ARTICLE
Auteur(s) : Gianpaolo
Tessari1, Luigi Naldi2, Luigino
Boschiero3, Claudio Cordiano3, Stefano
Piaserico4, Anna Belloni Fortina4, Decio
Cerimele5, Ilaria Lesnoni La Parola6, Maria
Capuano7, Eliana Gotti8, Piero
Ruggenenti8, Fabrizia Sassi2, Giuseppe
Remuzzi8, Giampiero Girolomoni1
1Section of Dermatology University of Verona,
Piazzale A. Stefani 1, 37126, Verona
2Centro Studi Gruppo Italiano di Studi Epidemiologici in
Dermatologia, Ospedali Riuniti di Bergamo, Bergamo
3Kidney Transplantation Center, University of Verona,
Piazzale A. Stefani 1, 37126, Verona
4Section of Dermatology, University of Padova,
Padova
5Section of Dermatology, University of Sassari,
Sassari
6Istituto Dermatologico San Gallicano, Roma
7Istituto Dermatologico dell’Immacolata, IRCCS, Roma
8Section of Nephrology, Ospedali Riuniti di Bergamo,
Bergamo, Italy
accepté le 24 Mai 2006
Kaposi’s sarcoma (KS) is a well-recognized complication of solid
organ transplantation [1]. The tumor develops in 0.4% of Western
renal transplant recipients, but at a much higher rate among
patients of Arab, Jewish or Mediterranean ancestry. KS accounts for
3.4% of the malignancies found in renal transplant recipients
(RTR). This is a hundred times higher than the percentage observed
in the general population. Immunosuppressive therapy plays a major
role in the development of KS in this group of patients. It has
been reported that the introduction of cyclosporine A (CYA) and
mycophenolate mofetil (MMF) has led to a further increase in the
incidence of KS among transplant recipients [2]. Dosage reduction
or withdrawal of immunosuppressive drugs in RTRs is often followed
by the regression of lesions, particularly when the disease is
limited to the skin [3]. In addition to immunosuppression, other
factors, such as genetic predisposition, environmental factors and
viruses seem to be involved in a multifactorial pathogenic
mechanism [4, 5]. DNA sequences of human herpesvirus 8 (HHV-8) have
been repeatedly found in KS, including the post-transplant variety,
indicating a role for this virus in KS pathogenesis [6-8]. Although
several studies have documented a higher prevalence of classic KS
in the Mediterranean area, limited data exist on incidence rate,
timing of disease, and clinical correlates of post-transplant KS.
We investigated the incidence and risk factors for KS in a cohort
of solid organ transplant recipients followed up at four transplant
centers in Italy.
Patients and methods
From 1997 to 2004, a series of 1721 consecutive organ (kidney,
heart, and liver) transplant patients followed up at four Italian
transplant centers (Verona, Bergamo, Padova, Catholic University of
the Sacred Heart, Roma), were included. Clinical records were
available for all the patients. Patients who survived less than 10
days after transplant and those with a pre-transplant history of
cancer were excluded from the study. The diagnosis of KS was always
confirmed by histological analysis. At the time of the study, no
routine serologic screening for HHV8 was performed. For each
patient the following data were recorded: age, sex, date of
transplantation, immunosuppressive therapy, number of acute
rejections requiring adjunctive immunosuppressive therapy, date of
KS diagnosis, date and cause of loss from follow-up.
Immunosuppressive regimen
Long term maintenance immunosuppressive therapy showed some
variations according to centers. It usually consisted of
combinations of azathioprine (AZA; 1-2.5 mg/kg/day), cyclosporine
(CYA; 3-9 mg/kg/day) with oral prednisolone (PRED; 5-10 mg/day).
Dosages of tacrolimus ranged from 0.15 to 0.30 mg/kg/day bid when
administered orally, regulated by periodic tests of blood levels
(through level 10-15 μg/L). Dosage of MMF was 2 g /day. Acute
rejection among heart transplant recipients (> 3A or more) was
treated with three intravenous pulses of methylprednisolone
(1 g/day for three consecutive days) according to the
guidelines of the International Society of Heart and Lung
Transplantation [9].
