Is an ounce of prevention worth a pound of cure?
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Antibodies, Monoclonal↗
Biomedical subjects
Thomas G Gross
Publications and source records attributed to Thomas G Gross.
Malignancy in pediatric transplant recipients.
Malignancy is a well defined complication of chronic immunosuppression. Post transplant malignancies appear to be related to cumulative doses of immunosuppression, and in pediatric patients, acute infection of previously naive patients. The most commonly encountered malignancy in this age population is Post Transplant Lymphoproliferative Disorder (PTLD). PTLD is not a single entity but rather represents a continuum of disease. Treatment of PTLD should be initiated with immunosuppression reduction. Standard dose chemotherapy leads to significant morbidity. With the introduction of anti-CD20 antibody treatment with rituximab, chemotherapy has become second line therapy. The occurrence of solid malignancy appears to be associated with chronic immunosuppression. These cancers include those of skin, gynecologic organs, and the rectum, all of which appear to have the strongest association with viral mediators. Several strategies have been postulated to minimize the occurrence of malignancy. These include ganciclovir prophylaxis for the prevention of PTLD and the use of mychophenolic acid and TOR inhibitor maintenance to diminish the incidence of PTLD and solid malignancies. This leaves transplant physicians with several new and novel immunosuppressive agents with uncertain oncologic potentials that will need to be examined over the next decade.
Adolescent↗
Autologous hematopoietic stem cell transplant with melphalan and thiotepa is safe and feasible in pediatric patients with low normalized glomerular filtration rate.
Normalized glomerular filtration rate (nGFR) <60 mL/min/1.73 m(2) often precludes hematopoietic stem cell transplant (HSCT) in pediatric patients. Three patients with nGFR < 60 mL/min/1.73 m(2) enrolled on an institutional phase I trial of HSCT preparative therapy for advanced and recurrent solid tumors with escalating melphalan, ranging from 135 to 180 mg/m(2), thiotepa (600 mg/m(2)), and vincristine (2 mg/m(2)). An additional patient with low nGFR was treated with the same preparative therapy. None of the patients developed acute renal failure, excess toxicities during HSCT or delayed engraftment. These cases demonstrate that it is feasible and safe to perform HSCT in pediatric patients with low nGFR using melphalan- and thiotepa-based preparative therapy.
Antineoplastic Agents, Alkylating↗
Malignancy after transplantation.
As newer immunosuppressive regimens have steadily reduced the incidence of acute rejection and have extended the life expectancy of allograft recipients, posttransplant malignancy has become an important cause of mortality. In fact, it is expected that cancer will surpass cardiovascular complications as the leading cause of death in transplant patients within the next 2 decades. An understanding of the underlying pathobiology and how to minimize cancer risks in transplant recipients are essential. The etiology of posttransplant malignancy is believed to be multifactorial and likely involves impaired immunosurveillance of neoplastic cells as well as depressed antiviral immune activity with a number of common posttransplant malignancies being viral-related. Although calcineurin inhibitors and azathioprine have been linked with posttransplant malignancies, newer agents such as mycophenolate mofetil and sirolimus have not and indeed may have antitumor properties. Long-term data are needed to determine if the use of these agents will ultimately lower the mortality due to malignancy for transplant recipients.
Azathioprine↗
Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation.
PURPOSE: To evaluate the efficacy of a low-dose chemotherapy regimen in children with Epstein-Barr virus (EBV) -positive, post-transplantation lymphoproliferative disease (PTLD) after organ transplantation who have experienced failure with front-line therapy for PTLD. PATIENTS AND METHODS: Eligible patients received cyclophosphamide (600 mg/m2 intravenous for 1 day) and prednisone (2 mg/kg orally for 5 days) every 3 weeks for six cycles. RESULTS: Thirty-six patients treated on study were assessable for analyses. Front-line therapies for PTLD before study entry included immune suppression reduction or withdrawal (n = 36), antiviral therapy (n = 33), surgical resection (n = 8), rituximab (n = 2), and interferon alfa (n = 1). Reasons for failure of front-line therapy included progressive disease (PD; n = 33) and persistent disease with concurrent allograft rejection (n = 3). Thirty patients (83%) had stage III to IV disease, 92% had extranodal disease, and 75% had > or = three sites of disease. The overall response rate was 83% (75% complete response + 8% partial response). The relapse rate was 19%, with only one of five relapsed patients alive and disease-free. Four patients presented with fulminant, disseminated PTLD; only one of these four patients achieved a response, and all four died of PD. Two patients died of treatment-related toxicity. Three patients (8%) experienced allograft loss, but two of the three patients are alive and disease-free after a second transplantation. The 2-year overall, relapse-free, and failure-free (without PTLD and with functioning original allograft) survival rates were 73%, 69%, and 67%, respectively. CONCLUSION: This low-dose chemotherapy regimen is effective for children with EBV-positive, nonfulminant PTLD who have experienced treatment failure with front-line therapy, and this study represents the largest series of PTLD patients treated prospectively with a uniform chemotherapy regimen.
