Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe aplastic anemia (SAA) is well described in children following liver transplantation for fulminant hepatic failure (FHF) secondary to non-A, non-B, non-C hepatitis, and is associated with a high mortality rate. Successful immunosuppressive treatment of SAA following liver transplantation has been reported, but death from infectious complications is not uncommon. We report the 8-year follow-up of a 3.5-year-old boy who underwent successful HLA-identical sibling donor bone marrow transplant for SAA 7 months following orthotopic liver transplant for non-A, non-B, non-C hepatitis. His post-bone marrow transplantation course was uneventful with no evidence of liver toxicity. Eight months following BMT he developed renal cell carcinoma metastatic to lymph nodes which was treated surgically. Six years following BMT he developed a mucoepidermoid carcinoma of the parotid gland also treated surgically. Despite these malignancies, he is currently well 8 years following liver and bone marrow transplantation, without signs of GVHD, growth failure or liver graft rejection. This is the first report of long-term follow-up of bone marrow transplantation for SAA following liver transplantation. The occurrence of two subsequent malignancies in this child underscores the need for close follow-up of future similar cases.
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PMID:Successful bone marrow transplantation for severe aplastic anemia following orthotopic liver transplantation: long-term follow-up and outcome. 1159 28

Thalidomide--removed from widespread clinical use by 1962 because of severe teratogenicity--has antiangiogenic and immunomodulatory effects, including the inhibition of tumor necrosis alpha factor. It has now returned to practice as an effective oral agent in the management of various disease states including erythema nodosum leprosum, for which it was approved by the U.S. Food and Drug Administration in 1998, and more recently certain malignancies, including multiple myeloma. Although thalidomide's mechanism of action remains incompletely understood, considerable insight has been generated by extensive preclinical studies in multiple myeloma. Moreover, clinical trials have confirmed benefit in relapsed disease, and the role of thalidomide in treating newly diagnosed patients is currently under study. Its use in other tumors is under evaluation, with promise in renal cell carcinoma, prostate cancer, glioma, and Kaposi's sarcoma. Activity has also been demonstrated in chronic graft-versus-host disease and in symptom relief as part of palliative care.
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PMID:Thalidomide: emerging role in cancer medicine. 1181 93

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective treatment for selected hematological malignancies. Its curative potential is largely mediated by an immune-mediated destruction of malignant cells by donor lymphocytes termed graft-versus-leukemia (GVL) effect. However, because of its toxicity, conventional allogeneic HSCT is restricted to younger and fitter patients. These observations led several groups to set up new (less toxic) transplant protocols (nonmyeloablative stem cell transplantation or NMSCT) based on a two-step approach: first, the use of immunosuppressive (but nonmyeloablative) preparative regimens providing sufficient immunosuppression to achieve engraftment of allogeneic hematopoietic stem cells and, in a second step, destruction of malignant cells by the GVL effect. Preliminary results showed that NMSCT were feasible with a relatively low transplant-related mortality (TRM), even in patients older than 65 years. In addition, strong antitumor responses were observed in several hematological malignancies as well as in some patients with renal cell carcinoma. After discussing the mechanisms and efficacy of the GVL effect as well as the rationale for NMSCT strategies, this article reviews the first results of ongoing clinical trials. Innovative modalities that may permit amplification of the GVL effect while minimizing the risk of GVHD are discussed. Because the benefits of NMSCT over alternative forms of treatment remain to be demonstrated, this strategy should be restricted to patients included in clinical trials.
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PMID:Nonmyeloablative allogeneic hematopoietic stem cell transplantation. 1198 97

The feasibility and toxicity of allogeneic stem cell transplantation after nonmyeloablative conditioning including thiotepa, fludarabine, and cyclophosphamide have been investigated in 6 patients with breast cancer and 7 patients with renal cell cancer. The program included the use of escalating doses of donor lymphocyte infusions (DLI) and/or interferon alpha (IFNalpha) for patients showing no tumor response and no graft-versus-host disease (GVHD). Patients were at high risk of transplant-related mortality (TRM) because of age, advanced stage, and previous treatments. We observed a partial remission in 4 renal cancer and in 2 breast cancer patients (one at the molecular level in the bone marrow), occurring after cyclosporine withdrawal or after DLI and/or IFNalpha. All the responses were accompanied by the occurrence of acute GVHD. We conclude that reduced-intensity allogeneic stem cell transplantation is a feasible procedure in renal and breast cancer, and that the exploitation of graft-versus-tumor effect after DLI is a promising finding.
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PMID:Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer. 1201 Aug 34