Statistical analysis
Cumulative incidence of the first episode of KS was computed. The
number of person-year was computed between the date of
transplantation (used as the opening date) and the date of KS
diagnosis, the patient’s death, loss from follow-up or the end of
the study in December 2004, which were used as the closing dates.
Kaplan and Meier survival curves were initially constructed.
Subsequently, for estimates of potential prognostic factors, a
Cox’s proportional hazards regression model was applied. An
assumption of Cox’s regression method is that the hazards for
different strata of each independent variable are proportional over
time. This assumption was verified using a graphical method. The
survival curves for the variable strata were plotted on a log-log
scale. If the curves were roughly parallel then the assumption of
the proportional hazards was considered as satisfied. A backward
stepping procedure with pre-assigned p values equal to 0.05 for
removal of variables was used [10]. For KS, the expected number
(standardized for sex, age, and area of residence) was computed
using incidence rates from all population-based cancer registries
of Italy for the period 1988-1992 [11]. Standardized incidence
ratio (SIR) of KS was computed and was obtained by dividing the
number of observed cases by the number of expected cases.
Ninety-five percent confidence intervals (CI) of SIR were
determined using the Poisson distribution [10].
Results
A total of 1721 patients were recruited, with 1220 males and 501
females. 1356 were RTR, 268 heart transplant recipients and 97
liver transplant recipients. The characteristics of the study
population are reported in table 1( Table
1 ). KS was diagnosed in 40 patients (37 males and 3
females), after a median follow-up time of 1 year and a mean of 1.5
years ± 1.3 SD (range 0.8-5.1). Thirty three patients had only
cutaneous KS and 7 had both cutaneous and visceral involvement. Of
the 7 patients with visceral KS, 5 had gastrointestinal and lung
involvement and 2 had regional lymph-node involvement. Four
patients died of disseminated disease; one RTR survived after
stopping immunosuppressive therapy but returned to dialysis; two
survived after stopping cyclosporine and replacing it with
rapamycin. The incidence rate of KS in the whole study population
was 2.3 cases per 1000 person -year (95% CI 1.7-3.2). Of the 40
patients with KS, 35 were RTR and 5 were heart or liver transplant
recipients. Incidence rates of KS did not significantly differ
among the three groups (p = 0.113) (table 1). Due to the low number
of patients with KS among nonrenal transplant recipients we decided
to exclude nonrenal transplant patients from further statistical
analysis.
The overall incidence rate of KS among RTR was 2.5 cases per 1
000 post-transplant person-year (95% CI 2.2-4.4). The incidence
rate was higher among males than females (2.9 vs. 1.7 cases/1 000
post-transplant person-year) but the difference was not
statistically significant (p = 0.168). The incidence rate decreased
with the time elapsed since the date of the transplant from 12.9
cases per 1 000 post-transplant person-year (95% CI 8.6-19.2)
within the first two years after transplantation to 2.7 cases per 1
000 post-transplant person-year in the third year (95% CI 1.3-5.8),
and to 0.2 cases per 1 000 post-transplant person-year for patients
with more than 4 years of follow-up (95% CI 0.1-1.2). The
standardized incidence rate for KS was 149.9 (95% CI 103.0-212.0),
but the excess risk was greater among women (316.0; 95% CI
116.0-688.0) than among men (133.6; 95% CI 87.0-196.0). Cumulative
hazard of the KS among RTR is reported in ( figure 1 ). Cumulative
incidence of KS at 1, 3, 5 and 10 years since transplantation was
1.2%, 2.4%, 3.2% and 3.2%, respectively. In univariate analysis,
male sex, age at transplantation equal older than 30 years and only
combined immunosuppressive regimen with MMF + CYA + PRED were found
to be significantly associated with KS (table 2)( Table 2 ). We found no statistically significant
relationship with the year of transplantation, use of
anti-thymocyte globulins or OKT3 monoclonal antibodies, the number
of treatments for acute rejections, the other immunosuppressive
regimens and the geographic origin and residence (Northern, Central
or Southern Italy). Grouping our patients in three new categories
(AZA alone or plus immunosuppressive drugs other than MMF or CYA,
MMF alone or plus other immunosuppressive drugs, other drugs not
including AZA or MMF) did not show any significant differences
(data not shown). Grouping the patients in two groups according to
whether or not they received CYA gave no statistically significant
results (data not shown). In the Cox proportional hazard regression
model, age at transplantation equal or older than 30 years and only
combined immunosuppressive therapy with MMF + CYA + PRED were
independently associated with KS (table 2).