Adolescent↗
United network for organ sharing publication on scientific registry of transplant recipients central nervous system donor cancer transmission data.
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Central Nervous System Neoplasms↗
Once in a lifetime.
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Antineoplastic Combined Chemotherapy Protocols↗
Analysis of factors that influence survival with post-transplant lymphoproliferative disorder in renal transplant recipients: the Israel Penn International Transplant Tumor Registry experience.
Significant mortality is associated with post-transplant lymphoproliferative disorder (PTLD) in kidney transplant recipients (KTX). Univariate/multivariate risk factor survival analysis of US PTLD KTX reported to Israel Penn International Transplant Tumor Registry from November 1968 to January 2000 was performed. PTLD presented 18 (median) (range 1-310) months in 402 KTX. Death rates were greater for those diagnosed within 6 months (64%) versus beyond 6 months (54%, p = 0.04). No differences in death risk for gender, race, immunosuppression, EBV, B or T cell positivity were identified. Death risk increased for multiple versus single sites (73% vs. 53%, hazards ratio (HR) 1.4). A 1-year increase in age increased HR for death by 2%. Surgery was associated with increased survival (55% vs. 0% without surgery) (p < 0.0001). Patients with allograft involvement, treated with transplant nephrectomy alone (n = 20), had 80% survival versus 53% without allograft removal (n = 15) (p < 0.001). Overall survival was 69% for allograft involvement alone versus 36% for other organ involvement plus allograft (n = 19 alive) (p < 0.0001). Death risk was greater for multiple site PTLD and increasing age, and risks were additive. Univariate analysis identified increased death risk for those not receiving surgery, particularly allograft involvement alone.
Graft Rejection↗
Experience with 274 cardiac transplant recipients with posttransplant lymphoproliferative disorder: a report from the Israel Penn International Transplant Tumor Registry.
BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication that occurs in a small but significant minority of solid organ transplant recipients. Published experiences with PTLD in cardiac transplant recipients are limited to relatively small single-center reports. METHODS: This report presents experience with 274 cases of PTLD in cardiac transplant recipients reported to the Israel Penn International Transplant Tumor Registry (IPITTR). RESULTS: PTLD carried an ominous prognosis: Kaplan Meier survival after PTLD diagnosis was 45%, 33%, 30%, and 13%, respectively, at 1, 3, 5, and 10 years. Common causes of death included: PTLD, cardiovascular collapse, and infection; all occurred at a median of less than 6 months. Risk of death from cardiovascular collapse secondary to immunosuppression withdrawal was substantial (28%), indicating that a fine balance exists between death from PTLD and from sudden cardiac death due to acute rejection. PTLD therapy in the majority of patients consisted of combination therapy (49%). Survival in patients receiving immunosuppression minimization (ISM) alone was 32%, with ISM plus other therapy was 27%, and with other therapies not containing ISM was 11% (P < 0.01). CONCLUSION: PTLD in cardiac transplant recipients is associated with low long-term survival rates. Analysis of PTLD therapies and outcomes suggest that immunosuppression minimization, when applied, improves survival. However, risk of sudden death may mitigate the positive effect of ISM. This observation has important implications for ISM in PTLD therapy in cardiac transplant recipients. Carefully designed prospective studies are needed to evaluate the positive and negative effects of ISM in cardiac transplant recipients with PTLD.
Adult↗
Recurrence risk after organ transplantation in patients with a history of Hodgkin disease or non-Hodgkin lymphoma.
