- Email: [email protected]
The importance of both an early orchidopexy and germ cell maturation for fertility
RESEARCH LETTERS
The influence of B2BKR was examined separately among those with the I/I and D/D ACE genotypes. Among those with the I/I genotype, but not among those with the D/D genotype, there was a significant association between B2BKR and left-ventricular growth (table). The results were not changed substantially when analysed for potential confounders by analysis of covariance, with backwards stepwise regression by generalised linear modelling for age, weight, height, losartan use, and genotype. Even when only those taking placebo were studied, B2BKR-genotype-associated differences in leftventricular growth persisted (1·3 g [2·8] for genotype ⫺9/⫺9, 8·7 g [2·1] for genotype ⫺9/+9, and 13·8 g [4·5] for genotype +9/+9; p for linear trend=0·03). Left-ventricular ACE activity1 and kinin concentrations3 are dependent on ACE genotype. Differing kinin concentrations act on bradykinin 2 receptors whose transcription is dependent on B2BKR genotype. Our data show a role for B2BKR genotype in determining the leftventricular growth response, and suggest that alterations in kinin concentrations (marked by the ACE genotype) and kinin-receptor transcription (marked by B2BKR genotype) interact biologically in an additive way. These data thus support a role for bradykinin in the regulation of left-ventricular growth, and suggest that the effects of ACE could be partly mediated through alterations in kinin concentrations. Such data support those from invivo animal studies and in-vitro cell-culture studies: kinins are growth-inhibitory to cardiomyocytes, the antihypertrophic effects of ACE inhibition might be substantially accounted for by increases in local kinin concentrations, whereas B2BKR knockout mice develop left-ventricular hypertrophy.5 Nonetheless, care must be taken in the extrapolation of these findings to the genesis of pathological hypertrophy, in which the magnitude of the role of kinins might differ. These data could have implications for the treatment of patients with pathological left-ventricular hypertrophy. In particular, they suggest potential roles for new combined neutral endopeptidase and ACE inhibitors in the manipulation of left-ventricular mass. 1
2
3
4
5
Danser AH, Schalekamp MA, Bax WA, et al. Angiotensin converting enzyme in the human heart: effect of the deletion/insertion polymorphism. Circulation 1995; 92: 1387–88. Myerson S, Montgomery H, Whittingham M, World M, Humphries S, Pannell D. Left ventricular hypertrophy with exercise and the angiotensin converting enzyme gene I/D polymorphism: a randomised controlled trial with losartan. Circulation 2001; 103: 226–30. Murphey LJ, Gainer JV, Vaughan DE, Brown NJ. Angiotensinconverting enzyme insertion/deletion polymorphism modulates the human in vivo metabolism of bradykinin. Circulation 2000; 102: 829–32. Lung CC, Chan EK, Zuraw BL. Analysis of an exon 1 polymorphism of the B2 bradykinin receptor gene and its transcript in normal subjects and patients with C1 inhibitor deficiency. J Allergy Clin Immunol 1997; 99: 134–46. Emanueli C, Maestri R, Corradi D, et al. Dilated and failing cardiomyopathy in bradykinin B(2) receptor knockout mice. Circulation 1999; 100: 2359–65.
Department of Cardiovascular Genetics, 3rd Floor, Rayne Institute, 5 University Street, London WC1E 6JJ, UK (D Brull MRCP, S Dhamrait MRCP, S Myerson MRCP, Prof S Humphries PhD, H Montgomery MD); Clinic of Internal Medicine II, University Hospital Regensburg, Germany (J Erdmann PhD); Deutsches Herzzentrum, Berlin, Germany (Prof V Regitz-Zagrosek MD); Royal Defence Medical College, Gosport, UK (Prof M World MD); and Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, London (Prof D Pennell FRCP) Correspondence to: Dr Hugh Montgomery (e-mail: [email protected])
1156
The importance of both an early orchidopexy and germ cell maturation for fertility F Hadziselimovic, B Herzog Delayed orchidopexy for undescended testes has been associated with abnormal tesitcular histology, but the effect on later fertility is unknown. We aimed to establish the importance of the first postnatal maturational step—ie, the transformation of gonocytes into Ad (dark) spermatogonia on fertility. We matched histological findings of the testes from 31 patients who had undergone an early orchidopexy with their total number of sperm. If Ad spermatogonia were present, 17 (94%) of 18 (95% CI 72·7–99·9) of the men had a total sperm count of 40⫻106/ejaculate or greater. By contrast, despite successful early surgery, if Ad spermatogonia were absent, 12 (92%) of 13, (64·0–99·8) patients had abnormal spermiograms. Thus, the transformation of gonocytes into Ad spermatogonia is crucial for male fertility.
