Ann Thorac Surg 2002;74:1979-1985
© 2002 The Society of Thoracic Surgeons
Original article: cardiovascular
Total lymphoid irradiation for refractory rejection in pediatric heart transplantation
Miki Asano, MDa,
Steven R. Gundry, MDa,
Anees J. Razzouk, MDa,
Michael J. del Rio, MDa,
Melanie Thomas, CCTCa,
Richard E. Chinnock, MDb,
Leonard L. Bailey, MDa* Pediatric Heart Transplantation Group
a Department of Surgery Loma Linda, California, USA
b Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California, USA
Accepted for publication July 9, 2002.
* Address reprint requests to Dr Bailey, Department of Surgery, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
e-mail: llbailey{at}som.llu.edu
 |
Abstract
|
|---|
BACKGROUND: We evaluated the role of total lymphoid irradiation (TLI) in the management of refractory rejection among pediatric heart transplant patients.
METHODS: Eleven of 298 patients underwent TLI at 6 to 195 months of age and were divided into subgroups: those who survived (group A, n = 7) and those who did not survive beyond 1 year after TLI (group D, n = 4). Non–TLI recipient data were considered as the controls.
RESULTS: Six out of 11 patients died eventually (54%). TLI was initiated 3 to 107 months after transplantation with a dosage of 600 to 840 cGy. The pre-TLI rejection rate (0.62 ± 0.40 per month) was higher (p < 0.0001); however, the post-TLI rejection rate (0.24 ± 0.65 per month) showed no significant difference from the control rejection rate. The Cox proportional hazard model found significance for TLI as a risk factor for development of posttransplant coronary artery disease (relative risk, 4.8; 95% CI, 1.1 to 21.3) and posttransplant lymphoproliferative disease (relative risk, 47.9; 95% CI, 1.6 to 1,475.3), respectively. Although the rejection rate decreased after TLI in both groups (group A pre/post, 0.51 ± 0.31/0.06 ± 0.08 per month; group D pre/post, 0.82 ± 0.49/0.57 ± 1.09 per month), significance was obtained only in group A (p = 0.018).
CONCLUSIONS: TLI was an effective adjunct for reversal of refractory rejection in pediatric heart transplantation by reducing the rejection rate. Great care must be taken for the risk of development of coronary artery disease or lymphoproliferative disease.
|
Introduction
|
|---|
Recurrent of intractable rejection that does not respond to the usual rescue therapies of methylepredonisolone and antithymocyte serum poses a serious problem for heart transplant recipients. They may develop irreversible allograft dysfunction and they are prone to develop coronary artery disease [1, 2]. Especially among pediatric recipients, repetitive steroid treatments increase the risk of delayed bone growth, adrenal suppression, and an increased susceptibility to infection. Modalities such as cytolytic therapy with antithymocyte globulin, monoclonal anti-CD3 antibody, methotrexate, and total lymphoid irradiation (TLI) have proven to be efficacious for recalcitrant rejections [3–6]. Cytolytic therapies may reverse acute cellular rejection in difficult patients, only to have them experience rebound rejection. Moreover, anti-CD3 antibody may increase the risk of lymphoproliferative disorders. A comparative study by Ross and associates indicated that methotrexate and TLI were both effective for recurrent or persistent rejection, reducing the endomyocardial biopsy grade and maintenance steroid dosage among adult recipients [4]. None of these modalities should be mutually exclusive, because of their different potential benefits and side effects. TLI is an effective adjunct therapy in adult patients; however, the use of TLI remains somewhat controversial for pediatric cases [7]. TLI has been selected and employed carefully after attempting virtually every other therapy available at our institution. This study aims to evaluate the role and safety of TLI in the management of refractory rejection among pediatric recipients, including those less than 12 months old.
|
Patients and methods
|
|---|
Patients
Among 298 patients who underwent 311 orthotopic heart transplantations at Loma Linda University Children’s Hospital from May 1, 1988 to September 30, 1997, 11 patients (3.7%) received TLI treatment for recurrent or intractable rejection. There were 8 male and 3 female patients ranging in age from 6 to 195 (mean 97.5 ± 71.0) months. Three patients less than 12 months old were included. The patients were also divided into two subgroups for further evaluation: group A, who survived more than 1 year after TLI (n = 7), and group D, who died or lost the graft less than 1 year after TLI (n = 4). Some variables of TLI recipients were compared with those of all other recipients who underwent transplantation at our institution in the same period (286 of 287 recipients). The follow-up was completed in August 2000.
