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Guidetti A.,Cristina Gandini Medical Oncology Unit | Carlo-Stella C.,Cristina Gandini Medical Oncology Unit | Carlo-Stella C.,University of Milan | Ruella M.,University of Turin | And 15 more authors.
Cancer | Year: 2011

BACKGROUND: Because the long-term toxicity of myeloablative radioimmunotherapy remains a matter of concern, the authors evaluated the hematopoietic damage and incidence of secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/AML) in patients who received myeloablative doses of the radiolabeled antibody yttrium-90 ( 90Y)-ibritumomab tiuxetan. METHODS: The occurrence of sMDS/AML was investigated prospectively in 53 elderly patients with non-Hodgkin lymphoma (NHL) who underwent an autograft after high-dose radioimmunotherapy (HD-RIT) myeloablative conditioning with 90Y-ibritumomab tiuxetan. Bone marrow (BM) hematopoietic progenitors and telomere length (TL) also were investigated. RESULTS: At a median follow-up of 49 months, 4 patients developed sMDS/AML at 6 months, 12 months, 27 months, and 36 months after HD-RIT, and the 5-year cumulative incidence of sMDS/AML was 8.29%. A significant but transient decrease in BM granulocyte-macrophage progenitors was observed; whereas multilineage, erythroid, and fibroblast progenitors were unaffected. A significant and persistent shortening of BM TL also was detected. A matched-pair analysis comparing the study patients with 55 NHL patients who underwent autografts after chemotherapy-based myeloablative conditioning demonstrated a 8.05% 5-year cumulative incidence of sMDS/AML. CONCLUSIONS: HD-RIT for patients with NHL was associated with 1) limited toxicity on hematopoietic progenitors, 2) accelerated TL shortening, and 3) non-negligible incidence of sMDS/AML, which nevertheless was comparable to the incidence observed in a matched group of patients who received chemotherapy-based conditioning. Thus, in the current series of elderly patients with NHL, the development of sMDS/AML was not influenced substantially by HD-RIT. Cancer © 2011 American Cancer Society. Source

Lavazza C.,Cristina Gandini Medical Oncology Unit | Lavazza C.,University of Milan | Carlo-Stella C.,Cristina Gandini Medical Oncology Unit | Carlo-Stella C.,University of Milan | And 16 more authors.
Blood | Year: 2010

Adenovirus-transduced CD34 + cells expressing membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL + cells) exert potent antitumor activity. To further investigate the mechanism(s) of action of CD34-TRAIL + cells, we analyzed their homing properties as well as antitumor and antivascular effects using a subcutaneous myeloma model in immunodeficient mice. After intravenous injection, transduced cells homed in the tumor peaking at 48 hours when 188 plus or minus 25 CD45 + cells per 10 5 tumor cells were detected. Inhibition experiments showed that tumor homing of CD34-TRAIL + cells was largely mediated by vascular cell adhesion molecule-1 and stromal cell-derived factor-1. Both CD34-TRAIL + cells and soluble (s)TRAIL significantly reduced tumor volume by 40% and 29%, respectively. Computer-aided analysis of TdT-mediated dUTP nick end-labeling-stained tumor sections demonstrated significantly greater effectiveness for CD34-TRAIL + cells in increasing tumor cell apoptosis and necrosis over sTRAIL. Proteome array analysis indicated that CD34-TRAIL + cells and sTRAIL activate similar apoptotic machinery. In vivo staining of tumor vasculature with sulfosuccinimidyl-6-(biotinamido) hexanoate-biotin revealed that CD34-TRAIL + cells but not sTRAIL significantly damaged tumor vasculature, as shown by TdT-mediated dUTP nick end-labeling + endothelial cells, appearance of hemorrhagic areas, and marked reduction of endothelial area. These results demonstrate that tumor homing of CD34-TRAIL + cells induces early vascular disruption, resulting in hemorrhagic necrosis and tumor destruction. © 2010 by The American Society of Hematology. Source

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