Lancet 2001; 358: 1156–57
In the early 1970s, it was reported that the cryptorchid testis has an almost normal histology during the first 2 years of life; whereas the prepubertal cryptorchid testis is abnormal.1 This finding prompted a change in the time of orchidopexy from 6 to 2 years of age. We aimed to analyse the fertility outcome in 31 patients who had had an orchidopexy and a testicular biopsy during their first 2 years of life. Six patients had bilateral and 25 had unilateral cryptorchidism. We examined patients regularly each year until their spermiograms were obtained 20 years later. If the first spermiogram was abnormal (<40⫻106/ejaculate), a second was repeated; and the most normal one was evaluated. No patient whose spermiogram was repeated (13 [42%] of 31 [95% CI 24·55–60·92]) changed from abnormal to normal. We used the Wilcoxon-Mann-Whitney U test and Spearman rank correlation coefficient to compare results. All 14 of the cryptorchid boys younger than 6 months at surgery had a normal total germ cell count on testicular biopsy sample (>2·0 germ cells/tubulus). By contrast, 17 boys older than 6 months at surgery had a low number of germ cells (figure). There was a negative association between age and germ cell count (p<0·0001). We expected that cryptorchid boys with a normal number of germ cells and a successful orchidopexy should have a normal sperm count.2 However, 20 years later, this was not the case. A third of boys (12 [31%] of 31 [95% CI 9·09–61·4]) aged less than 6 months with a normal germ cell count had an abnormal sperm count (<40⫻106). There was no association between germ cell count in the testicular biopsy sample and total sperm count (p=0·58). Although the testicular histology was abnormal in all boys aged more than 6 months at orchidopexy, their total sperm count 20 years later did not differ (<6 months 136⫻106 sperm/ejaculate; >6 months: 96⫻106 sperm/ejaculate, p=0·28). This finding was also surprising since we expected to find a direct association between the loss of germ cells and fertility.2 We then assessed the specific stage of germ cell maturation in the testicular biopsy samples. Ad spermatogonia, the stem cells for spermatozoa, have a large nuclei with a light zone in the karyoplasm. They develop from gonocytes during the first postnatal maturational step induced by surge of testosterone and gonadotropins.3 Almost all cryptorchid males (17 [94%] of 18 [72·7–99·9]) whose germ cells had completed the second maturational step, independent of the time of early surgery, had a normal sperm count (figure). By contrast, an abnormal sperm count was recorded in 12 (92%) of 13 (64·0–99·8) cryptorchid males
THE LANCET • Vol 358 • October 6, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
A
p<0·0001
B
Survival after bone marrow transplantation from cytomegalovirus seropositive sibling donors
p<0·0001
9·5
440
9·0
420 400
8·5
380 8·0
6·5 6·0 5·5 Mean
4·5 4·0 3·5 3·0
Total sperm count (cells ⫻106/ejaculate)
Number of germ cells/tubulus
7·0
5·0
David Nachbaur, Hugo Bonatti, Wilhelm Oberaigner, Brigitte Eibl, Gaby Kropshofer, Günther Gastl, Walter Nussbaumer, Hermann Einsele, Clara Larcher
360
7·5
340 320 300 280 260 240 220 200 180 Mean
160 140 120
2·5
100
2·0
80 1·5
60
1·0 0·5
40 Mean
0
20 Mean
0 <6 >6 Age (months)
Absent Present Ad spermatogonia
Number of germ cells (A) and sperm count (B) in cryptorchid boys Circles represent patients, boxes represent IQR.
