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Angels Camp, CA, United States

Kirkpatrick J.P.,Duke University | van der Kogel A.J.,Radboud University Nijmegen | Schultheiss T.E.,City of Hope Cancer Center
International Journal of Radiation Oncology Biology Physics | Year: 2010

Dose-volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8-2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (α/β = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage becoming evident about 6 months post-RT and increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare (<1%) when the maximum spinal cord dose is limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose-volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen. © 2010 Elsevier Inc. All rights reserved. Source


Schultheiss T.E.,City of Hope Cancer Center
Advances in experimental medicine and biology | Year: 2012

Radiation myelopathy is a rare but devastating injury to the spinal cord that usually results from an excessive radiation dose. In this chapter, we discuss the traditional and current understandings of the pathogenesis of this injury. A distinction is made between radiation damage, which occurs at the subcellular level, and radiation injury, which occurs at the tissue and organ level in response to radiation damage. Recent findings regarding the amelioration and treatment of both radiation damage and radiation injury are explored. These studies are promising developments but, as always, there are attendant caveats. Source


Gahrton G.,Karolinska Institutet | Krishnan A.,City of Hope Cancer Center
Expert Review of Hematology | Year: 2014

Allogeneic transplantation has the potential to cure subgroups of patients with multiple myeloma, but its role is controversial due to high transplant-related mortality. Therefore, myeloablative allogeneic transplantation has fallen out of favor. Allogeneic transplantation using reduced-intensity conditioning (RICallo) has lower transplant-related mortality and may be an option for subgroups of patients. Upfront tandem autologous/RICallo (auto/RICallo) was shown to be superior to single auto or tandem auto/auto in both progression-free and overall survival in two studies with long-term follow-up, while four similarly designed studies with shorter follow-up did not show a significant advantage. All studies included patients less than 70 years of age. No study has shown that the auto/RICallo approach is inferior to auto or auto/auto. There have been indications that poor-risk cytogenetics may be overcome by the auto/RICallo approach. Encouraging results have also been seen in treatment of relapsed patients. Small studies indicate that combining allogeneic transplant with new proteasome inhibitors and immunomodulatory drugs may further improve results. Prospective studies including these drugs for induction, conditioning and post-allogeneic transplant maintenance are warranted and planned. New cell therapies, such as with natural killer cells have shown encouraging results in experimental animals and should be tried in combination with allotransplantation. © Informa UK, Ltd. Source


Nguyen L.H.,City of Hope Cancer Center
Advances in experimental medicine and biology | Year: 2012

Advancement of in vitro osteogenesis, or the production of bone, is a complex process that has significant clinical implications. Surgical intervention of several spinal disorders entails decompression of the spinal cord and nerves which can lead to subsequent biomechanical instability of the spine. Spinal arthrodesis (fusion) is often required to correct this instability and necessary to eliminate the resulting pathological motion of vertebral segments. Therefore, the achievement of proper spinal fusion, is a critical determinant of treatment efficacy. This chapter focuses on the molecular and cellular components that are involved in bone growth and healing. Mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are the precursor cells essential for the formation of the five different types of bone cells: osteoprogenitor cells, osteoblasts, osteoclasts, osteocytes and lining cells. Similarly, endothelial progenitor cells (EPCs) differentiate into endothelial cells, which are essential in angiogenesis and neovascularization. MSCs tri-lineage potential (osteogenic, chondrogenic and adipogenic lineages) have made them the focus of most experimental approaches. Here, we describe their individual roles, as well as pose novel concepts on how their collective role may be the optimal strategy to improve upon in vitro osteogenesis and whether this could also be translated to improved bone formation in vivo. Further, we discuss the various molecular markers that are available for cell identification and the tissue engineering strategies that could replicate the osteoinductive, osteoconductive and osteoproductive milieuthat is available in autograft. Finally, we present a broad primer on the possible integration of cellular, molecular and tissue engineering strategies to improve osteogenesis and the future trends that may bring the promise seen in the laboratory to fruition in preclinical animal models. Source


Zhang B.,Beckman Research Institute | Li M.,City of Hope Cancer Center | McDonald T.,Beckman Research Institute | Holyoake T.L.,University of Glasgow | And 4 more authors.
Blood | Year: 2013

Tyrosine kinase inhibitors (TKIs) are highly effective in treatment of chronic myeloid leukemia (CML) but do not eliminate leukemia stemcells (LSCs), which remain a potential source of relapse. TKI treatment effectively inhibits BCR-ABL kinase activity inCML LSCs, suggesting that additional kinase-independent mechanisms contribute to LSC preservation. We investigated whether signals from the bone marrow (BM) microenvironment protect CML LSCs from TKI treatment. Coculture with human BM mesenchymal stromal cells (MSCs) significantly inhibited apoptosis and preserved CML stem/progenitor cells following TKI exposure, maintaining colony-forming ability and engraftment potential in immunodeficient mice. We found that the N-cadherin receptor plays an important role inMSC-mediated protection of CML progenitors fromTKI.N-cadherin-mediated adhesion to MSCs was associated with increased cytoplasmic N-cadherin-β-catenin complex formation as well as enhanced b-catenin nuclear translocation and transcriptional activity. Increased exogenousWnt-mediated b-catenin signaling played an important role in MSC-mediated protection of CML progenitors from TKI treatment. Our results reveal a close interplay between N-cadherin and the Wnt-β-catenin pathway in protecting CML LSCs during TKI treatment. Importantly, these results reveal novel mechanisms of resistance of CML LSCs to TKI treatment and suggest new targets for treatment designed to eradicate residual LSCs in CML patients. © 2013 by The American Society of Hematology. Source

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