There are accumulating evidence of immunological therapeutic effect induced by reduced-intensity allogeneic hematopoietic stem cell transplantation (mini-transplantation) for solid malignancies. The reduced toxicity of a mild preconditioning regimen in mini-transplantation has facilitated its application to patients with various solid tumors. The so-called graft-versus-tumor (GVT) effect usually appears when graft-versus-host disease develops. Therefore, it is suggested that the fundamental mechanism of the GVT effect is a reaction by T-lymphocytes against various tumor-associated alloantigens of the tumor cells. Although mini-transplantation appears effective in some patients with renal cell carcinoma or breast cancer, it is still unclear whether the therapeutic mechanism could work on other solid tumors. Well-designed prospective clinical trials are warranted in order to determine the role of mini-transplant in the therapeutic strategy for solid tumors.
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PMID:[Reduced-intensity allogeneic hematopoietic stem cell transplantation (mini-transplantation) for solid tumors]. 1209 32

Nonablative hematopoietic cell transplantation (HCT) is becoming a preferred treatment for those recipients in whom the potential toxicity risk of standard ablative allogeneic therapy may be unacceptable. Graft-versus-malignancy effects may be generated against epithelial malignancies which are similar to the graft-versus-leukemia activity that is well documented in human hematological malignancies. Renal cell carcinoma has been shown to be responsive to immunotherapy with recombinant human cytokines and may be an ideal model for exploring this novel therapy. Clinical investigations have demonstrated regression of metastatic renal cell carcinoma occurs in some patients following nonablative allogeneic HCT. However, graft-versus-host disease remains a significant toxicity of nonablative transplantation, and further investigations are warranted to further evaluate this promising approach and to improve its safety.
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PMID:Nonablative hematopoietic cell transplantation for the treatment of metastatic renal cell carcinoma. 1247 72

We evaluated the feasibility and efficacy of a reduced-intensity conditioning (RIC) regimen of fludarabine and melphalan to achieve rapid complete donor chimerism after allogeneic stem cell transplantation (SCT) in patients with metastatic solid tumors. Between January 1999 and January 2003, 8 patients with metastatic breast cancer (BC) and 15 with metastatic renal cell carcinoma (RCC) underwent allogeneic SCT after an RIC regimen of 5 days of fludarabine and 2 days of melphalan. Filgrastim-mobilized stem cells from HLA-identical related or unrelated donors were infused. Prophylaxis for graft-versus-host disease (GVHD) consisted of tacrolimus and methotrexate. All 22 evaluable patients had 100% donor chimerism at day 30 and at all measurement times thereafter. One patient died 19 days after SCT. Nine patients (39%) had grades II to IV acute GVHD and 10 patients (43%) had chronic GVHD. Five patients (22%) died of nonrelapse treatment-related complications. Treatment-related disease response was seen in 10 patients (45%), with 3 complete responses, 2 partial responses, and 5 minor responses. Fludarabine-melphalan is a feasible and effective RIC regimen for allogeneic SCT in metastatic BC and RCC. It induces rapid complete donor chimerism without the need for donor lymphocyte infusion. Tumor regression associated with GVHD is consistent with graft-versus-tumor effect.
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PMID:Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. 1288 8