Table 1 Study population and KS incidence
|
Transplanted organ
|
|
Kidney
|
Heart
|
Liver
|
|
No of patients (males/ females)
|
1356 (920 /436)
|
268 (230 /38)
|
97 (70/27)
|
|
Mean ± SD age at transplantation (years)
|
38.4 ± 13.9
|
50.8 ± 12.8
|
45.2 ± 11.1
|
|
Mean ± SD follow-up time at the end of the study (years)
|
10.7 ± 6.3
|
11.1 ± 3.3
|
9.2 ± 2.3
|
|
(Range)
|
(0.2-25.1)
|
(0.2-19.4)
|
(0.3-16.5)
|
|
No of posttransplant person year
|
14051
|
2787
|
742
|
|
No of censored observations
|
121
|
0
|
0
|
|
Death
|
55
|
1
|
0
|
|
Chronic rejection of the graft
|
66
|
0
|
0
|
|
No of patients with KS
|
35
|
2
|
3
|
|
Incidence rate*
|
2.5
|
0.7
|
4.0
|
|
(95% CI) p = 0.113
|
(2.2-4.4)
|
(0.1-2.8)
|
(1.3-12.5)
|
|
Mean ± SD follow up time at the diagnosis of KS (years)
|
1.5 ± 1.2
|
1.6 ± 1.3
|
0.3 ± 0.2
|
Table 2 Incidence rates and risk factors for Kaposi
sarcoma among renal transplant recipients [Univariate and
multivariate analysis (Cox proportional hazard regression model)]
|
|
|
Univariate analysis
|
Cox proportional hazards regression model
|
|
No of KS/ total patients
|
I.R. (95% CI)
|
Hazard ratio (95% CI)
|
p
|
Hazard ratio (95% CI)
|
p
|
|
Age at transplantation
|
|
|
|
|
|
|
|
< 30 years
|
1/360
|
0.2 (0.0-1.7)
|
1*
|
|
1*
|
|
|
30-50 years
|
11/433
|
2.3 (1.4-4.0)
|
9.0 (3.6-22.5)
|
0.001
|
8.6 (1.1 - 67.5)
|
0.040
|
|
> 50 years
|
23/563
|
5.2 (3.4-8.0)
|
15.6 (7.3-24.6)
|
0.001
|
16.1 (2.2 -119.9)
|
0.007
|
|
Immunosuppressive therapy
|
|
|
|
|
|
|
|
AZA + CYA + PRED
|
9/516
|
1.7 (0.9- 3.4)
|
1*
|
|
1*
|
|
|
AZA + PRED
|
0/87
|
0.0
|
0.0
|
|
0.0
|
|
|
CYA + PRED
|
13/398
|
3.1 (1.8-5.3)
|
2.1 (0.9- 5.0)
|
0.082
|
2.0 (0.9-4.8)
|
|
|
MMF + PRED
|
0/14
|
0.0
|
0.0
|
|
0.0
|
0.106
|
|
MMF + CYA + PRED
|
10/201
|
8.0 (3.8-16.9)
|
3.4 (1.3- 8.6)
|
0.009
|
3.0 (1.2-7.5)
|
0.020
|
|
OTHER drugs
|
3/140
|
3.6 (1.7-7.6)
|
1.2 (0.3- 4.2)
|
0.828
|
0.8 (0.2 -3.0)
|
0.711
|
|
Acute rejections
|
3/109
|
|
0.3 (0.1-1.0)
|
0.064
|
0.4 (0.1-1.4)
|
0.165
|
|
ATG (yes vs. no)
|
2/37
|
|
1.3 (0.8- 2.2)
|
0.274
|
|
|
|
OKT3 (yes vs. no)
|
2/338
|
|
0.6 (0.2- 2.5)
|
0.492
|
|
|
|
Sex
|
|
|
|
|
|
|
|
Female
|
6/436
|
1.7 (0.7-3.4)
|
1*
|
|
1*
|
|
|
Male
|
29/920
|
2.9 (2.1-4.3)
|
2.2 (1.1-4.5)
|
0.054
|
2.0 (0.8-4.6)
|
0.111
|
|
Year of transplantation
|
|
|
|
|
|
|
|
< 1980
|
3/39
|
9.0 (2.3-36.0)
|
1*
|
|
|
|
|
1980-1984
|
0/98
|
0.0
|
0.0
|
|
|
|
|
1985-1989
|
6/205
|
4.6 (2.0-10.2)
|
0.5 (0.1-4.1)
|
0.456
|
|
|
|
1990-1994
|
11/412
|
4.4 (2.4-7.9)
|
0.6 (0.1-4.3)
|
0.687
|
|
|
|
1995-1999
|
13/472
|
4.6 (2.7-8.0)
|
0.6 (0.1-4.2)
|
0.494
|
|
|
|
> 2000
|
2/132
|
2.5 (0.6-10.1)
|
0.4 (0.0-3.8)
|
0.101
|
|
|
|
Transplantation center
|
|
|
|
|
|
|
|
Verona
|
5/260
|
1.5 (0.6-3.5)
|
1*
|
|
|
|
|
Bergamo
|
18/610
|
3.9 (2.5-6.1)
|
0.7 (0.3 -1. 7)
|
0.566
|
|
|
|
Padova
|
2/180
|
0.9 (0.2-3.7)
|
1.7 (0.5 -5. 9)
|
0.393
|
|
|
|
Roma
|
10/306
|
2.6 (1.5-5.1)
|
0.9 (0.3 -2. 7)
|
0.394
|
|
|
|
Place of birth and living
|
|
|
|
|
|
|
|
Northern Italy
|
21/775
|
5.0 (3.3-7.6)
|
1*
|
|
|
|
|
Central Italy
|
5/292
|
3.3 (1.2 - 8.8)
|
1.2 (0.3- 4.2)
|
0.74
|
|
|
|
Southern Italy
|
9/289
|
10.3 (5.3- 19.9)
|
0.8 (0.2- 4.0)
|
0.78
|
|
|
Discussion
In our group of RTR, incidence rate of KS was 2.5 cases per 1000
person-year, after a mean follow up time of 1.5 years. This rate
was higher than expected in the general population. Incidence rates
of KS in the whole Italian population during the time period of our
study, were 2.4 cases per 100,000 person/year in males and 0.7