who had gonocytes, multinuclear germ cells, and no Ad spermatogonia, indicating an incomplete maturation of germ cells. Four in this group had azoospermia; and five had severe oligospermia (<5⫻106). The defective maturation of gonocytes into Ad spermatogonia has been reported in patients with complete androgen insensitivity syndrome.4 These data provide an additional basis for previously published work that showed the benefit of a low dose luteinising hormone releasing hormone analogue treatment for cryptorchid boys in the infertile risk group.3,5 The transformation of gonocytes into Ad spermatogonia and not the total number of germ cells in patients who undergo orchidopexy before 2 years of age seems to be the best indicator of fertility. 1
2
3
4
5
Hedinger C. The moment of the earliest recognizable changes of the testicles in cryptorchidism of infants. Verh Dtsch Ges Path 1971; 55: 172–75. Hadziselimovic F, Herzog B, Höcht B, Hecker E, Miescher E, Buser M. Screening for cryptorchid boys risking sterility and results of long-term buserelin treatment after successful orchidopexy. Eur J Pediatr 1987; 146 (suppl 2): 59–62. Hadziselimovic F, Thomen L, Girard J, Herzog B. The significance of postnatal gonadotropin surge for testicular development in normal and cryptorchid testes. J Urol 1986; 136: 274–77. Hadziselimovic F, Snyder HM, Huff DS. Impaired gonocyte transformation due to androgen receptor defect. Pediatrics 1999; 104: 843–45. Hadziselimovic F, Herzog B. Treatment with a luteinizing hormonereleasing hormone analogue after successful orchidopexy markedly improves the chance of fertility later in life. J Urol Sep 1997; 158: 1193–95.
Kindertagesklinik, Oristalstrasse 87a, CH-4410 Liestal, Switzerland (Prof F Hadziselimovic MD, B Herzog MD) Correspondence to: Prof F Hadziselimovic (e-mail: [email protected])
THE LANCET • Vol 358 • October 6, 2001
HLA-A2-restricted T cells show peptide-specific activity against cytomegalovirus and leukaemia cells. We retrospectively analysed the influence of donor cytomegalovirus serostatus on the outcome of 103 consecutive patients who had leukaemia and who received bone-marrow transplants from HLA-identical sibling donors. We found that donor cytomegalovirus seropositivity significantly improved overall survival (p=0·02) as a result of lower relapse incidence (p=0·035) in HLA-A2positive but not HLA-A2-negative recipients. In HLA-A2-positive recipients donor cytomegalovirus seropositivity was associated with chronic graft-versus-host disease (GVHD), but even in patients without chronic GVHD donor cytomegalovirus seropositivity significantly improved survival (p=0·0483). These preliminary data provide evidence that at least in HLAA2-positive recipients, transplantation of bone marrow from cytomegalovirus positive, HLA-identical sibling donors seems to be associated with substantial graft-versus-leukaemia activity, and suggests a cross-reactivity of cytomegalovirusspecific donor-derived cytotoxic T cells with HLA-A2-restricted recipient minor histocompatibility antigens.
Lancet 2001; 358: 1157–59
Cytomegalovirus-negative bone marrow donors are preferable because of the reduced risk of post-transplant cytomegalovirus infection and disease in the recipient.1 Host T cells play a crucial part in defence against cytomegalovirus. The adoptive transfer of cytomegalovirus-specific cytotoxic T cell lines for prevention or treatment of cytomegalovirus infection and disease is currently under investigation.2 More recently, HLAA2-restricted cytomegalovirus epitopes have been identified as the target antigens for cytotoxic T cells.3 In our retrospective study, we included 103 consecutive patients with leukaemia over age 10 years who received bone marrow transplants between 1983 and 1998 at Innsbruck University Hospital, Innsbruck, Austria, from HLA-identical, mixed-lymphocyte culture non-reactive sibling donors. Patients with chronic myelogenous leukaemia in its first chronic phase or acute leukaemia in first or second complete remission were considered as having a standard-risk of relapse, whereas all other indications were considered high-risk. Pretransplant conditioning consisted of high-dose cyclophosphamide in combination with total body irradiation in 97 patients and of myeloablative chemotherapy alone in the remaining six patients. From 1988, cytomegalovirus pneumonia prophylaxis consisted of infusions of cytomegalovirus hyperimmunoglobulin (Cytotect, Biotest Pharma, Dreieich, Germany) every other week until day 100, either alone or in combination with high-dose acyclovir. Prophylaxis for graft-versus-host disease (GVHD) consisted of ciclosporin with or without a short-course of methotrexate. Cytomegalovirus-screening (serological surveillance, rapid centrifugation cultures, and from 1995, pp65 screening) was done weekly until day 100. Cytomegalovirus infection and disease were defined according to standard criteria.4 Since 1995, pre-emptive gancyclovir was given at the time of detection of cytomegalovirus in peripheral blood. Cytomegalovirus interstitial pneumonia was treated with gancyclovir with or without hyperimmunoglobulin.