Standard maintenance antirejection therapy consisted of cyclosporine (10 to 20 mg/kg/day) and azathioprine (1 to 3 mg/kg/day, maintaining a white blood cell count of more than 4,000/mL). Immunosuppression was maintained at higher levels for patients with a difficult rejection course, including long-term methotrexate in place of azathioprine. Rescue therapy for acute cellular rejection consists of methylprednisolone (20 to 25 mg/kg IV every 12 hours for eight doses), methotrexate (10 mg/m2/week as a single- or three-dose regimen every 12 hours once or three times per week), or antithymocyte globulin (15 mg/kg/day for 7 to 10 days). Methotrexate was utilized for the following indications: (1) multiple rejection episodes requiring repeated dosing with steroids (ie, more than two courses within 2 months) or failure to respond to at least one or more courses of antithymocyte globulin; (2) a single severely symptomatic rejection with no signs of improvement, or continued aggravation despite at least 3 or 4 days of combination steroid and antithymocyte globulin treatment; and (3) symptomatic rejection untreatable by antithymocyte globulin because of sensitization after previous antithymocyte globulin therapy. FK506 (drug target level was 8 to 10 ng/mL) was used for maintenance in place of cyclosporine for recalcitrant rejection.
Total lymphoid irradiation
Indications for use of TLI among pediatric heart transplant patients included: (1) recipient of a primary cardiac graft; (2) recurrent or persistent graft rejection confirmed with endomyocardial biopsy (3A or greater according to the International Society for Heart and Lung Transplantation grade [8]); (3) previous rescue therapy using polyclonal antibodies or inability to reuse cytolytic therapy because of recipient sensitization; and (4) maximal maintenance immunosuppression. Recipients with posttransplant lymphoproliferative disease and previous radiation were excluded from TLI use. The target dose of TLI was 800 cGy, and 80 cGy was given twice a week for 5 weeks. Before and during TLI, blood was sampled twice weekly for the leukocyte and platelet count. TLI was postponed or suspended if the absolute leukocyte count was less than 2,000/mL or the platelet count was less than 100,000/mL. Patients received maintenance immunosuppressive therapy during TLI. Additional immunoregulative agents were used if needed. The protocol for administration of TLI was similar to that of the Stanford Group [9]. Patients were treated in the supine position utilizing cobalt-60 photon irradiation of AP-PA fields calculated to mid-plane utilizing customized cerrobend casting, which resulted in irradiation of nodal areas in the neck, supraclavicular fossa, axillae, periaortics, pelvic, and classic mantle field.
Definition
Rejection episodes were diagnosed and treated with rescue therapy based upon clinical symptoms, echocardiography, and endomyocardial biopsy, defined as 3A or greater. Infection episodes were defined by the need for intravenous antimicrobial therapy. Pre/post-TLI rejection rate and infection rate represent the number of treated cellular rejection and infection episodes before and after TLI divided by the follow-up period (months) from transplantation to TLI and from TLI, respectively. Biopsy score represents the sum of the numerical assignments given to International Society for Heart and Lung Transplantation grade on the biopsy specimens (grade 0 = 0, 1A = 1, 1B = 2, 2 = 3, 3A = 4, 3B = 5, 4 = 6), divided by the number of biopsies [4].
Statistical analysis
All results are presented as means ± standard deviation. Continuous variables were compared by use of nonparametric tests. A Mann-Whitney U test was used to compare continuous variables in unpaired comparison, such as between TLI group and control and between subgroups. A Wilcoxon signed-rank test was used to compare continuous variables in paired comparison (eg, between pre- and post-TLI values in one group). Nominal variables were compared by Fisher’s exact probability test. Actuarial survival curves by the Kaplan-Meier method were compared by use of log-rank analysis. The Cox proportional hazards model was used for the posttransplant coronary artery disease or posttransplant lymphoproliferative disease risk analysis of time to the date of diagnosis to evaluate the impact of TLI. Time zero was the date of transplantation in control cases. Therefore, TLI was the time-related covariable and time zero was the date of TLI in TLI recipients. The proportional hazards model was approved in this condition. The relative risk of occurrence of posttransplant coronary artery disease or posttransplant lymphoproliferative disease was calculated with 95% confidence intervals. All statistical analyses were performed by StatView 5.0 for Macintosh edition (SAS Institute Inc., Cary, NC). Ap value < 0.05 was considered significant.
|
Results
|
|---|
Profile of recipients receiving TLI
The 11 recipients managed with TLI are profiled in Table 1.
