TGFß and IL10 have an impact on risk group and prognosis in childhood ALL.

BACKGROUND: Cytokines and their genes have been described to have an influence on incidence and prognosis in malignant, infectious and autoimmune disease. We previously described the impact of cytokine production on prognosis in paediatric standard-risk acute lymphoblastic leukaemia (ALL). PROCEDURE: In this study, we investigated the influence of cytokine gene polymorphisms (TNFα, TGFß, IL10 and IFNγ) on frequency, risk group and prognosis in 95 paediatric ALL-patients. We further report on intracellular production of these cytokines in T-cells. RESULTS: IL10 high-producer-haplotypes were reduced in ALL-patients compared with healthy controls and resulted in a reduced relapse rate compared with low-producer haplotypes. TGFß high-producer-haplotypes were correlated with a high initial blast-count (codon 25: G/G) and were elevated in high-risk ALL-patients (codon 10: T/T). IL10 was positively and IFNγ-production was negatively correlated with initial blast-count. At diagnosis the expression of TNFα and IFNγ was reduced in patients compared with healthy controls. This was more pronounced in high-risk and in T-ALL-patients. CONCLUSION: We conclude that gene-polymorphisms of the regulatory/anti-inflammatory cytokines, TGFß and IL10, but not of the pro-inflammatory cytokines, IFNγ and TNFα, have an impact on prognosis and risk-group of ALL. However, the reduced capacity to produce pro-inflammatory cytokines at diagnosis may serve as another important, functional risk factor. These data may help in further risk stratification and adaptation of therapy-intensity in paediatric patients with ALL.

Successful treatment of an infant with CDA type II by intrauterine transfusions and postnatal stem cell transplantation.

Congenital dyserythropoietic anemias are rare hematological disorders leading to ineffective erythropoiesis with chronic anemia, complicated by iron overload. Here we present a remarkable clinical course of an infant with CDA type II who first presented as a severe fetal hydrops, requiring serial intrauterine red cell transfusions. While postnatal transfusion dependency persisted, the patient was successfully transplanted with a myeloablative conditioning regimen and peripheral blood stem cells of a matched donor. We believe that allogeneic HSCT is a reasonable therapeutic approach for patients with very severe CDA, even if only a matched unrelated donor is available.

Human leukocyte antigen distribution in German Caucasians with advanced Ewing's sarcoma.

BACKGROUND: Risk stratification criteria for patients with Ewing's sarcoma family of tumors (ESFT) are still limited. We hypothesized divergent human leukocyte antigen (HLA) patterns in ESFT patients and compared HLA-A, -B and -DR phenotype frequencies of patients with advanced ESFT with those of healthy controls. PATIENTS: HLA types of all German Caucasian patients with advanced ESFT and available HLA-A, -B and -DR data registered in the European Group for Blood and Marrow Transplantation, Paediatric Registry for Stem Cell Transplantation and the MetaEICESS data bases (study group, n=30) were retrospectively compared with HLA types of healthy German stem cell donors (control group, n=8 862 for single HLA frequencies and n=8 839 for allele combinations). Study group patients had been immuno-typed due to eligibility for allogeneic stem cell transplantation for high risk of treatment failure, and thus constituted a selected subgroup of ESFT patients. RESULTS: After Bonferroni correction for multiple testing (PC), phenotype frequencies of HLA-A24 remained significantly higher in the study group compared to controls (PC<0.05). Furthermore, several HLA combinations were significantly more frequent in the study group compared to controls (all PC<0.05). CONCLUSION: We report an increased incidence of circumscribed HLA patterns in German Caucasians with advanced ESFT. The possible clinical significance of this observation has to be re-assessed in prospective trials comprising larger ESFT patient numbers of all risk groups.

No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients.

BACKGROUND: Outcomes of Ewing tumor (ET) patients treated with allogeneic stem cell transplantation (allo-SCT) were compared regarding the use of reduced-intensity conditioning (RIC) and high-intensity conditioning (HIC) regimens as well as human leukocyte antigen (HLA)-matched and HLA-mismatched grafts. PATIENTS AND METHODS: We retrospectively analyzed data of 87 ET patients from the European Group for Blood and Marrow Transplantation, Pediatric Registry for Stem Cell Transplantations, Asia Pacific Blood and Marrow Transplantation and MetaEICESS registries treated with allo-SCT. Fifty patients received RIC (group A) and 37 patients received HIC (group B). Twenty-four patients received HLA-mismatched grafts and 63 received HLA-matched grafts. RESULTS: Median overall survival was 7.9 months [±1.24, 95% confidence interval (CI) 5.44-10.31] for group A and 4.4 months (±1.06, 95% CI 2.29-6.43) for group B patients (P = 1.3). Death of complications (DOC) occurred in 4 of 50 (0.08) and death of disease (DOD) in 33 of 50 (0.66) group A and in 16 of 37 (0.43) and 17 of 37 (0.46) group B patients, respectively. DOC incidence was decreased (P < 0.01) and DOD/relapse increased (P < 0.01) in group A compared with group B. HLA mismatch was not generally associated with graft-versus-Ewing tumor effect (GvETE). CONCLUSIONS: There was no improvement of survival with RIC compared with HIC due to increased DOD/relapse incidence after RIC despite less DOC incidence. This implicates general absence of a clinically relevant GvETE with current protocols.

Allogeneic hematopoietic stem cell transplantation in Glanzmann thrombasthenia complicated by platelet alloimmunization.

