VEGF was detected at four weeks (but not one week) PIR and, as noted in Fig 4, VEGF expression increased over time, tracking, approximately, RN lesion development. and RN, systematic screening of tumor and RN therapeutics, and exploring the complex interplay between RN pathogenesis RN and tumor recurrence. Herein, we describe the fundamental clinical challenges associated with RN and the progress made towards addressing these difficulties by combining our novel mouse model of late-onset RN and magnetic resonance imaging (MRI). MRI techniques discussed include standard T1- and T2-weighted imaging, diffusion-weighted imaging, magnetization transfer, and steps of tissue oxygenation. Studies of RN mitigation and neuroprotection are explained, including the use of anti-VEGF antibodies, and inhibitors of GSK-3, HIF-1, and CXCR4. We conclude with some future perspectives around the irradiated brain and the study and treatment of recurrent tumor growing in an irradiated tumor microenvironment. Graphical Abstract Introduction Background The management of high-grade tumors of the central nervous system (CNS) remains a challenging clinical problem, often requiring multimodal therapy including surgical resection, chemotherapy, and radiation (RT). Radiation therapy has traditionally played a central role in the treatment of primary brain tumors. Yet, despite recent improvements in RT treatment precision, local recurrences following therapy remain common. Radiation treatment planning MRS 1754 is usually a complex process involving competing considerations: treating metabolic active tumor and areas of microscopic disease, while minimizing dose to crucial structures and normal brain. Radiation necrosis (RN) is usually a severe, late complication of RT in the brain. Factors associated with increased risk of RN include total RT dose, RT dose per portion, total treatment volume, and use of concurrent chemotherapy. The incidence of RN following radiotherapy is on the rise, with the increased use of concurrent chemotherapy and other novel therapeutic brokers with radiation sensitizing effects [1]. The onset of RN typically occurs 6 or more months following standard fractionated RT or single portion stereotactic radiosurgery. RN is usually a substantial clinical problem often associated with devastating neurologic complications. RN is, therefore, a significant obstacle to safely delivering higher RT doses to areas of disease to improve local control. Clinical symptoms from damage to normal brain following therapeutic radiation can include cognitive decline following whole-brain RT treatment and focal neurologic deficits associated with RN. Patients who develop clinically significant side effects from RT have limited therapeutic options. Therapeutic strategies, including neuroprotectants, have been described, but have not been widely translated in routine clinical use [2]. When clinically significant focal radiation necrosis evolves, interventions, including treatment with steroids and surgical resection, may be required. Additional therapies available include anti-coagulation, pentoxifylline with Vitamin E, hyperbaric oxygen and bevacizumab. Detailed characterization of RN, including the factors that influence its onset and progression, and identification of imaging markers that facilitate noninvasive diagnosis, would significantly and positively impact the clinical management of brain-tumor patients. Together with the identification and development of neuroprotectants to reduce the incidence of necrosis and/or therapeutics to treat necrosis once created, such characterization will allow more ITGA7 aggressive radiation therapy, and minimize the need for a return to the operating room for tissue diagnosis. To these ends, we have developed a mouse model that recapitulates all of the major pathologic features of late-onset RN for the purposes of: (i) characterizing the basic pathogenesis of RN; (ii) identifying non-invasive (imaging) biomarkers MRS 1754 of RN that might allow for the radiologic discernment of tumor and RN, pathologies which demand divergent therapies; (iii) systematic screening of tumor and RN therapeutics, and (iv) exploring the complex interplay between RN pathogenesis RN and tumor recurrence. Herein, we detail the fundamental clinical challenges associated with RN and summarize recent progress made towards addressing these difficulties by combining our novel mouse model MRS 1754 of late-onset RN and magnetic resonance imaging (MRI). Clinical Difficulties Accurate assessment of treatment response remains a challenge in the treatment of primary brain tumors. Standard imaging paradigms are MRS 1754 often unable to distinguish between recurrent tumor and treatment-related changes. Pseudo progression, a phenomenon that mimics tumor progression, occurs following completion of chemo-radiation (chemo-RT) in 20C30% of GBM patients [3C7]. MR imaging following chemo-RT for brain tumor patients often demonstrates an increase in post-gadolinium, T1-weighted image intensity (contrast enhancement) and T2-weighted/FLAIR hyperintensity. Differential diagnosis includes recurrent tumor treatment-related changes or.
VEGF was detected at four weeks (but not one week) PIR and, as noted in Fig 4, VEGF expression increased over time, tracking, approximately, RN lesion development