TLI was initiated a mean 24.0 ± 32.8 (range 3 to 107) months after transplantation, and the mean follow-up period after TLI was 32.6 ± 27.2 (range 0.3 to 78) months. The mean dose of 775 ± 68 (range 600 to 840) cGy was administered during a mean 33 ± 5 calendar days, and the target dose was completed in 8 patients (73%). The period in which recipients remained free from rejection (biopsy grade 0 or 1A) after TLI was a mean 306 ± 296 (range 0 to 960) days, and 3 patients experienced no subsequent rejection.
Patient 3 did not receive a final TLI treatment because of a pulmonary infection. The TLI target dose for patient 4 was 600 cGy (60 cGy, twice weekly for 5 weeks) from the beginning. Leukopenia was observed in patient 7 (WBC, 1,600/mL; platelets, 146,000/mL) during TLI, and one treatment was withheld. During TLI, no patients experienced body weight loss, gastrointestinal tract complications, or radiation dermatitis.
All patients received methotrexate and cytolytic therapy intravenously at least once before TLI was administered. Patients 6, 7, 9, and 11 also received one treatment course of monoclonal anti-CD3 antibody. After TLI, at least one course of methotrexate therapy was employed in 8 patients (73%), including 2 survivors (Nos. 10 and 11), and one course of cytolytic therapy in 4 (Nos. 1, 2, 6, and 7) (36%), including 1 survivor.
Patient 1 suffered on-going rejection during TLI, and pathological examination of the graft at autopsy showed mild acute cellular rejection. He was supported by use of a left ventricular assist device for several days, and the diagnosis directly related to mortality was acute graft failure. Patient 2 died of moderately severe rejection with coronary artery disease (grade 2-A) proved by autopsy in pathological findings. Patient 4 showed moderate cellular rejection with patchy myocardial infarction due to exten-sive coronary vasculitis (nonocclusive fibromuscular intimal proliferation and focal occlusive coronary arteries). One patient (No. 3) died of B cell lymphoma 4 months after TLI without any further rejection episode, and 1 (No. 5) died of severe toxic epidermal necrolysis 24 months after TLI. Four patients showed posttransplant coronary artery disease at autopsy. One of the survivors (No. 7) underwent retransplantation due to severe coronary artery lesions 8 months after TLI. This patient experienced a rejection rate of 0.108 before TLI and 0.125 between completion of TLI and retransplantation. After retransplantation, the rejection frequency was 0.068. The biopsy score was changed from 2.2 to 0.75 and 1.05 after TLI and retransplantation, respectively. He is still alive and well.
Clinical characteristics of non-TLI recipients and TLI recipients
Rejection rate and biopsy scores fell from 0.62 ± 0.40 and 2.13 ± 1.09 to 0.24 ± 0.65 and 0.74 ± 1.23 (p = 0.0453, 0.0124) after TLI, respectively. The infection rate changed from 0.09 ± 0.12 to 0.38 ± 0.69 (p = 0.2604) after TLI. Total rejection and infection rates of the control group were 0.14 ± 0.38 and 0.18 ± 0.85, respectively. The pre-TLI rejection rate was remarkably higher than among recipients in the control group (p < 0.0001). No important differences were observed between the TLI and non-TLI groups in four other variables. The time to first rejection tended to be earlier in TLI recipients (non-TLI, 5.6 ± 14.7 months; TLI, 0.7 ± 0.8 months) (Table 2).
Actuarial survival 1, 3, and 5 years after transplantation was 72.7%, 62.3%, and 37.4% among TLI recipients, and 85.3%, 78.3%, and 74.4% among controls, respectively (p = 0.025; 95% CI, 1.1 to 5.9) (Fig 1).