BACKGROUND: For Thrombasthenia Glanzmann (GT) patients presenting with a severe clinical phenotype due to complete lack of thrombocyte function or increased titres of anti-platelet antibodies hematopoietic stem cell transplantation (SCT) is the only curative therapy. CASE REPORT: We report the case of a 13-month-old boy, presenting with a severe course of GT, who was successfully treated with an HLA-identical sibling bone marrow transplant. SCT was complicated by anti-platelet alloimmunization after platelet transfusion successfully treated with high dosage immunoglobulins (2 g/kg) and partial plasma exchange. CONCLUSION: SCT may be a viable option for selected patients with GT. However, SCT in GT carries its own significant risks, resulting from the development of anti-platelet antibodies. A critical risk-benefit analysis is mandatory prior to SCT.

Stem cells, melanoma and cancer stem cells: the good, the bad and the evil?

Most cancers contain morphologically heterogeneous populations of cells. While this observation may partly be explained by the coexistence of multiple genetic sub-clones arising through independent somatic mutations and/or as a result of differentiation processes in the tumor microenvironment, it also implies that the tumor may be formed from undifferentiated ''stem cell-like'' cells called ''cancer stem cells'' or ''cancer-initiating cells''. These cells are thought to constitute one or several rare subpopulations in a given tumor and would be strongly responsible for initiation of tumor development and growth as well as for metastasis and recurrence after cytoreductive therapy. However, while the concept of cancer stem cells has been first established for human myeloid leukemia in the 1960s, it has only much later been extended to other solid tumors such as breast or brain cancers and most recently to melanoma. Thus, it is presently unclear which role a sufficiently characterized population of melanoma stem cells plays in cancer promotion and progression. Here, we review the emerging melanoma stem cell model and discuss the biological and therapeutic implications of the model.

Transplantation of highly purified peripheral-blood CD34+ progenitor cells from related and unrelated donors in children with nonmalignant diseases.

Transplantation of allogeneic stem cells is currently the only curative treatment for some nonmalignant pediatric diseases. We investigated whether transplantation of purified CD34(+) stem cells prevents acute and chronic GvHD and reduces transplant-related mortality. A total of 25 pediatric patients with nonmalignant diseases underwent allogeneic transplantation from 26 donors (matched related n=4, matched or partially matched unrelated n=14, mismatched related n=8). All grafts were purified peripheral-blood CD34(+) stem cells mobilized with G-CSF. Patients received a median of 12.9 x 10(6) CD34(+) progenitor cells with a median of 6.1 x 10(3) contaminating T-lymphocytes per kilogram of body weight. No post transplant immunosuppressive drugs were given for prophylaxis of GvHD. Engraftment was seen in 21 patients. Three patients engrafted after a second transplant and one patient failed to engraft. Two patients had autologous reconstitution 1.5 years post transplant and one of them was successfully retransplanted. No acute GvHD >grade II was seen, and only two patients developed limited, chronic GvHD. In all, 22 patients (88%) are alive with a median follow-up of 3.7 years. In total, 19 patients (76%) are free of disease or of progression. Transplantation of highly purified peripheral-blood CD34(+) stem cells is associated with low toxicity in patients with nonmalignant diseases.

Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.

Adenovirus is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation and there is no established therapy. Cidofovir has in vitro efficacy against adenovirus. We performed a retrospective analysis of 45 patients treated with cidofovir for adenovirus from 10 centers. In total, 16 patients had definite adenovirus disease, 13 probable disease, and 16 asymptomatic infections. A total of 31 (69%) patients were successfully treated with cidofovir, 10 failed, and four were not evaluable owing to early death from other causes. Cidofovir therapy was successful in 10 patients with adenovirus disease, 10 patients with probable disease, and in 10 patients with asymptomatic infections. The overall survival at 28 days and 6 months after initiation of cidofovir therapy was 76 and 46%, respectively. Of the patients, 18 developed toxicity associated with cidofovir: 14 developed renal toxicity and four other types of toxicities. We conclude that cidofovir may be useful against adenovirus after allogeneic hematopoietic stem cell transplantation but additional studies are needed.

A prospective comparison of immune reconstitution in pediatric recipients of positively selected CD34+ peripheral blood stem cells from unrelated donors vs recipients of unmanipulated bone marrow from related donors.

Positively selected CD34(+) hematopoietic stem cells from unrelated donors (UD-HSCT) have been successfully transplanted, but little is known about immune reconstitution in this setting. Here we report a prospective comparison of immune reconstitution in recipients of UD-HSCT and of unmanipulated bone marrow from matched sibling donors (MSD-BMT). T-cell reconstitution occurred more than 100 days later in the UD-HSCT than in the MSD-BMT group. The first T cells after UD-HSCT were almost exclusively CD45RO(+) HLA-DR(+), whereas early-emerging T cells after MSD-BMT more frequently expressed CD62L, CD28, and CD25. In both groups, numbers of CD45RA(+) naive T cells increased after 180 days. After UD-HSCT, the T-cell-receptor (TCR)-repertoire was severely skewed and showed significantly reduced diversity during the first year, but only minor abnormalities were seen after MSD-BMT. TCR-diversity increased simultaneously with the number of naive T cells. In both groups, we observed transient expansions of gammadelta T cells. B cells were reconstituted more rapidly in UD-HSCT than in MSD-BMT recipients, whereas the rapidity of NK-cell reconstitution was similar in the two groups. In summary, T-cell reconstitution was slower after UD-HSCT than after MSD-BMT because of the delayed recovery of early memory-type T cells with reduced TCR-diversity, whereas naive T-, NK-, and B cells were reconstituted similarly in the two groups.