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    • The first line of treatment for the majority of primary

    2018-10-20

    The first-line of treatment for the majority of primary malignant molecular weight calculator tumors is maximal safe resection followed by radiation therapy, with or without chemotherapy, based on numerous studies that demonstrate a survival benefit with the addition of radiation (Stupp et al., 2009; Stupp et al., 2005; Roth et al., 1960; Walker et al., 1978; Gaspar et al., 1997). Radiation therapy causes damage to the genetic material of cells and consequently most of these cells die after attempting mitosis (Jackson et al., 2009). This halts progression and recurrence of tumors (Fig. 4). While modern radiation techniques such as intensity-modulated radiation therapy allow for focused treatment, adjacent normal structures continue to receive radiation dose which may lead to functional impairment, such as neurocognitive sequelae (Padovani et al., 2012; Armstrong et al., 2013; Redmond et al., 2013; Panagiotakos et al., 2007; Blomstrand et al., 2012; Gondi et al., 2014). The current theory is that these side effects may in part be related to the radiation dose that the neurogenic niches receive. In this context, several studies have shown that it is possible to reduce radiation dose to the NSCs by defining them as objects at risk during radiation therapy planning (Blomstrand et al., 2012; Gondi et al., 2014; Wan et al., 2013; Oehler et al., 2013; Redmond et al., 2011; Barani et al., 2007; van Kesteren et al., 2012; Gondi et al., 2010). A retrospective study of pediatric patients with medulloblastoma suggested a potential benefit of reducing radiation dose to the neurogenic niches. Specifically, the mean dose to the hippocampus and SVZ was limited to 42.3% without compromising the whole-brain target volume using intensity-modulated proton therapy. The neurogenic niches sparing resulted in a lower risk of developing neurological impairments, compared to more aggressive therapies (Blomstrand et al., 2012). Similarly, a phase II prospective study of patients with brain metastases demonstrated that conformal avoidance of the hippocampus during whole-brain cranial radiation associates with preservation of memory and quality of life (Gondi et al., 2014). By contrast, published studies suggest that tumor outcomes in patients with high-grade gliomas may be improved with higher radiation doses to the SVZ (Chen et al., 2013; Gupta et al., 2012; Kast et al., 2013; Evers et al., 2010; Lee et al., 2013a; Lee et al., 2013b). For example, a retrospective review of patients with glioblastoma treated with radiation and temozolomide chemotherapy demonstrated improved progression-free survival (from 10.3months to 15.1months) in those patients that underwent gross total resection and received >40Gy to the ipsilateral SVZ, compared with patients who received lower radiation doses to this area (Chen et al., 2013). Likewise, a prospective study of hypofractionated radiation therapy for newly diagnosed glioblastoma demonstrated improved outcomes in patients that developed necrosis within the SVZ after radiation (Iuchi et al., 2014). These studies base on the hypothesis that the SVZ plays a role in tumorigenesis, contributing to tumor progression (Chen et al., 2015; Galli et al., 2004; Yan et al., 2013; Quinones-Hinojosa et al., 2007; Jackson et al., 2006). In this context, tumor microenvironment radiation could be affecting the migration of SVZ cells into the tumor, improving patients\' outcomes. Tumor cells need to modify the ECM to invade the normal brain parenchyma. These modifications affect ECM components, such as tenascin, fibronectin, laminin, vitronectin, and different types of collagen, which influence SVZ cells by attracting them into the tumor (Capilla-Gonzalez et al., 2015a; Ziu et al., 2006). However, after irradiating the tumor microenvironment, the incorporation of SVZ-derived cells into the tumor area could be modified, decreasing the SVZ cells-mediated tumorigenic effect. Prospective studies will be critical in further understanding the seemingly contradictory data regarding radiation dose to the SVZ, toxicity, and tumor outcomes (Table 1). At present, two clinical trials are being conducted, in which the radiation treatment plan is modified to deliver higher radiation doses to the NSC compartments (ClinicalTrials.gov Identifiers: NCT02177578, NCT02039778). Another clinical trial, which has completed patient recruitment, aims to establish a relationship between stem cells sparing radiation and an improvement of neurocognitive outcomes in glioblastoma patients (ClinicalTrials.gov Identifiers: NCT01478854). These studies will help determine whether stem cell radiation therapy improves progression-free survival and other outcomes of patients with brain tumor or whether radiation definitively presents a toxic effect.