View larger version (14K):
[in this window]
[in a new window]
|
Fig 1. Actuarial graft survival of total lymphoid irradiation (TLI) recipients (n = 11) and non-TLI recipients (n = 287) after initial heart transplantation. The 1-, 3-, and 5-year actuarial graft survival rates were 72.7%, 62.3%, and 37.4% among TLI recipients and 85.3%, 78.3%, and 74.4% among non-TLI recipients, respectively (p = 0.025; 95% CI, 1.1 to 5.9).
|
|
Posttransplant coronary artery disease or lymphoproliferative disease risk analysis for TLI
Posttransplant coronary artery disease (more than grade 3) was observed among 5 TLI recipients (45.5%), in 4 of whom the diagnosis was made or confirmed at autopsy. Among controls, posttransplant coronary artery disease was documented by angiography, graft explant, or at autopsy in 35 recipients (12.2%). The multivariable hazards model found TLI to be a significant risk factor for development of coronary lesions (relative risk, 4.8; 95% CI, 1.08 to 21.33). The relative risk was 1.12 for each rejection episode. Cytomegalovirus infection also increased the risk remarkably by 2.48 (Table 3).
The malignancy developed after TLI in 1 recipient (9.1%) was B cell lymphoma. Among controls, 13 recipients developed posttransplant lymphoproliferative disease, and 1 recipient developed a solid cancer (4.9%). An analysis limited to the occurrence of posttransplant lymphoproliferative disease also found TLI to be a significant isolated contributing factor (relative risk, 47.93; 95% CI, 1.56 to 1,475.29). A history of Epstein-Barr virus infection increased the risk of lymphoproliferative disease by 19.16 (Table 4).
Clinical characteristics of TLI subgroups A and D
Among TLI recipients, no statistical differences were found in the average time from transplantation to TLI, the age at transplantation, and the age at TLI. Group D showed earlier first rejections, but no significant difference existed (group A, 0.57 ± 0.31 group D, 0.39 ± 0.16). Although the rate of rejection and biopsy scores decreased after TLI in both groups, statistical significance was obtained only in group A (group A pre/post, 0.51 ± 0.31/0.06 ± 0.08, p = 0.018; 1.843 ± 1.071/0.471 ± 0.695, p = 0.0273 group D pre/post, 0.82 ± 0.49/0.57 ± 1.09, p = 0.5807; 2.800 ± 0.909/1.200 ± 1.904, p = 0.1441). Post-TLI rejection rate of group D could not be reduced even below the level of pre-TLI rejection rate of group A. Furthermore, the rejection-free period after TLI described in Table 1 was at least over 1 year in all seven group A recipients. On the contrary, all but 1 group D patient, who died of B-cell lymphoma 4 months after TLI, experienced rejection ranging from 0 to 8 months after TLI. Only one rescue case was immediately retransplanted after the first rejection post-TLI.
There was a tendency for the infection rate to increase after TLI in both groups (group A pre/post, 0.06 ± 0.10/0.15 ± 0.24, p = 0.3452; group D pre/post, 0.14 ± 0.15/0.80 ± 1.05; p = 0.4631). The high group D infection rate indicated that stronger immunosuppression would be needed to manage more severe rejections, and would also result in infection vulnerability in either the pre- or post-TLI condition. Moreover, poor cardiac function induced by severe rejection resulting in circulatory distress also made recipients more susceptible to infection. Converting from cyclosporine to FK506 just before or immediately after TLI did not impact survival (Table 5).
|
Comment
|
|---|
TLI may induce donor-specific tolerance by suppressing T-cell function, especially suppression of the interleukin-2 pathway, and number of activated T cells [10]. Donor-specific tolerance after cadaveric kidney transplantation preceded by TLI has been reported [7, 13]. Moreover, TLI in conjunction with cytolytic therapy or bone marrow transfusion has led to donor-specific tolerance through establishment of chimerism [11, 12]. Considering that some recipients reported here received at least one course of cytolytic therapy before TLI, they may have developed a degree of donor-specific tolerance. Seven recipients among 11 (63.6%) are completely free from rejection more than 1 year after TLI. The longest one has been free of rejection for more than 5 years. The development of chimerism is possibly one reason for the prolonged freedom from allograft rejection. Unfortunately, we have not established the existence of allogeneic microchimerism or donor-specific hyporeactivity.
