Allogeneic hematopoietic stem cell transplantation in two brothers with DNA ligase IV deficiency: a case report and review of the literature.

BACKGROUND: DNA ligase IV deficiency is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA ligase IV (LIG4) gene. DNA ligase IV is an essential protein for the development of a healthy immune system as well as for the protection of genomic integrity. Apart from typical stigmata, patients with DNA ligase IV deficiency are characterized by progressive bone marrow failure and a predisposition to malignancy. To our knowledge this reported case is the first description of two brothers with ligase IV deficiency who are treated with different hematopoietic stem cell transplantation (HSCT) regimens resulting in vastly divergent outcomes. CASE PRESENTATION: The cases of two brothers suffering from severe recurrent infections and growth retardation are described. The laboratory findings showed pancytopenia with significant lymphopenia. The two boys were diagnosed with DNA ligase IV deficiency, associated with severe combined immunodeficiency (SCID). Both patients received HSCT from two different matched unrelated donors (MUD) at the age of 33 and 18 months. The older brother succumbed post-transplant due to fatal side-effects 143 days after allogeneic HSCT. The younger brother - conditioned with a different regimen - received a T cell depleted graft 4 months later. No severe side-effects occurred, neither post-transplant nor in the following years. Ten years after HSCT the patient is well off, living a normal life and attending a regular high school. His immune system is fully reconstituted, resulting in a maximum of T cell receptor (TCR) diversity, which is a prerequisite for immune competence. However, he still suffers from microcephaly, dwarfism and dystrophy. CONCLUSIONS: This case report gives an example of a successful HSCT as a treatment option in a genetic disorder such as ligase IV deficiency, using a rather mild conditioning regimen. Further studies are required to determine the viability and efficacy of this treatment option.

Correction to: Allogeneic hematopoietic stem cell transplantation in two brothers with DNA ligase IV deficiency: a case report and review of the literature.

After publication of the original article (1), it was brought to our attention that references 24 and 31 are inappropriately cited in the article.

Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed.

BACKGROUND: Ganglioneuroma (GN) and ganglioneuroblastoma intermixed (GNBI) are mature variants of neuroblastic tumors (NT). It is still discussed whether incomplete resection of GN/GNBI impairs the outcome of patients. METHODS: Clinical characteristics and outcome of localized GN/GNBI were retrospectively compared to localized neuroblastoma (NB) and ganglioneuroblastoma-nodular (GNBN) registered in the German neuroblastoma trials between 2000 and 2010. RESULTS: Of 808 consecutive localized NT, 162 (20 %) were classified as GN and 55 (7 %) as GNBI. GN/GNBI patients presented more often with stage 1 disease (68 % vs. 37 %, p < 0.001), less frequently with adrenal tumors (31 % vs. 43 %, p = 0.001) and positive mIBG-uptake (34 % vs. 90 %, p < 0.001), and had less often elevated urine catecholamine metabolites (homovanillic acid 39 % vs. 62 %, p < 0.001, vanillylmandelic acid 27 % vs. 64 %, p < 0.001). Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001). Complete tumor resection was achieved at diagnosis in 70 % of 162 GN and 67 % of 55 GNBI, and after 4 to 32 months of observation in 4 GN (2 %) and 5 GNBI (9 %). Eleven patients received chemotherapy without substantial effect. Fifty-five residual tumors (42 GN, 13 GNBI) are currently under observation (median: 44 months). Five patients (3 GN, 2 GNBI) showed local progression; all had tumor residuals > 2 cm. No progression occurred after subtotal resection. Two patients died of treatment, none of tumor progression. CONCLUSIONS: GN/GNBI account for one quarter of localized NT and differ from immature tumors in their clinical features. Chemotherapy is not effective. Subtotal resection appears to be a sufficient treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers - NB97 (NCT00017225; registered June 6, 2001); NB2004 (NCT00410631; registered December 11, 2006).

Long-term human CD34+ stem cell-engrafted nonobese diabetic/SCID/IL-2R gamma(null) mice show impaired CD8+ T cell maintenance and a functional arrest of immature NK cells.

Allogeneic hematopoietic stem cell transplantation represents the most effective form of immunotherapy for chemorefractory diseases. However, animal models have been missing that allow evaluation of donor-patient-specific graft-versus-leukemia effects. Thus, we sought to establish a patient-tailored humanized mouse model that would result in long-term engraftment of various lymphocytic lineages and would serve as a donor-specific surrogate. Following transfer of donor-derived peripheral blood stem cells into NOD/SCID/IL-2Rgamma(null) (NSG) mice with supplementation of human IL-7, we could demonstrate robust engraftment and multilineage differentiation comparable to earlier studies using cord blood stem cells. Phenotypical and functional analyses of lymphoid lineages revealed that >20 wk posthematopoietic stem cell transplantation, the majority of T lymphocytes consisted of memory-type CD4(+) T cells capable of inducing specific immune functions, whereas CD8(+) T cells were only present in low numbers. Analysis of NSG-derived NK cells revealed the expression of constitutively activated CD56(bright)CD16(-) killer Ig-like receptor(negative) NK cells that exhibited functional impairments. Thus, the data presented in this study demonstrate that humanized NSG mice can be successfully used to develop a xenotransplantation model that might allow patient-tailored treatment strategies in the future, but also highlight the need to improve this model, for example, by coadministration of differentiation-promoting cytokines and induction of human MHC molecules to complement existing deficiencies in NK and CD8(+) T cell development.