This study defines the incidence and recurrence risk of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) after organ transplant. Patients from the United States with a history of HD or NHL before organ transplantation reported to the Israel Penn International Transplant Tumor Registry from 1968 to 2001 were analyzed. A total of 91 patients underwent organ transplantation with a lymphoma history: HD (38 patients) and NHL (53 patients). Median disease-free interval pretransplant was 99 (range 0-459.1) months, and median follow-up posttransplant was 25.7 (0.4-131.1) months. Ten patients were excluded from further analysis because of lack of follow-up information (n=9) or they never achieved remission (n=1). Recurrence incidence was 8 of 81 patients (10%) (HD=3/34 [9%] vs. NHL=5/47 [11%]). Gender, race, allograft type and source, age at lymphoma diagnosis, and immunosuppression did not influence recurrence. Patients with less than a 2-year period between diagnosis and transplant seem to be at increased risk of relapse. Median disease-free interval before transplant was longer for patients without recurrence (115 vs. 30.2 months, P=0.24), but was not statistically significant. Median time to recurrence posttransplant was 18.7 (range 1.9-82.2) months (HD=3.7 vs. NHL 23.6 months, P=0.10). Survival after recurrence was poor (HD [1/3] and NHL [1/5], median survival 6.8 [range 0-22.1] months). There is no difference in recurrence rates for HD and NHL. The outcome for recurrent lymphoma is poor. The low risk of recurrence (10%) indicates that preexisting HD and NHL need not be an absolute contraindication to transplantation.
Adolescent↗
Characteristics and survival patterns of solid organ transplant patients developing de novo colon and rectal cancer.
PURPOSE: Immunosuppression used in transplantation is associated with an increased incidence of various cancers. Although the incidence of colorectal cancer in transplant patients seems to be equal to nontransplant population, the effects of immunosuppression on patients who develop colorectal cancer are not well defined. The purpose of this study was to define the characteristics and survival patterns of transplant patients developing de novo colorectal cancer. METHODS: The Israel Penn International Transplant Tumor Registry was queried for patients with colorectal cancer. Analysis included patient demographics, age at transplantation and colorectal cancer diagnosis, tumor stage, and survival. Age and survival rates were compared to United States population-based colorectal cancer statistics using the National Cancer Institute Surveillance Epidemiology and End Results database. RESULTS: A total of 150 transplant patients with de novo colorectal cancer were identified: 93 kidney, 29 heart, 27 liver, and 1 lung. Mean age at transplantation was 53 years. Age at transplantation and colorectal cancer diagnosis was not significant for gender, race, or stage of disease. Compared to National Cancer Institute Surveillance Epidemiology and End Results database, transplantation patients had a younger mean age at colorectal cancer diagnosis (58 vs. 70 years; P < 0.001), and a worse five-year survival (overall, 44 vs. 62 percent, P < 0.001; Dukes A and B, 74 vs. 90 percent, P < 0.001; Dukes C, 20 vs. 66 percent, P < 0.001; and Dukes D, 0 vs. 9 percent, P = 0.08). CONCLUSIONS: Transplant patients develop colorectal cancer at a younger age and exhibit worse five-year survival rates than the general population. These data suggest that chronic immunosuppression results in a more aggressive tumor biology. Frequent posttransplantation colorectal cancer screening program may be warranted.
Aged↗
Posttransplant malignancy.
In the past few decades, great advances have been made in the field of solid-organ transplantation. A greater understanding of immune system function, the development of modern immunosuppression, and advancements in surgical technique have led to marked improvements in both recipient and graft survivals, as well as recipients' quality of life. However, improved survival rates have also led to prolonged exposure to chronic immunosuppression, which increases the risk for the development of posttransplant malignancies. In addition, older transplant candidates are being considered, carrying with them the increased likelihood of preexisting malignancy. Consequently, the potential risk of posttransplant malignancy must be considered. Moreover, as long-term transplant survivors continue to age, posttransplant malignancies will be seen more frequently. This review presents the more commonly encountered posttransplant malignancies and the measures that are currently being utilized to prevent and treat them.
Adult↗
Donor transmitted malignancies.