The adverse effect of TLI in the short term is myelosuppression. Leukopenia, thrombocytopenia, or both begin within 1 week after TLI, reach a nadir by 3 to 5 weeks, and persist for more than 1 month [7]. A single TLI treatment was temporarily withheld from 1 recipient, who experienced transient leukopenia. This recipient ultimately completed the target dose within 36 calendar days. TLI was employed safely even in small children (<12 months old) without distressing myelosuppression. In addition, the availability of granulocyte colony-stimulating factor can minimize the risk of severe leukopenia of TLI.
Thyroid dysfunction is a major concern when utilizing TLI during childhood. Indeed, 25% of patients, who received bone marrow transplantation in conjunction with TLI reportedly developed compensated hypothyroidism during long-term follow-up [16]. Thyroid dysfunction after TLI has not as yet been observed in the present patient cohort.
The infection rate increased after TLI, but no important differences were observed between the pre- and post-TLI values or between the TLI group and controls. All classes of serum immunoglobulins were maintained in the normal range despite TLI, and this may protect against infection [17]. Only one lethal infection developed in a recipient 24 months after TLI. It is difficult to implicate TLI in this infection because the child’s infection vulnerability was affected by a variety of other types of immunosuppressant therapy. Logically, recipients who require TLI in conjunction with a variety of other immunosuppressive strategies are at increased risk for infection complications, and require careful, long-term surveillance.
Although TLI may exert a protective effect on graft coronary artery endothelium among adult recipients, the response of graft endothelium remains unknown among children [5]. Intracranial vessel vasculopathy after radiation therapy has involved mainly pediatric patients, and vessel injury has correlated with radiation dose (over 50 Gy) and age at radiation (under 4 years) [18, 19]. Among this present cohort of pediatric recipients, TLI was found to be a significant risk factor for development of posttransplant coronary artery disease. Two of 4 recipients who showed coronary artery disease were less than 1 year old at TLI. Three recipients experienced a cytomegaloviral infection. However, because the total dose of irradiation was not high, the synergistic influence of TLI and cytomegaloviral infection may have induced posttransplant coronary artery disease early in the post-TLI phase. Moreover, an age of less than 1 year at TLI may affect the posttransplant coronary artery disease.
One TLI recipient who eventually died of B-cell lymphoma with an intracranial tumor showed the seroconversion of Epstein-Barr virus during the TLI treatment. She also had received two courses of antithymocyte globulin before TLI. Epstein-Barr viral infection or multiple courses of antithymocyte globulin therapy have been reported to increase the risk of lymphoma. Radiation-induced malignancy is dose related, with more than 30 Gy increasing the risk of some secondary malignancies in children [20]. Yet, even this relatively low dose of TLI was found to pose a significant risk of lymphoproliferative disease among this cohort. Pediatric TLI recipients are especially vulnerable to posttransplant lymphoproliferative disease due to their immuno-compromised condition associated with preceding Epstein-Barr viral infection.
The efficacy of TLI could be evaluated especially by the time of the first rejection after TLI and the reduction of the rejection rate. Seven recipients who survived at least more than 1 year after TLI were free from rejection over 1 year post-TLI, and also showed a lower post-TLI rejection rate than the non-TLI recipients. If the first rejection difficult to be managed occurs within 1 year after TLI, retransplantation should be scheduled immediately as a rescue therapy.
In addition, the time of the first rejection after initial transplantation (borderline 0.38 to 0.57 months), pre-TLI rejection rate (borderline 0.5 to 0.8/month), and pre-TLI biopsy score (borderline 1.8 to 2.8) may be better predictors for selecting candidates for TLI.
Conclusions
TLI is an effective adjunct for the management of refractory rejection among recipients in the pediatric heart transplantation population. It reduces the rejection rate and the biopsy score by inducing donor-specific tolerance. However, the risk of posttransplant coronary artery disease or lymphoproliferative disease increase after TLI. Patient prognosis after TLI appears to depend on the time of the first post-TLI rejection and the reduction of the rejection rate between pre-TLI and post-TLI [14,15].
|
Acknowledgments
|
|---|
We thank James Fitts and Joyce Johnston for their help in gathering the data for this analysis.
|
References
|
|---|
- Costanzo-Nordin M. Cardiac allograft vasculopathy: relationship with acute cellular rejection and histocompatibility. J Heart Lung Transplant 1992;11:S90-103.[Medline]
- Pahl E., Zales V.R., Fricker J., Addonizio L.J. Posttransplant coronary artery disease in children: a multicenter national survey. Circulation 1994;90:56-60.
