-node metastases)—she was treated with eight cycles of MMM and local radiotherapy (total dose 50 Gy to the breast) immediately after chemotherapy. In April, 1992, she developed progressive pancytopenia. By October, 1992, her blood
showed Hb 80 g/dL, white cells 17 x 109/L, 109/L, occasional blasts, and platelets 11 x 1012/L. aspirate was hypercellular with dysplastic features,
count
neutrophils 06
x
Bone marrow 32% myeloid
blasts;
Immunophenotyping
no
megakaryocytes
were
seen.
showed CD34+, CD13+, CD33+, CD14 +, HLA-DR +, CD7 +, and CD2 +. Cytogenetic analysis showed a small unidentified marker chromosome. These two patients developed CD34 + secondary myeloid leukaemias presenting as peripheral blood pancytopenia early (18 months and 6 months) after primary treatment for breast carcinoma with combined modality therapy, including mitomycin and radiotherapy. There are six cases of myelodysplastic syndrome and
RE, Boice JD, Moloney WC, et al. Leukaemia following chemotherapy for breast cancer. Cancer Res 1990; 50: 2741-56. 2. Curtis RE, Boice JD, Storal M, et al. Risk of leukaemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med 1992; 326: 1745-51. 3. Bouillet T, Lepage E, Gisselbrecht C, Boiron M. Acute non-lymphocytic leukaemia following FAM combination adjuvant chemotherapy for gastric and lung adenocarcinoma. Now Rev Fr Hematol 1990; 32: 207-09. 4. Sonneveld P, Kurth KH, Hagemeyer A, Abels J. Secondary haematologic neoplasm after intravesical chemotherapy for superficial bladder carcinoma. Cancer 1990; 65: 23-25. 5. Advani SH, Doval DC, Gopal R, et al. Therapy-related leukaemia. Oncology 1983; 40: 268-72. 6. Burde B, Haim N, Gez E, Polliack A. Acute myeloblastic leukaemia following treatment with mitomycin C: a case report. Cancer Chem Pharmacol 1989; 24: 71. 1. Curtis
Loss of heterozygosity on chromosome 7q31 in breast cancer et all reported that loss of heterozygosity at the proto-oncogene locus on chromosome 7q31 was correlated with decreased survival in patients with primary breast cancer. 49 out of 121 patients had lost heterozygosity at 7q31 in tumour DNA compared with blood DNA. However, this finding disagrees with others/,3 although these two reports were of smaller numbers. We examined blood and tumour DNA from 111patients with primary breast cancer with the c-met probe. In blood DNA samples, 52 patients were heterozygous for the TaqI RFLP of 7-5 and 40 kb, with 36 being homozygous for the larger allele and 23 homozygous for the smaller allele. Thus the overall frequency for the rarer allele was 44% which is similar to the 42% found by Bieche et al. When tumour DNA from the 52 heterozygous patients was tested with the c-met probe after digestion with TaqI, only 2 patients showed loss of heterozygosity. We cannot confirm the high level of loss of heterozygosity at 7q31.1
SIR,-Bieche
c-met
Duncan Guthrie Institute of Medical Genetics,
Yorkhill,
Glasgow G3 8SJ, UK
Department of Surgery, Infirmary, Glasgow
Western
A. COOKE Y. T. KIM T. I. HARVEY J. M. CONNOR
J. NAGY W. D. GEORGE
I, Champeme MH, Matifas F, Hacene K, Callahan R, Lidereau R. Loss of heterozygosity on chromosome 7q and aggressive primary breast cancer. Lancet
1. Bieche
1992; 339: 139-43. 2. Devilee P, Van Vliet M, Van Sloun P, et al. Allelotype of human breast carcinoma: a second major site for loss of heterozygosity is on chromosome 6q. Oncogene 1991; 6: 1705-11. 3. Larsson C, Bystrom C, Skoog L, Rotstein S, Nordenskjold M. Genomic alterations in human breast carcinomas. Genes Chrom Cancer 1990; 2: 191-97.
Retinoic acid syndrome SiR,—We report two cases of a new syndrome that can occur when all-trans retinoic acid is used to induce remission in promyelocytic leukaemia. The first case was a 22-year-old woman with acute promyelocytic (French-American-British m3) leukaemia treated with all-trans retinoic acid with a view to standard chemotherapy at the stage of minimal residual disease. The initial white cell count was