Escalating topotecan in combination with treosulfan has acceptable toxicity in advanced pediatric sarcomas.

Patients with advanced pediatric sarcomas have a poor prognosis and novel combination therapies are needed to improve the response rates. Hematological and organ related toxicities have been observed when administering topotecan in combination with, e. g., high dose thiotepa. This study evaluates the toxicity of escalating doses of topotecan alone or in combination with thiotepa or treosulfan. We compared the toxicity including death of complication (DOC) of topotecan alone or in combination with thiotepa or treosulfan in advanced pediatric sarcomas (n = 12). Ten of 12 patients (0.83) suffered from advanced tumors of the Ewing family (i.e., bone or marrow metastases or relapse <24 month after diagnosis, including one neuroepithelial tumor of the kidney) and two from alveolar rhabdomyosarcoma stage IV (0.17). Median age was 15 years (range 5-28). Ratio of female to male was 1:1. Two patients received topotecan alone (1.25 mg/m(2) q 5d and 1.5 mg/m(2) q 5d), three patients received four courses of topotecan (2 mg/m(2) q d 1-5) in combination with thiotepa (100 mg/m(2) q d 1-5), and seven patients received topotecan (2 mg/m(2) q d 1-5) in combination with treosulfan (10g/m(2) q d 3-5). Overall toxicity was not different between all three groups; mean scores were 1.6, 1.8, and 1.7 according to WHO grading (Scale 0-4). Organ related toxicity ranged between 0 and 4 and was not different as well. DOC was 0/2, 1/3, and 0/7 patients respectively. Escalating therapy with topotecan in combination with treosulfan has acceptable toxicity and warrants further investigation in advanced pediatric sarcomas

Podoplanin increases migration and angiogenesis in malignant glioma.

Expression of podoplanin in glial brain tumors is grade dependent. While serving as a marker for tumor progression and modulating invasion in various neoplasms, little is known about podoplanin function in gliomas. Therefore we stably transfected two human glioma cell lines (U373MG and U87MG) with expression plasmids encoding podoplanin. The efficacy of transfection was confirmed by FACS analysis, PCR and immunocytochemistry. Cells were then sorted for highly podoplanin expressing cells (U373P(high)/U87P(high)). Transfection did not influence the production of pro-angiogenic factors including VEGF, VEGF-C and D. Also, expression of VEGF receptors (VEGFR) remained unchanged except for U87P(high), where a VEGFR3 expression was induced. U373P(high) showed significantly reduced proliferation as compared to mock transfected group. By contrast, podoplanin significantly increased migration and invasion into collagen matrix. Furthermore, conditioned media from P(high) glioma cells strongly induced tube formation on matrigel. In conclusion, podoplanin increased migration of tumor cells and enhanced tube formation activity in endothelial cells independent from VEGF. Thus, podoplanin expression may be an important step in tumor progression

Strong expression of CXCL12 is associated with a favorable outcome in osteosarcoma.

Hematogenous spread determines the outcome of osteosarcoma (OS) patients, but the pathogenesis of developing metastatic disease is still unclear. Chemokines are critical regulators of cell trafficking and adhesion, and have been reported to be aberrantly expressed and to correlate with an unfavorable prognosis and metastatic spread in several malignant tumors. The chemokine receptors CXCR4 and CXCR7 together with their common ligand CXCL12 form one of the most important chemokine axes in this context. To investigate a potential role of these chemokines in OSs, we analyzed their expression in a series of 223 well-characterized and pretherapeutic OS samples. Interestingly, we found the expression of CXCL12 and CXCR4 to correlate with a better long-term outcome and with a lower prevalence of metastases. These findings suggest a distinct role of CXCR4/CXCR7/CXCL12 signaling in the tumors of bone, as has also been previously described in acute leukemia. As many malignant tumors metastasize to bone, and tumor cells are thought to be directed to bone in response to CXCL12, OS cells expressing both CXCL12 and the corresponding receptors might be detained at their site of origin. The disruption of CXCR4/CXCR7/CXCL12 signaling could therefore be crucial in OSs for the migration of tumor cells from bone into circulation and for developing systemic disease

Effect of a single autologous cord blood infusion on beta-cell and immune function in children with new onset type 1 diabetes: A non-randomized, controlled trial.

Background The application of autologous cord blood in children with type 1 diabetes has been found to be safe, but not to preserve beta-cell function in a previous study, which, however, had not included a control group. Objective To compare the changes of metabolic and immune function over time between cord blood infused children and natural controls. Subjects and methods Seven children with newly diagnosed type 1 diabetes underwent a single autologous cord blood infusion and 10 children were enrolled as natural controls in a non-randomized, controlled, open label intervention trial. Primary analyses were performed 1 year following cord blood infusion. Cases and controls were compared regarding metabolic [area under the curve (AUC) and peak C-peptide, insulin use, and HbA1c] and immune outcome (islet autoantibody titer and T-cell response), adjusted for age, gender, diabetes duration, and baseline levels. Results There were no significant adverse events related to the infusion. Metabolic and immune outcomes were not significantly different at 12 months follow-up between infused children and controls (e.g., adjusted p = 0.244 for AUC C-peptide, adjusted p = 0.820 for insulin use, adjusted p = 0.772 for peripheral regulatory T cells). Six-month change of AUC C-peptide correlated significantly with the number of infused CD34+ cells (r = 0.931, p = 0.002). Conclusions An autologous cord blood infusion does not change the natural course of metabolic and immune parameters after disease onset. However, the content of CD34+ cells in the stored blood sample might offer potential for improvement of future cell therapies