cases per 100,000 person/year in females [11]. Therefore, a 100
times higher risk for KS can be calculated for RTR. The excess risk
was higher in females. Incidence rate was higher in the first two
years and decreased markedly thereafter. Age at transplantation
older than 30 years and only combined immunosuppressive therapy
with MMF + CYA + PRED, were both independent risk factors for KS.
The prevalence of KS among solid organ transplant recipients varies
greatly with the geographic region. Three studies from the United
Kingdom, the Netherlands and France reported prevalence of KS among
organ transplant recipients varying from 0% to 0.52% [12-14]. In
the Mediterranean area, KS was diagnosed only in 1.7% of 1055 Greek
RTR and in only 0.49% of 1230 Spanish RTR [15, 16]. Percentages up
to 5.3% were reported in Saudi Arabia [1]. The North Italian
Transplant Program, described KS in 1.11% of RTR and in 0.84% of
heart transplant recipients [17-19] In a recent study, Serraino
observed KS in 1.2% of RTR. KS was nearly six times more frequent
in patients from Southern Italy, as compared to those from Northern
Italy, probably in relation to the different epidemiology of HHV-8
infection [20]. These data are in contrast with our findings, but
in our study, the majority of patients were from Northern and
Central Italy (table 2). As reported by Serraino, [20] we also
detected an excess risk of KS in female RTR. There is no definitive
explanation for this observation but it is possibly related to the
low incidence of KS in nonimmunosuppressed women. KS was a
relatively early appearing tumor, with most of the patients
developing KS within the first two years after transplantation,
confirming previous findings in other populations [2, 3]. In the
Cincinnati Transplant Tumour Registry, 46% of the tumours appeared
within one year of transplantation [2]. In the first year following
the transplant, the incidence of KS can be 4.5-fold more frequent
than after four or more years [20]. There is no definitive
explanation for this observation, but the progressive reduction in
the dosage of immunosuppressive drugs may have a role. As
previously reported, age at transplantation older than 30 years
appeared as the strongest independent risk factor for KS [20]. KS
has complicated the use of all immunosuppressive agents, including
the more recently introduced compounds, MMF and tacrolimus. In our
study, the combined immunosuppressive therapy with MMF + CYA + PRED
was an independent risk factor for KS. As reported in the
Cincinnati Transplant Tumour Registry, up to 90% of the patients
with KS had previously received CYA-based regimens [2]. In a
historical Italian retrospective study, CYA-treated patients
demonstrated a higher incidence of KS in comparison with AZA-based
immunosuppression [21]. A higher incidence of lymphomas and other
tumours, including KS, with unusually aggressive phenotypes has
been correlated with CYA immunosuppression [22-24]. CYA has been
reported to have also a proangiogenic activity, direct tumor
promoting effects and to reduce DNA repair ability [23, 24]. In a
clinical study, a maintenance immunosuppressive regimen with low
doses of CYA was associated with fewer malignant disorders but more
frequent rejections; in contrast normal dosage of CYA yielded less
rejection but a higher incidence of cancer [25]. In a recent study,
transplant recipients receiving CYA had an increased risk of KS
after the switch from the old formulation to a new microemulsion
formulation characterized by a higher bioavailability [26].