Originally, allogeneic hematopoietic stem cell transplantation (HSCT) was viewed as a form of rescue from the marrow lethal effects of high doses of chemo-radiotherapy used to both eradicate malignancy and to provide sufficient immunosuppression to ensure allogeneic engraftment. Clear evidence of a therapeutic graft-versus-tumor (GVT) effect mediated by allogeneic effector cells (T cells) has prompted the exploration of HSCT regimens that rely solely upon host immunosuppression (non-myeloablative) to facilitate allogeneic donor engraftment. The engrafted donor effector cells are then used to accomplish the task of eradicating host malignant cells. The non-myeloblative regimen developed in Seattle uses 2 Gy total body irradiation (TBI) before transplant followed by postgrafting cyclosporine (CSP) and mycophenolate mofetil (MMF). This regimen resulted in initial mixed donor-host chimerism in all patients with hematologic malignancies and genetic disorders who received HLA-matched sibling allografts. The 17% incidence of graft rejection was reduced to 3% with the addition of fludarabine, 30 mg/m2/day on d -4, -3, and -2. The non-myeloablative combination of fludarabine/TBI has also been successful at achieving high engraftment rates in recipients of 10 of 10 HLA antigen matched unrelated donor HSCTs in patients with hematologic malignancies. By reducing acute toxicities relative to conventional HSCT, most patients have received their pre- and post-HSCT therapy almost exclusively as outpatients. Acute and chronic GVHD occur after non-myeloablative HSCT, but the incidence and severity appear less compared to conventional HSCT. As in conventional transplants, immune dysregulation from GVHD and its treatment and delayed reconstitution of immune function continue to present risks to patients who have otherwise undergone successful non-myeloablative HSCT. Cellular therapeutic effects have been observed after non-myeloablative HSCT such as correction of inherited genetic disorders, and eradication of hematologic malignant diseases and renal cell carcinoma via GVT responses.
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PMID:The transplantation of hematopoietic stem cells after non-myeloablative conditioning: a cellular therapeutic approach to hematologic and genetic diseases. 1294 21

The lack of efficacy of chemotherapeutics, radiotherapy, and cytokine-based immunotherapy has catalyzed the preliminary enthusiasm for nonmyeloablative stem cell transplants as a novel investigational tool for treating metastatic RCC. The observation that cytokine-refractory metastatic RCC may regress following allogeneic transplantation attests to the powerful nature of the graft-versus-tumor effect that results from this treatment modality. Pilot trials and recent in vitro data provide the first clear evidence that the graft-versus-tumor effect mounted against RCC can produce clinically meaningful regression of a metastatic solid tumor. Given this observation, the authors have begun to expand the investigational use of nonmyeloablative stem cell transplants to other treatment-refractory genitourinary tumors, including metastatic bladder and prostate cancer. It is hoped that future demonstrations of graft-versus-tumor effects in other solid malignancies will lay the groundwork for the development of tumor-targeted strategies that use allogeneic transplantation of donor lymphocytes as an immunotherapeutic platform. Further advances in systemic and selective immunosuppressive agents that limit acute GVHD hold the potential to decrease the toxicity associated with nonmyeloablative stem cell transplants and may ultimately broaden the clinical applicability of this approach.
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PMID:Allogeneic stem cell transplantation as immunotherapy for renal cell carcinoma: from immune enhancement to immune replacement. 1295 59

We investigate the feasibility of CD34-selected peripheral blood stem cell (PBSC) transplantation followed by pre-emptive CD8-depleted donor lymphocyte infusions (DLI) after a minimal conditioning regimen. Six patients with advanced hematological malignancies ineligible for a conventional myeloablative transplant (n=5) or metastatic renal cell carcinoma (n=1), and with an HLA-identical (n=4) or alternative (n=2) donor were included. The nonmyeloablative conditioning regimen consisted in 2 Gy TBI alone (n=4), 2 Gy TBI and fludarabine (RCC patient, n=1) or cyclophosphamide and fludarabine (patient who had previously received 12 Gy TBI, n=1). Post transplant immunosuppression was carried out with cyclosporin (CyA) and mycophenolate mofetil (MMF). Initial engraftment was achieved in all patients. One out of six patients (17%) experienced grade > or =2 acute GVHD only after abrupt cyclosporin discontinuation and alpha interferon therapy for life-threatening tumor progression. T-cell chimerism was 23% (19-30) on day 28, 32% (10-35) on day 100, 78% (49-95) on day 180 and 99.5% (99-100) on day 365. Three out of four patients who had measurable disease before the transplant experienced a complete response. We conclude that CD34-selected NMSCT followed by CD8-depleted DLI is feasible and preserves engraftment and apparently also the graft-versus-leukemia (GVL) effect. Further studies are needed to confirm this encouraging preliminary report.
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PMID:Low T-cell chimerism is not followed by graft rejection after nonmyeloablative stem cell transplantation (NMSCT) with CD34-selected PBSC. 1452 Apr 30


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