1157
For personal use. Only reproduce with permission from The Lancet Publishing Group.
The influence of B2BKR was examined separately among those with the I/I and D/D ACE genotypes. Among those with the I/I genotype, but not among those with the D/D genotype, there was a significant association between B2BKR and left-ventricular growth (table). The results were not changed substantially when analysed for potential confounders by analysis of covariance, with backwards stepwise regression by generalised linear modelling for age, weight, height, losartan use, and genotype. Even when only those taking placebo were studied, B2BKR-genotype-associated differences in leftventricular growth persisted (1·3 g [2·8] for genotype ⫺9/⫺9, 8·7 g [2·1] for genotype ⫺9/+9, and 13·8 g [4·5] for genotype +9/+9; p for linear trend=0·03). Left-ventricular ACE activity1 and kinin concentrations3 are dependent on ACE genotype. Differing kinin concentrations act on bradykinin 2 receptors whose transcription is dependent on B2BKR genotype. Our data show a role for B2BKR genotype in determining the leftventricular growth response, and suggest that alterations in kinin concentrations (marked by the ACE genotype) and kinin-receptor transcription (marked by B2BKR genotype) interact biologically in an additive way. These data thus support a role for bradykinin in the regulation of left-ventricular growth, and suggest that the effects of ACE could be partly mediated through alterations in kinin concentrations. Such data support those from invivo animal studies and in-vitro cell-culture studies: kinins are growth-inhibitory to cardiomyocytes, the antihypertrophic effects of ACE inhibition might be substantially accounted for by increases in local kinin concentrations, whereas B2BKR knockout mice develop left-ventricular hypertrophy.5 Nonetheless, care must be taken in the extrapolation of these findings to the genesis of pathological hypertrophy, in which the magnitude of the role of kinins might differ. These data could have implications for the treatment of patients with pathological left-ventricular hypertrophy. In particular, they suggest potential roles for new combined neutral endopeptidase and ACE inhibitors in the manipulation of left-ventricular mass. 1
2
3
4
5
Danser AH, Schalekamp MA, Bax WA, et al. Angiotensin converting enzyme in the human heart: effect of the deletion/insertion polymorphism. Circulation 1995; 92: 1387–88. Myerson S, Montgomery H, Whittingham M, World M, Humphries S, Pannell D. Left ventricular hypertrophy with exercise and the angiotensin converting enzyme gene I/D polymorphism: a randomised controlled trial with losartan. Circulation 2001; 103: 226–30. Murphey LJ, Gainer JV, Vaughan DE, Brown NJ. Angiotensinconverting enzyme insertion/deletion polymorphism modulates the human in vivo metabolism of bradykinin. Circulation 2000; 102: 829–32. Lung CC, Chan EK, Zuraw BL. Analysis of an exon 1 polymorphism of the B2 bradykinin receptor gene and its transcript in normal subjects and patients with C1 inhibitor deficiency. J Allergy Clin Immunol 1997; 99: 134–46. Emanueli C, Maestri R, Corradi D, et al. Dilated and failing cardiomyopathy in bradykinin B(2) receptor knockout mice. Circulation 1999; 100: 2359–65.
Department of Cardiovascular Genetics, 3rd Floor, Rayne Institute, 5 University Street, London WC1E 6JJ, UK (D Brull MRCP, S Dhamrait MRCP, S Myerson MRCP, Prof S Humphries PhD, H Montgomery MD); Clinic of Internal Medicine II, University Hospital Regensburg, Germany (J Erdmann PhD); Deutsches Herzzentrum, Berlin, Germany (Prof V Regitz-Zagrosek MD); Royal Defence Medical College, Gosport, UK (Prof M World MD); and Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, London (Prof D Pennell FRCP) Correspondence to: Dr Hugh Montgomery (e-mail: [email protected])
1156
The importance of both an early orchidopexy and germ cell maturation for fertility F Hadziselimovic, B Herzog Delayed orchidopexy for undescended testes has been associated with abnormal tesitcular histology, but the effect on later fertility is unknown. We aimed to establish the importance of the first postnatal maturational step—ie, the transformation of gonocytes into Ad (dark) spermatogonia on fertility. We matched histological findings of the testes from 31 patients who had undergone an early orchidopexy with their total number of sperm. If Ad spermatogonia were present, 17 (94%) of 18 (95% CI 72·7–99·9) of the men had a total sperm count of 40⫻106/ejaculate or greater. By contrast, despite successful early surgery, if Ad spermatogonia were absent, 12 (92%) of 13, (64·0–99·8) patients had abnormal spermiograms. Thus, the transformation of gonocytes into Ad spermatogonia is crucial for male fertility.