Conflicting reports exist about the risk associated with MMF. In
three randomized double-blinded multicenter trials no increased
incidence of KS was observed at 6 or 12 months after
transplantation in patients receiving MMF when compared to standard
immunosuppression [27-32]. However, the statistical power of these
studies was limited to detect an increased tumor risk. A
prospective observational study cohort from the United Network for
Organ Sharing (USA) and Collaborative Transplant Study (Europe),
and a review of 35,000 kidney transplantations in the USA showed
that MMF was not independently associated with post-transplant
lymphoproliferative disorders and other cancers [33, 34]. However,
in all these studies KS occurrence was not the primary outcome.
Conversely, in a cohort of 1835 renal transplant recipients, the
onset of KS was reported in 0.81% of 371 patients treated with a
MMF-based therapy and in 0.14% of 1464 patients treated with an
MMF-free protocol. KS became evident 7 ± 2 months after initiation
of MMF therapy [3]. The occurrence of a KS more than five years
after transplantation, after replacing CYA with MMF has been
reported [35]. Our study provided limited data about tacrolimus.
Recent experimental studies demonstrate a higher proliferation rate
of human hepatoma cells in the presence of tacrolimus [36]. After
liver transplantation, patients on either tacrolimus or CYA based
immunosuppression showed a similar increase in tumor incidence
[24]. It is thus plausible to assume that the degree of
immunosuppression by itself rather than the specific agents adopted
may be responsible for the development of KS. Unfortunately, we
were unable to collect information on the cumulative dosage of
immunosuppressive drugs in our patients.
The complete regression of KS after stopping cyclosporine and
replacing it with rapamycin has been reported [37]. Rapamycin has
an antineoplastic action due to its anti-angiogenic effect, which
is independent of its immunosuppressive activity [37]. We did not
investigate the role of rapamycin in our study because only a few
of our patients received this drug.
HHV-8 has been associated with all the forms of KS (classic, HIV
related and iatrogenic). HHV-8 reactivation as a result of
immunosuppressive treatment is probably the most relevant mechanism
involved, but primary infection transmitted via organ
transplantation has been also reported [1, 38]. Unfortunately, we
could not obtain data about HHV-8 seroprevalence or actual presence
of HHV-8 in KS lesions, as many patients had been transplanted
before 1994, a time when no serologic assays of donors and
recipients for HHV8 were available.
In conclusion, our findings confirm that organ transplant
recipients in Italy are at high risk for KS, especially during the
first two years after transplantation. Careful monitoring of
transplant patients is therefore warranted. Further studies on
larger multi-center cohorts should investigate the role of new
immunosuppressive drugs taking into account cumulative dosage and
interaction with other risk factors, i.e., viruses.
Acknowledgements
We gratefully acknowledge Dr. Diego Serraino from the Spallanzani
Institute (Roma, Italy) for providing incidence rates of KS in
Italy. This study was supported by a grant from the Banca Popolare
di Verona e Novara, Verona, Italy.