- Swinnen L., Costanzo-Nordin M., Fisher S., et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac transplant recipients. N Engl J Med 1990;323:1723-1728.[Abstract]
- Ross H.J., Gullestad L., Park J., Slauson S., Valantine H.A., Hunt S.A. Methotrexate or total lymphoid radiation for treatment of persistent or recurrent allograft cellular rejection: a comparative study. J Heart Lung Transplant 1997;16:179-189.[Medline]
- Keogh A., Morgan G., Macdonald P., Spratt P., Mundy J., McCosker C. Total lymphoid irradiation for resistant rejection after heart transplantation: only moderate success medium-term. J Heart Lung Transplant 1996;15:231-233.[Medline]
- Trachiotis G.D., Johnston T.S., Vega J.D., et al. Single-field total lymphoid irradiation in the treatment of refractory rejection after heart transplantation. J Heart Lung Transplant 1998;17:1045-1048.[Medline]
- Kirklin J.K., George J.F., McGiffin D.C., Naftel D.C., Salter M.M., Bourge R.C. Total lymphoid irradiation: is there a role in pediatric heart transplantation?. J Heart Lung Transplant 1993;12:S293-300.[Medline]
- Billingham M., Cary N., Hammond E., et al. A working formulation for the standardization of nomenclature in diagnosis of heart and lung rejection: Heart Rejection Study Group. J Heart Transplant 1990;9:587-593.[Medline]
- Hunt S.A., Strober S., Hopper R.T., Stinson E.B. Total lymphoid irradiation for treatment of intractable cardiac allograft rejection. J Heart Lung Transplant 1991;10:211-216.[Medline]
- Halperin E.C., Bollinger R.R. The role of irradiation in solid organ transplantation. Int J Radiat Oncol Biol Phys 1988;15:979-988.[Medline]
- Levin B., Collins G., Waer M., et al. Treatment of cadaveric renal transplant recipients with total lymphoid irradiation, antithymocyte globulin, and low-dose prednisone. Lancet 1985;2:1321-1325.[Medline]
- Sharabi Y., Sachs D.H. Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen. J Exp Med 1989;169:493-502.[Abstract/Free Full Text]
- Saper V., Chow E.D., Engleman R.T., et al. Clinical and immunological studies of cadaveric renal transplant recipients given total lymphoid irradiation and maintained low dose predonisone. Transplantation 1988;45:540-546.[Medline]
- Yamaoka K, Kim KM, Ishigami T, et al. Cyclosporin A and FK506 block the negative signaling mediated by surface IgM cross-linking in normal human mature B cells. Immunol Lett 1993;36:203
- Goldfeld AE, Flemington EK, Boussiotis VA, et al. Transcription of the tumor necrosis factor alpha gene is rapidly induced by antiimmunoglobulin and blocked by cyclosporin A and FK506 in human B cells. Proc Natl Acad Sci USA 1992;89:12198
- Katsanis E., Shapiro R.S., Robinson L.L., et al. Thyroid dysfunction following bone marrow transplantation: long-term follow-up of 80 pediatric patients. Bone Marrow Transplant 1990;5:335-340.[Medline]
- Roslin M.S., Tranbaugh R.E., Panza A., et al. One-year monkey heart xenograft survival in cyclosporine-treated baboons. Transplantation 1992;54:949-955.[Medline]
- Bitzer M., Topka H. Progressive cerebral occlusive disease after radiation therapy. Stroke 1995;26:131-136.[Abstract/Free Full Text]
- Omura M., Aida N., Sekido K., Kakehi M., Matsubara S. Large intracranial vessel occlusive vasculopathy after radiation therapy in clinical features and usefulness of magnetic resonance imaging. Int J Radiat Oncol Biol Phys 1997;38:241-249.[Medline]
- Tucker M.A., D’Angio G.J., Boice J.D., Jr, et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 1987;317:588-593.[Abstract]
This article has been cited by other articles:
|
|
|
|
 
B. P. Griffith, M. Haddad, and R. S. Poston
Immunobiology of Heart and Heart-Lung Transplantation
Card. Surg. Adult,
January 1, 2008;
3(2008):
1513 - 1538.
[Full Text]
|
|
|
Top
Abstract
Introduction