Early experiences in transplantation, which pre-dated brain death laws, utilized organs from donors with active malignancies. The use of organs from such donors occasionally resulted in the transmission of malignancy from the donor to an unknowing recipient. Over a period of three decades, Israel Penn, M. D. catalogued some two hundred and fifty cases of organs transplanted from donors with a history of malignancy; carefully examining each reported case for tumor histology, donor risk factors, method of tumor presentation and recipient outcome. Some recipients never developed malignancies, while others were less fortunate, developing cancers that were suspicious for donor origin. The evolution of transplantation has resulted in improved patient survival, which in turn has led to an increased demand for organ transplantation. Unfortunately, the supply of organs available for transplantation has failed to keep pace with the demand, with the worldwide deficit growing annually. In an effort to bridge the widening gap, utilization of older and more marginal donors has been suggested. However, use of older donors is accompanied by the likelihood that a significant proportion may have undiagnosed malignancies. Multiple transplant programs have considered the use of donors with tumors of non-malignant or even low-grade malignant histology, most often involving the central nervous system (CNS). According to a survey from the United Network for Organ Sharing (UNOS), central nervous system malignancies are among the most commonly identified malignancies found in potential donors. This study examines the distribution of potential donor transmitted malignancies reported to the Israel Penn International Transplant Tumor Registry. The incidence of tumor transmission is examined in the overall group as well as among individual histologies. We also seek to identify specific factors associated with the risk of malignancy transmission from donor to recipient, in an effort to minimize future transmission of donor tumors to unwitting recipients. The study is based on voluntary registry data, which some argue can be criticized for a lack of true incidence data. In reality, however, this data may provide a more accurate insight since it is based on transmissions from high-risk donors rather than from the general population.
Humans↗
A pilot study of chemoimmunotherapy (cyclophosphamide, prednisone, and rituximab) in patients with post-transplant lymphoproliferative disorder following solid organ transplantation.
PURPOSE: We have previously demonstrated a >80% complete response (CR) rate with cyclophosphamide/prednisone (Cy/Pred) chemotherapy alone in patients with post-transplant lymphoproliferative disease (PTLD) after solid organ transplantation (SOT), but only a 58% 2-year event-free survival. The response rate to immunotherapy (rituximab) is only about 46% with a 54% relapse/progression rate. In this study, we investigated the use of a combination of Cy/Pred with rituximab as treatment for this disease. EXPERIMENTAL DESIGN: Patients received two to six courses of cyclophosphamide (600 mg/m(2), on day 1 of each course) and prednisone (1 mg/kg, every 12 h x 10 doses), given every 3 weeks. The first two courses were given in combination with 4-6 weekly doses of rituximab (375 mg/m(2), i.v.). Imaging studies were done every 2 months to document response. RESULTS: There were six PTLD patients (two fulminant); age, 4-23 year; sex, male:female (3:3); status post SOT (two cardiac, two liver, two renal); median onset, 39 months (10-144 months). Fifty percent were polyclonal, 100% were CD20+, and 83% were EBV+. The overall response rate was 100% (five CRs and one PR). All five CRs showed no evidence of disease, and one PR eventually progressed and died of fulminant disease. All allografts in surviving patients were functional. There was no grade III/IV toxicity and/or no infectious complications related to the combination of Cy/Pred with rituximab. Median follow-up was 12.5 months (range, 4-29 months). CONCLUSIONS: These preliminary results suggest that the combination of Cy/Pred and targeted immunotherapy (rituximab) is well tolerated and may be more efficacious in patients with PTLD after SOT. Future prospective larger trials with longer follow-up investigating this combination will be required to confirm these preliminary results.
Adolescent↗
Donors with central nervous system malignancies: are they truly safe?
BACKGROUND: In an era of organ shortage, the use of expanded or marginal donors has been attempted to increase transplantation rates and diminish waiting list mortality. One strategy is the use of organs from patients with a history of or active central nervous system (CNS) tumor. METHODS: Sixty-two recipients were identified as the recipients of organs from donors with a history of or active CNS malignancy. Patient demographics, donor tumor management, incidence of tumor transmission, and patient survival were examined. RESULTS: Of the organs recovered and transplanted from donors with astrocytoma, 14 were associated with at least one risk factor including high-grade tumor (n=4), prior surgery (n=5), radiation therapy (n=4), and systemic chemotherapy (n=4). One tumor transmission was identified at 20 months posttransplant with the patient expiring from metastatic disease. Twenty-six organs were transplanted from glioblastoma patients with 15 demonstrating risk factors including high-grade tumor (n=9) and prior surgery (n=10). Eight transmissions were identified with a range of 2 to 15 months posttransplant, with seven patients dying as the result of metastatic disease. Seven organs were used from donors with a medulloblastoma. Three transmissions were identified at a range of 5 to 7 months, all associated with ventriculoperitoneal shunts. Two medulloblastoma recipients died as the result of metastatic disease, whereas the third is alive with diffuse disease. The rate of donor tumor transmission, in the absence of risk factors, was 7%, whereas in the presence of one or more risk factor this rate dramatically rose to 53% (P<0.01). CONCLUSIONS: Organs from donors with CNS tumors can be used with a low risk of donor tumor transmission in the absence of the following risk factors: high-grade tumors, ventriculoperitoneal or ventriculoatrial shunts, prior craniotomy, and systemic chemotherapy.