References
1 Bécuwe C, Euvrard S, Bosshard S, et al.
Maladie de Kaposi et transplantation d’organes: 22 cas. Ann
Dermatol Venereol 2005; 132: 839-43.
2 Penn I. Kaposi’s sarcoma in transplant recipients.
Transplantation 1997; 64: 669-73.
3 Eberhard OK, Kliem V, Brunkhors R. Five cases
of Kaposi’s sarcoma in kidney graft recipients: possible influence
of the immunosuppressive therapy. Transplantation 1999; 67:
180-4.
4 Ensoli B, Sgadari C, Barillari G,
Sirianni MC, Sturzl M, Monini P. Biology of Kaposi’s
Sarcoma. Eur J Cancer 2001; 37: 1251-69.
5 Iscovich J, Boffetta P, Franceschi S,
Azizi E, Sarid R. Classic Kaposi’s sarcoma. Epidemiology
and risk factors. Cancer 2000; 88: 500-17.
6 Geraminejad P, Memar O, Aronson I,
Rady PL, Hengge U, Tyring SK. Kaposi’s sarcoma and
other manifestations of human herpesvirus 8. J Am Acad Dermatol
2002; 47: 641-55.
7 Deborska D, Durlik M, Sadowska A, et al.
Human herpesivirus 6 in renal transplant recipients: potential risk
factors for the development of human herpesvirus 6 serconversion.
Transpl Proc 2003; 35: 2199-201.
8 Ablashi DV, Chatlynne LG, Whitman JE,
Cesarman E. Spectrum of Kaposi’s sarcoma-associated
herpesvirus, or human herpesvirus-8, diseases. Clin Microbiol Rev
2002; 15: 439-64.
9 Deng MC. Cardiac transplantation. Heart 2002; 87:
177-84.
10 Armitage P, Berry G. The planning of statistical
investigations. In: Armitage P, Berry G, eds. Statistical
Methods in Medical Research. 4th ed. Oxford: Blackwell
Scientific Publications, 1994: 175-85.
11 Parkin DM, Whelan SL, Ferlay J. Cancer
incidence in five continents. Vol. VII Lyon, France. IARC Sci Publ
1997; 143: 1028.
12 London NJ, Farmery SM, Will EJ,
Davison AM, Lodge JP. Risk of neoplasia in renal
transplant recipients. Lancet 1995; 346: 403.
13 Marsman WA, Van Gelder T, Mulder AH,
Ijzermans NM, Zietse R, Weimar W. Succesful
treatment of Kaposi’s sarcoma in a renal allograft recipient.
Nephrol Dial Transplant 1995; 10: 900-1.
14 Farge D. Kaposi’s sarcoma in organ transplant
recipients. The Collaborative Transplantation Research Group of Ile
de France. Eur J Med 1993; 2: 339-43.
15 Mitxelena J, Gomez-Ullate P, Aguirre A,
Rubio G, Lampreabe I, Díaz-Pérez JL. Kaposi’s
sarcoma in renal transplant patients: experience at the Cruces
Hospital in Bilbao. Int J Dermatol 2003; 42: 18-22.
16 Zavos G, Bokos J, Papaconstantinou I,
et al. Clinicopathological aspects of 18 Kaposi’s sarcoma
among 1055 Greek renal transplant recipients. Artif Organs 2004;
28: 595-9.
17 Pedotti P, Cardillo M, Rossini G, et al.
Incidence of cancer after kidney transplant: results from the North
Italy transplant program. Transplantation 2003; 76: 1448-51.
18 Cardillo M, Rossini G, Scalamogna M,
et al. Tumor incidence in heart transplant patients: Report of
the North Italy Transplant Program Registry. Transplant Proc 2001;
33: 1840-3.
19 Lesnoni La Parola I, Masini C, Nanni G,
Diociauti A, Panocchia N, Cerimele D. Kaposi’s
sarcoma in renal transplant recipients: experience at the Catholic
University in Rome, 1988-1996. Dermatology 1997; 194: 229-33.
20 Serraino D, Piselli P, Angeletti C,
et al. Risk of Kaposi’s sarcoma and of other cancers in
Italian renal transplant patients. Br J Cancer 2005; 92: 572-5.