Feasibility and outcome of reduced-intensity conditioning in haploidentical transplantation.

Allogeneic stem cell transplantation is for a number of patients with malignant and nonmalignant diseases the only curative approach. For those patients who do not have an HLA-identical-related or -unrelated stem cell donor, a related three-loci mismatch haploidentical stem cell transplantation with T cell-depleted stem cells is a viable option. T cell depletion either by CD34(+) positive selection or by CD3-negative depletion strategies is available and has been investigated. We have shown that reduced-intensity conditioning haploidentical transplantation using mobilized peripheral stem cells negatively depleted from T and B lymphocytes is associated with a rapid immune reconstitution, a low transplant-related mortality rate, and a favorable outcome in patients in remission at the time of transplant. For chemorefractory patients, additional posttransplant cellular and humoral immunotherapeutic strategies are needed for prevention of relapse after transplantation.

Mesenchymal stromal cells for treatment of steroid-refractory GvHD: a review of the literature and two pediatric cases.

Severe acute graft versus host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. Human mesenchymal stromal cells (MSCs) play an important role in endogenous tissue repair and possess strong immune-modulatory properties making them a promising tool for the treatment of steroid-refractory GvHD. To date, a few reports exist on the use of MSCs in treatment of GvHD in children indicating that children tend to respond better than adults, albeit with heterogeneous results.We here present a review of the literature and the clinical course of two instructive pediatric patients with acute steroid-refractory GvHD after haploidentical stem cell transplantation, which exemplify the beneficial effects of third-party transplanted MSCs in treatment of acute steroid-refractory GvHD. Moreover, we provide a meta-analysis of clinical studies addressing the outcome of patients with steroid-refractory GvHD and treatment with MSCs in adults and in children (n = 183; 122 adults, 61 children). Our meta-analysis demonstrates that the overall response-rate is high (73.8%) and confirms, for the first time, that children indeed respond better to treatment of GvHD with MSCs than adults (complete response 57.4% vs. 45.1%, respectively).These data emphasize the significance of this therapeutic approach especially in children and indicate that future prospective studies are needed to assess the reasons for the observed differential response-rates in pediatric and adult patients.

Retransplantation with stem cells from mismatched related donors after graft rejection in pediatric patients.

Graft failure is a life-threatening complication after transplantation of hematopoietic stem cells. We report a cohort of 11 pediatric patients with leukemias (n=8) and severe aplastic anemia (n=3) who experienced graft rejection after myeloablative transplantation from mismatched related donors (n=6) or after cord blood or matched unrelated donor transplantation (n=5). In the latter, the original donor was not available anymore. All patients were re-transplanted with CD34(+) selected or CD3/CD19 depleted stem cells from a second, haploidentical donor. Median time span from diagnosis of rejection to second transplant was 9 days. Reconditioning regimens comprised total lymphoid irradiation, thiotepa, fludarabine, ATG/OKT3 and were well tolerated. A median number of 23.5x10(6)/kg stem cells with 95,000/kg residual T-cells were infused. Sustained engraftment of neutrophiles/platelets and complete donor chimerism was achieved in all patients (ANC>500/microl: 9 (11-32) days). No GvHD>grade II was observed. 8/11 patients are disease free (median follow up 1.9 years; 1 year-EFS=72%). Causes of death were: pneumonitis, infection, relapse. Thus, haploidentical transplantation represents a realistic option to rescue patients with graft failure within a short time span, for whom a second donation from the original donor is not available. The use of different donors may contribute to avoid a second rejection.

Extracorporeal shock wave therapy for plantar fasciitis: randomised controlled multicentre trial.

OBJECTIVE: To determine the effectiveness of extracorporeal shock wave therapy compared with placebo in the treatment of chronic plantar fasciitis. DESIGN: Randomised, blinded, multicentre trial with parallel group design. SETTING: Nine hospitals and one outpatient clinic in Germany. PARTICIPANTS: 272 patients with chronic plantar fasciitis recalcitrant to conservative therapy for at least six months: 135 patients were allocated extracorporeal shock wave therapy and 137 were allocated placebo. MAIN OUTCOME MEASURES: Primary end point was the success rate 12 weeks after intervention based on the Roles and Maudsley score. Secondary end points encompassed subjective pain ratings and walking ability up to a year after the last intervention. RESULTS: The primary end point could be assessed in 94% (n=256) of patients. The success rate 12 weeks after intervention was 34% (n=43) in the extracorporeal shock wave therapy group and 30% (n=39) in the placebo group (95% confidence interval - 8.0% to 15.1%). No difference was found in the secondary end points. Few side effects were reported. CONCLUSIONS: Extracorporeal shock wave therapy is ineffective in the treatment of chronic plantar fasciitis.