Lancet 2001; 358: 1156–57
In the early 1970s, it was reported that the cryptorchid testis has an almost normal histology during the first 2 years of life; whereas the prepubertal cryptorchid testis is abnormal.1 This finding prompted a change in the time of orchidopexy from 6 to 2 years of age. We aimed to analyse the fertility outcome in 31 patients who had had an orchidopexy and a testicular biopsy during their first 2 years of life. Six patients had bilateral and 25 had unilateral cryptorchidism. We examined patients regularly each year until their spermiograms were obtained 20 years later. If the first spermiogram was abnormal (<40⫻106/ejaculate), a second was repeated; and the most normal one was evaluated. No patient whose spermiogram was repeated (13 [42%] of 31 [95% CI 24·55–60·92]) changed from abnormal to normal. We used the Wilcoxon-Mann-Whitney U test and Spearman rank correlation coefficient to compare results. All 14 of the cryptorchid boys younger than 6 months at surgery had a normal total germ cell count on testicular biopsy sample (>2·0 germ cells/tubulus). By contrast, 17 boys older than 6 months at surgery had a low number of germ cells (figure). There was a negative association between age and germ cell count (p<0·0001). We expected that cryptorchid boys with a normal number of germ cells and a successful orchidopexy should have a normal sperm count.2 However, 20 years later, this was not the case. A third of boys (12 [31%] of 31 [95% CI 9·09–61·4]) aged less than 6 months with a normal germ cell count had an abnormal sperm count (<40⫻106). There was no association between germ cell count in the testicular biopsy sample and total sperm count (p=0·58). Although the testicular histology was abnormal in all boys aged more than 6 months at orchidopexy, their total sperm count 20 years later did not differ (<6 months 136⫻106 sperm/ejaculate; >6 months: 96⫻106 sperm/ejaculate, p=0·28). This finding was also surprising since we expected to find a direct association between the loss of germ cells and fertility.2 We then assessed the specific stage of germ cell maturation in the testicular biopsy samples. Ad spermatogonia, the stem cells for spermatozoa, have a large nuclei with a light zone in the karyoplasm. They develop from gonocytes during the first postnatal maturational step induced by surge of testosterone and gonadotropins.3 Almost all cryptorchid males (17 [94%] of 18 [72·7–99·9]) whose germ cells had completed the second maturational step, independent of the time of early surgery, had a normal sperm count (figure). By contrast, an abnormal sperm count was recorded in 12 (92%) of 13 (64·0–99·8) cryptorchid males
THE LANCET • Vol 358 • October 6, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
A
p<0·0001
B
Survival after bone marrow transplantation from cytomegalovirus seropositive sibling donors
p<0·0001
9·5
440
9·0
420 400
8·5
380 8·0
6·5 6·0 5·5 Mean
4·5 4·0 3·5 3·0
Total sperm count (cells ⫻106/ejaculate)
Number of germ cells/tubulus
7·0
5·0
David Nachbaur, Hugo Bonatti, Wilhelm Oberaigner, Brigitte Eibl, Gaby Kropshofer, Günther Gastl, Walter Nussbaumer, Hermann Einsele, Clara Larcher
360
7·5
340 320 300 280 260 240 220 200 180 Mean
160 140 120
2·5
100
2·0
80 1·5
60
1·0 0·5
40 Mean
0
20 Mean
0 <6 >6 Age (months)
Absent Present Ad spermatogonia
Number of germ cells (A) and sperm count (B) in cryptorchid boys Circles represent patients, boxes represent IQR.
