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Purpose: The success of hematopoietic stem cell transplantation (HSCT) depends on donor cell homing to the bone marrow. However, there is no reliable method of noninvasively monitoring the kinetics and distribution of transferred cells. Using zirconium-89 (89Zr)-oxine cell labeling combined with PET imaging, we sought to visualize and quantify donor cell homing in a mouse bone marrow transplantation model.Experimental Design: The effect of 89Zr-oxine labeling on bone marrow cell viability and differentiation was evaluated in vitro. 89Zr-labeled bone marrow cells (2 × 107 cells, 16.6 kBq/106 cells) were transferred intravenously, and serial microPET images were obtained (n = 5). The effect of a CXCR4 inhibitor, plerixafor (5 mg/kg) and G-CSF (2.5 μg) on bone marrow homing and mobilization were examined (n = 4). Engraftment of the transferred 89Zr-labeled cells was evaluated (n = 3).Results: 89Zr-oxine–labeled bone marrow cells showed delayed proliferation, but differentiated normally. Transferred bone marrow cells rapidly migrated to the bone marrow, spleen, and liver (n = 5). Approximately 36% of donor cells homed to the bone marrow within 4 hours, irrespective of prior bone marrow ablation. Inhibition of CXCR4 by plerixafor alone or with G-CSF significantly blocked the bone marrow homing (P < 0.0001, vs. nontreated, at 2 hours), confirming a crucial role of the CXCR4–CXCL12 system. Mobilization of approximately 0.64% of pretransplanted bone marrow cells induced a 3.8-fold increase of circulating bone marrow cells. 89Zr-labeled donor cells engrafted as well as nonlabeled cells.Conclusions: 89Zr-oxine PET imaging reveals rapid bone marrow homing of transferred bone marrow cells without impairment of their stem cell functions, and thus, could provide useful information for optimizing HSCT. Clin Cancer Res; 23(11); 2759–68. ©2016 AACR.

Purpose: Patients with large, high-grade soft tissue sarcomas are commonly treated with aggressive limb preservation regimens. This study aimed to assess cancer control outcomes of patients treated with neoadjuvant chemoradiation (CRT) compared with radiation therapy (RT) alone. Methods: We reviewed records of patients with high-grade extremity or trunk soft tissue sarcomas ≥5 cm who were treated with neoadjuvant radiation with or without chemotherapy. Patient and disease characteristics were compared using t test and χ2 tests. Standardized mortality ratio weighted method was used to compare overall survival (OS), local control, and disease-free (DFS) survival. Acute radiation and surgical toxicity were reported. Results: In the study, 64 patients (34 CRT and 30 RT) treated between 1997 and 2015 were analyzed. In the RT group compared with the CRT group, the patient population was older, with a median age of 65 versus 50 years (P < .001), and more likely to have cardiovascular disease (CVD; 30% vs 0%, P < .001). At a median follow-up of 41 months, after adjusting for propensity score of receiving RT, the 3-year LC was 87.3% versus 86.1%, DFS was 58.5% versus 56.6%, and OS was 75.6% versus 69.0% for the CRT and RT groups, respectively (P > .05). Acute dermatitis occurred in 18% versus 3% and surgical complications occurred in 32% versus 17% of CRT and RT patients, respectively. Conclusions: In this study, patients receiving RT alone were more likely to be older and have comorbid cardiovascular disease. When controlling for baseline differences, neoadjuvant CRT and RT provided similar rates of LC, DFS, and OS.

Purpose: The success of hematopoietic stem cell transplantation (HSCT) depends on donor cell homing to the bone marrow. However, there is no reliable method of noninvasively monitoring the kinetics and distribution of transferred cells. Using zirconium-89 (89Zr)-oxine cell labeling combined with PET imaging, we sought to visualize and quantify donor cell homing in a mouse bone marrow transplantation model. Experimental Design: The effect of 89Zr-oxine labeling on bone marrow cell viability and differentiation was evaluated in vitro. 89Zr-labeled bone marrow cells (2 × 107 cells, 16.6 kBq/106 cells) were transferred intravenously, and serial microPET images were obtained (n = 5). The effect of a CXCR4 inhibitor, plerixafor (5 mg/kg) and G-CSF (2.5 μg) on bone marrow homing and mobilization were examined (n = 4). Engraftment of the transferred 89Zr-labeled cells was evaluated (n = 3). Results: 89Zr-oxine–labeled bone marrow cells showed delayed proliferation, but differentiated normally. Transferred bone marrow cells rapidly migrated to the bone marrow, spleen, and liver (n = 5). Approximately 36% of donor cells homed to the bone marrow within 4 hours, irrespective of prior bone marrow ablation. Inhibition of CXCR4 by plerixafor alone or with G-CSF significantly blocked the bone marrow homing (P < 0.0001, vs. nontreated, at 2 hours), confirming a crucial role of the CXCR4–CXCL12 system. Mobilization of approximately 0.64% of pretransplanted bone marrow cells induced a 3.8-fold increase of circulating bone marrow cells. 89Zr-labeled donor cells engrafted as well as nonlabeled cells. Conclusions: 89Zr-oxine PET imaging reveals rapid bone marrow homing of transferred bone marrow cells without impairment of their stem cell functions, and thus, could provide useful information for optimizing HSCT. Clin Cancer Res; 23(11); 2759–68. ©2016 AACR.

In hematopoietic stem cell (HSC) transplantation, the efficacy of bone marrow homing and engraftment of HSCs directly correlates with the success of treatment. At the same time, reduction of graft-versus-host-disease (GVHD) incidence would be critical. Development of a non-invasive, real time monitoring system for the donor cells would be important for optimizing the HSC transplantation conditions. Recently, we have developed a 89Zr-oxine complex cell labeling technique that enables visualization of cell trafficking at a high sensitivity using positron emission tomography (PET)/computed tomography (CT) imaging. We employed this technique to monitor bone marrow transplantations in mice. PET/CT imaging visualized that 89Zr-labeled donor bone marrow cells rapidly migrated to the bone marrow of the recipient, as well as to the spleen and liver. More than 20% of the donor cells homed to the bone marrow within 4 hours, irrespective of prior bone marrow ablation. While monitoring the donor cell homing, we have found that a small fraction of cells migrating to the intestine. This was observed only when the recipient mice had undergone a conditioning by a whole-body irradiation and the cells targeted the distal part of the small intestine. The most of the cells expressed CD45 and CD103. These cells could be the cause of GVHD in case of allogeneic transplantation. 89Zr PET/CT would be useful to monitor donor cell trafficking in HSC transplantations.