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Morgan D. Schulz, MD, Kimberly Ann V. Zubris, PhD, Jacqueline E

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1 Paclitaxel-Loaded Expansile Nanoparticles in a Multimodal Treatment Model of Malignant Mesothelioma 
Morgan D. Schulz, MD, Kimberly Ann V. Zubris, PhD, Jacqueline E. Wade, BS, Robert F. Padera, MD, PhD, Xiaoyin Xu, PhD, Mark W. Grinstaff, PhD, Yolonda L. Colson, MD, PhD  The Annals of Thoracic Surgery  Volume 92, Issue 6, Pages (December 2011) DOI: /j.athoracsur Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

2 Fig 1 Cytoreductive surgery with intraoperative intracavitary chemotherapy in a mouse model of malignant mesothelioma. At 14 days post-xenograft implantation, the bulk of solid tumor burden (A) is within the omentum (dashed circle) and the lower abdominal fat pads (arrows indicate tumor nodules). The abdominal fat pads are ligated and divided (B), and omental tumor (C) is resected following clamp hemostasis (D). Following removal of all resectable solid tumor (E), a 24G catheter is used to instill drug or control solution (F) just prior to completing fascial closure. The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

3 Fig 2 Cytoreductive surgery achieves significant reduction of viable tumor burden. Bioluminescent imaging of representative animals at 14 days of tumor growth before cytoreductive surgery (A) and 24 hours after cytoreductive surgery (B), done with a Xenogen IVIS 100 bioluminescence imaging station with a 2-second exposure time after the administration of 150 mg/kg firefly luciferin, shows significant reduction of viable tumor burden after cytoreductive surgery. The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

4 Fig 3 Overall survival after cytoreductive surgery (CRS). Mice that underwent surgical debulking without adjuvant chemotherapy at 14 days after establishment of mesothelioma xenograft (n = 8) and animals with untreated disease (n = 11) were monitored until morbid disease progression necessitated euthanasia. The median survival was 35 days in untreated animals and 42 days among animals treated with cytoreductive surgery without adjuvant intraoperative chemotherapy (p = 0.137). The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

5 Fig 4 Adjuvant treatment with paclitaxel-loaded expansile nanoparticles (eNP) improves survival as compared with surgery alone. Overall survival from time of establishment of mesothelioma xenograft was compared among untreated animals (n = 11), animals that underwent cytoreductive surgery (CRS) with intraoperative intracavitary chemotherapy (10 mg/kg paclitaxel as paclitaxel–Cremophor EL [Pax-CE] or paclitaxel-loaded expansile nanoparticles [Pax-eNP], n = 9/group), and animals in which cytoreductive surgery was performed with a volume-equivalent vehicle control consisting of unloaded expansile nanoparticle polymer (n = 8) at fascial closure. Median survival was prolonged to 53 days among animals treated with either paclitaxel formulation (p < vs no cytoreductive surgery; p = vs cytoreductive surgery alone). Median overall survival of animals treated with paclitaxel–Cremophor EL was 52 days (range, 29 to 66 days, p = vs no cytoreductive surgery; p = vs saline). Treatment with paclitaxel-loaded expansile nanoparticles resulted in a statistically significant increase in survival relative to both untreated disease and cytoreductive surgery without adjuvant paclitaxel (54 days; range, 49 to 104 days; p < vs no cytoreductive surgery, p = vs unloaded expansile nanoparticles). The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions


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