21 Montagnino G, Lorca E, Tarantino A,
et al. Cancer incidence in 854 kidney transplant recipients
from a single institution: comparison with normal population and
with patients under dialytic treatment. Clin Transplant 1996; 10:
461-9.
22 Masuhara M, Ogasawara H, Katyal SL,
Nakamura T, Shinozuka H. Cyclosporine stimulates
hepatocyte proliferation and accelerates development of
hepatocellular carcinomas in rats. Carcinogenesis 1993; 14:
1579-84.
23 Guba M, von Breitenbuch P, Steinbauer M,
et al. Rapamycin inhibits primary and metastatic tumor growth
by antiangiogenesis: involvement of vascular endothelial growth
factor. Nat Med 2002; 8: 128-35.
24 Guba M, Graeb C, Jauch KW, Geissler EK.
Pro- and anti-cancer effects of immunosuppressive agents used in
organ transplantation. Transplantation 2004; 27: 1777-82.
25 Maisonneuve P, Agodoa L, Gellert R,
et al. Cancer in patients on dialysis for end-stage renal
disease: an international collaborative study. Lancet 1999; 354:
93-9.
26 Cattaneo D, Gotti E, Perico N,
Bertolini G, Kaiser G, Remuzzi G. Cyclosporine
formulation and Kaposi’s sarcoma after renal transplantation.
Transplantation 2005; 80: 743-8.
27 Farge D, Lebbè C, Marjanovic Z, et al.
Human Herpes virus-8 and other risk factors for Kaposi’s sarcoma in
kidney transplant recipients. Groupe Cooperatif de Transplantation
d’Ile de France (GCIF). Transplantation 1999; 67: 1236-42.
28 European mycophenolate mofetil Cooperative Study Group.
Placebo controlled study of mycophenolate mofetil combined with
cyclosporine and corticosteroids for prevention of acute rejection.
Lancet 1995; 345: 1321-5.
29 Sollinger HW. A blinded randomized clinical trial of
mycophenolate mofetil for the prevention of acute rejection in
primary cadaveric renal allograft recipients. US renal transplant
Mycophenolate Mofetil study group. Transplantation 1995; 60:
225-32.
30 The tricontinental mycophenolate mofetil study group. A
blinded randomized clinical trial of mycophenolate mofetil for the
prevention of acute rejection in cadaveric renal transplantation.
Transplantation 1996; 61: 1029-37.
31 Zhang WK, Wei Li YQ, Yang Y, Lu Y. Safety
of mycophenolate mofetil versus azathioprine in renal
transplantation. A systematic review. Transplant Proc 2004; 36:
2068-70.
32 Vanrenterghem Y, van Hooff JP, Squifflet JP,
et al. European Tacrolimus/MMF Renal Transplantation Study
Group. Minimization of immunosuppressive therapy after renal
transplantation: results of a randomized controlled trial. Am J
Transplant 2005; 5: 87-95.
33 Kasiske BL, Synder JJ, Gilbertson DT,
Wang C. Cancer after kidney transplantation in the United
States. Am J Transplant 2004; 4: 905-13.
34 Gomez E, Aguado S, Rodriguez M, Alvarez
Grande J. Kaposi’s sarcoma after renal transplantation –
disappearance after reduction of immunosuppression and reappearance
7 years later after start of mycophenolate mofetil treatment.
Nephrol Dial Transplant 1998; 13: 3279-80.
35 Silva SL, Silva SF, Cavalcante RO, et al.
Mycophenolate mofetil attenuates Walker’s tumor growth when used
alone, but the effect is lost when associated with cyclosporine.
Transplant Proc 2004; 36: 1004-6.
36 Andreoni M, Goletti D, Pezzotti P, et al.
Prevalence, incidence and correlates of HHV-8/KSHV infection and
Kaposi’s sarcoma in renal and liver transplant recipients. J Infect
2001; 43: 195-9.
37 Stallone G, Schena A, Infante B, et al.
Sirolimus for Kaposi’s Sacroma in renal transplant recipients. N
Engl J Med 2005; 352: 1317-23.
38 Marcelin AG, Roque-Afonso AM, Hurtova M,
et al. Fatal disseminated Kaposi’s sarcoma following human
Herpesvirus 8 primary infections in liver-transplant recipients.
Liver Transpl 2004; 10: 295-300.
|
Version imprimable
Version PDF