Astrocytoma↗
Determination of risk factors for Epstein-Barr virus-associated posttransplant lymphoproliferative disorder in pediatric liver transplant recipients using objective case ascertainment.
BACKGROUND: Previous studies have suggested an increased risk of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder (EBV-PTLD) in patients receiving tacrolimus for immunosuppression. We hypothesized that after correction for confounding variables, immunosuppression with tacrolimus is not associated with an increased risk of EBV-PTLD. METHODS: Potential cases of EBV-PTLD, identified by chart review, were independently ascertained by three clinicians and defined using published criteria. Agreement in diagnosing EBV-PTLD was measured using Kappa coefficients. Unadjusted and adjusted relative risk estimates were determined using proportional hazards regression. RESULTS: Twenty-three cases of EBV-PTLD were identified in 221 patients, a proportion of 10.4% (95% confidence interval [CI]: 6.4%-14.4%). Multivariable analysis revealed that immunosuppression with tacrolimus was associated with an increased risk of EBV-PTLD (relative risk 3.10: 95% CI: 1.21-7.92), as was age at transplantation as a continuous variable (parameter estimate -0.15, P=0.03). Kappa coefficients in diagnosing EBV-PTLD and subclassifying as neoplastic and non-neoplastic EBV-PTLD were 0.73 (95% CI: 0.54-0.93) and 0.54 (95% CI: 0.40-0.68), respectively. Patients with neoplastic PTLD demonstrated a lower probability of survival than patients with non-neoplastic PTLD and non-cases. CONCLUSIONS: Immunosuppression with tacrolimus and young age at transplantation are associated with an increased risk of EBV-PTLD in children undergoing liver transplantation, although we cannot exclude detection bias as an explanation for this observed increase. Good agreement between observers can be achieved using previously published criteria for defining EBV-PTLD. Patients with neoplastic EBV-PTLD may have a worse prognosis, and thus identification of risk factors for the development of this subtype of the disorder may be more important.
Aging↗
Epstein-Barr virus associated disease following blood or marrow transplant.
EBV associated disease continues to be a problem in the post-BHT population. The pathogenesis, risk factors, and diagnosis of PTLD, as well as the rationale, efficacy and advantages/disadvantages of various prophylactic, pre-emptive and treatment strategies are discussed.
Blood Transfusion↗
Low risk of graft-versus-host disease with transplantation of CD34 selected peripheral blood progenitor cells from alternative donors for Fanconi anemia.
OBJECTIVES: Transplant results for Fanconi anemia with alternative-donor bone marrow transplantation currently entail a high incidence of graft failure and graft-versus-host disease (GVHD). The authors sought to improve outcome in this disease category with alternative donors with a 5-6/6 antigen match by transplantation of highly purified peripheral blood progenitor cells (PBPC) using the Isolex 300i v2.5 device as a means of T-cell depletion to lessen the risk of GVHD. METHODS: All Fanconi anemia patients (n = 8) received the same preparative regimen that included total body irradiation (450 cGy), Cytoxan (20 mg/kg), ATGAM, and fludarabine (120 mg/m2). The cell dose of CD34+ cells was a median of 11.4 x 10(6)/kg; the cell dose of CD3+ cells was a median of 1.9 x 10(4)/kg. Primary engraftment was rapid in all patients, with neutrophil recovery occurring at a median of day 10 and platelet count more than 50,000 on day 27. Two patients subsequently had secondary graft failure. Despite lack of cyclosporine GVHD prophylaxis, only two patients developed acute GVHD (both grade I), and no patients developed chronic GVHD. Three patients died: one at day 59 secondary to disseminated fungal infection, the second at day 196 during a second transplant, and the third at day 202 due to graft failure. With a median follow-up of 12 months, the overall survival was 58 +/- 18%. CONCLUSIONS: Transplantation of CD34-selected PBPCs from alternative donors results in a very low risk of GVHD in patients with Fanconi anemia.
Adolescent↗