who had gonocytes, multinuclear germ cells, and no Ad spermatogonia, indicating an incomplete maturation of germ cells. Four in this group had azoospermia; and five had severe oligospermia (<5⫻106). The defective maturation of gonocytes into Ad spermatogonia has been reported in patients with complete androgen insensitivity syndrome.4 These data provide an additional basis for previously published work that showed the benefit of a low dose luteinising hormone releasing hormone analogue treatment for cryptorchid boys in the infertile risk group.3,5 The transformation of gonocytes into Ad spermatogonia and not the total number of germ cells in patients who undergo orchidopexy before 2 years of age seems to be the best indicator of fertility. 1
2
3
4
5
Hedinger C. The moment of the earliest recognizable changes of the testicles in cryptorchidism of infants. Verh Dtsch Ges Path 1971; 55: 172–75. Hadziselimovic F, Herzog B, Höcht B, Hecker E, Miescher E, Buser M. Screening for cryptorchid boys risking sterility and results of long-term buserelin treatment after successful orchidopexy. Eur J Pediatr 1987; 146 (suppl 2): 59–62. Hadziselimovic F, Thomen L, Girard J, Herzog B. The significance of postnatal gonadotropin surge for testicular development in normal and cryptorchid testes. J Urol 1986; 136: 274–77. Hadziselimovic F, Snyder HM, Huff DS. Impaired gonocyte transformation due to androgen receptor defect. Pediatrics 1999; 104: 843–45. Hadziselimovic F, Herzog B. Treatment with a luteinizing hormonereleasing hormone analogue after successful orchidopexy markedly improves the chance of fertility later in life. J Urol Sep 1997; 158: 1193–95.
Kindertagesklinik, Oristalstrasse 87a, CH-4410 Liestal, Switzerland (Prof F Hadziselimovic MD, B Herzog MD) Correspondence to: Prof F Hadziselimovic (e-mail: [email protected])
THE LANCET • Vol 358 • October 6, 2001
HLA-A2-restricted T cells show peptide-specific activity against cytomegalovirus and leukaemia cells. We retrospectively analysed the influence of donor cytomegalovirus serostatus on the outcome of 103 consecutive patients who had leukaemia and who received bone-marrow transplants from HLA-identical sibling donors. We found that donor cytomegalovirus seropositivity significantly improved overall survival (p=0·02) as a result of lower relapse incidence (p=0·035) in HLA-A2positive but not HLA-A2-negative recipients. In HLA-A2-positive recipients donor cytomegalovirus seropositivity was associated with chronic graft-versus-host disease (GVHD), but even in patients without chronic GVHD donor cytomegalovirus seropositivity significantly improved survival (p=0·0483). These preliminary data provide evidence that at least in HLAA2-positive recipients, transplantation of bone marrow from cytomegalovirus positive, HLA-identical sibling donors seems to be associated with substantial graft-versus-leukaemia activity, and suggests a cross-reactivity of cytomegalovirusspecific donor-derived cytotoxic T cells with HLA-A2-restricted recipient minor histocompatibility antigens.
Lancet 2001; 358: 1157–59
Cytomegalovirus-negative bone marrow donors are preferable because of the reduced risk of post-transplant cytomegalovirus infection and disease in the recipient.1 Host T cells play a crucial part in defence against cytomegalovirus. The adoptive transfer of cytomegalovirus-specific cytotoxic T cell lines for prevention or treatment of cytomegalovirus infection and disease is currently under investigation.2 More recently, HLAA2-restricted cytomegalovirus epitopes have been identified as the target antigens for cytotoxic T cells.3 In our retrospective study, we included 103 consecutive patients with leukaemia over age 10 years who received bone marrow transplants between 1983 and 1998 at Innsbruck University Hospital, Innsbruck, Austria, from HLA-identical, mixed-lymphocyte culture non-reactive sibling donors. Patients with chronic myelogenous leukaemia in its first chronic phase or acute leukaemia in first or second complete remission were considered as having a standard-risk of relapse, whereas all other indications were considered high-risk. Pretransplant conditioning consisted of high-dose cyclophosphamide in combination with total body irradiation in 97 patients and of myeloablative chemotherapy alone in the remaining six patients. From 1988, cytomegalovirus pneumonia prophylaxis consisted of infusions of cytomegalovirus hyperimmunoglobulin (Cytotect, Biotest Pharma, Dreieich, Germany) every other week until day 100, either alone or in combination with high-dose acyclovir. Prophylaxis for graft-versus-host disease (GVHD) consisted of ciclosporin with or without a short-course of methotrexate. Cytomegalovirus-screening (serological surveillance, rapid centrifugation cultures, and from 1995, pp65 screening) was done weekly until day 100. Cytomegalovirus infection and disease were defined according to standard criteria.4 Since 1995, pre-emptive gancyclovir was given at the time of detection of cytomegalovirus in peripheral blood. Cytomegalovirus interstitial pneumonia was treated with gancyclovir with or without hyperimmunoglobulin.
1157
For personal use. Only reproduce with permission from The Lancet Publishing Group.