Tissue damage caused by exposure to pathogens, chemicals and physical agents such as ionizing radiation triggers production of generic "danger" signals that mobilize the innate and acquired immune system to deal with the intrusion and effect tissue repair with the goal of maintaining the integrity of the tissue and the body. Ionizing radiation appears to do the same, but less is known about the role of "danger" signals in tissue responses to this agent. This review deals with the nature of putative "danger" signals that may be generated by exposure to ionizing radiation and their significance. There are a number of potential consequences of "danger" signaling in response to radiation exposure. "Danger" signals could mediate the pathogenesis of, or recovery from, radiation damage. They could alter intrinsic cellular radiosensitivity or initiate radioadaptive responses to subsequent exposure. They may spread outside the locally damaged site and mediate bystander or "out-of-field" radiation effects. Finally, an important aspect of classical "danger" signals is that they link initial nonspecific immune responses in a pathological site to the development of specific adaptive immunity. Interestingly, in the case of radiation, there is little evidence that "danger" signals efficiently translate radiation-induced tumor cell death into the generation of tumor-specific immunity or normal tissue damage into autoimmunity. The suggestion is that radiation-induced "danger" signals may be inadequate in this respect or that radiation interferes with the generation of specific immunity. There are many issues that need to be resolved regarding "danger" signaling after exposure to ionizing radiation. Evidence of their importance is, in some areas, scant, but the issues are worthy of consideration, if for no other reason than that manipulation of these pathways has the potential to improve the therapeutic benefit of radiation therapy. This article focuses on how normal tissues and tumors sense and respond to danger from ionizing radiation, on the nature of the signals that are sent, and on the impact on the eventual consequences of exposure.

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A distinguishing feature of high-grade gliomas is the infiltration of neoplastic cells into adjacent brain tissues that mark most of these tumors surgically incurable. To study the factors associated with tumor invasion, we established a new murine brain tumor model, ALTS1C1 derived from SV40 large T antigen-transfected astrocytes. This new brain tumor model recapitulates several histopathological features of human high-grade glioma including increased cellularity, prominent cellular pleomorphism, geographic necrosis, active mitosis, and extensive invasion of tumor cells into adjacent brain tissues. More importantly, ALTS1C1 expressed a relatively high level of stromal-derived factor-1 (SDF-1/CXCL12) in vitro and in vivo and higher microvascular density (MVD) in vivo. To define the roles of SDF-1 in this tumor model, the expression of SDF-1 in ALTS1C1 cells was inhibited by specific siRNA. SDF-knockdown ALTS1C1 (SDF kd ) cells took longer than parental ALTS1C1 cells to form tumors and in contrast to the wild-type tumors they had well-defined regular borders and lacked infiltration tracts. The SDF kd tumors were also associated with a lower MVD and more hypoxic areas. In contrast to parental tumors, the density of F4/80-positive tumor-associated macrophages (TAMs) in SDF kd tumor was higher in non-hypoxic than in hypoxic regions. SDF-1 production by tumor cells therefore seems critical for the aggregation of TAMs into areas of hypoxia and tumor invasiveness. This study not only provides new insight into the role of SDF-1 in brain tumor invasion and the relationship between TAMs and hypoxia, but also provides a new preclinical brain tumor model for designing new treatment options for invasive cases.

Macrophages display different phenotypes with distinct functions and can rapidly respond to environmental changes. Previous studies on TRAMP-C1 tumor model have shown that irradiation has a strong impact on tumor microenvironments. The major changes include the decrease of microvascular density, the increase of avascular hypoxia, and the aggregation of tumor-associated macrophages in avascular hypoxic regions. Similar changes were observed no matter the irradiation was given to tissue bed before tumor implantation (pre-IR tumors), or to established tumors (IR tumors). Recent results on three murine tumors, TRAMP-C1 prostate adenocarcinoma, ALTS1C1 astrocytoma, and GL261 glioma, further demonstrate that different phenotypes of inflammatory cells are spatially distributed into different microenvironments in both IR and pre-IR tumors. Regions with avascular hypoxia and central necrosis have CD11bhigh/Gr-1+ neutrophils in the center of the necrotic area. Next to them are CD11blow/F4/80+ macrophages that sit at the junctions between central necrotic and surrounding hypoxic regions. The majority of cells in the hypoxic regions are CD11blow/CD68+ macrophages. These inflammatory cell populations express different levels of Arg I. This distribution pattern, except for neutrophils, is not observed in tumors receiving chemotherapy or an anti-angiogenesis agent which also lead to avascular hypoxia. This unique distribution pattern of inflammatory cells in IR tumor sites is interfered with by targeting the expression of a chemokine protein, SDF-1α, by tumor cells, and this also increases radiation-induced tumor growth delay. This indicates that irradiated-hypoxia tissues have distinct tumor microenvironments that favor the development of M2 macrophages and that is affected by the levels of tumor-secreted SDF-1α.

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Purpose: The physical properties of proton therapy allow for decreased dose delivery to nontarget structures. The purpose of this study was to determine if this translates into a clinical benefit by comparing acute and chronic morbidity between patients with nasopharyngeal carcinoma who are treated with intensity-modulated proton therapy (IMPT) and those treated with intensity-modulated radiation therapy (IMRT). Materials and Methods: Patients receiving IMPT for nasopharyngeal cancer from 2011-13 were matched in a 2:1 IMPT to IMRT ratio. Matching criteria were, in order, T-stage, N-stage, radiation dose, chemotherapy type, World Health Organization classification, sex, and age. Results: Ten patients treated with IMPT and 20 matched patients treated with IMRT were included. By the end of treatment, 2 IMPT-treated patients (20%) and 13 IMRTtreated patients (65%) required gastrostomy tube (GT) insertion (P ¼ .020). Patients receiving IMPT had significantly lower mean doses to the oral cavity, brainstem, whole brain, and mandible. Increased mean dose to the oral cavity was associated with a higher rate of GT placement (P , .001), but mean dose to the brainstem, whole brain, and mandible was not. Partitioning analysis showed that no patient required GT insertion if the mean oral cavity dose was ,26 Gy, but all patients with a mean oral cavity dose. 41.8 Gy required GT insertion. Treatment type (IMPT versus IMRT), induction chemotherapy (yes versus no), mean oral cavity dose, mean brainstem dose, and mean mandible dose were entered into the multivariable model. Only higher mean oral cavity dose remained significantly associated with higher GT rates on multivariable analysis http://theijpt.org

This study shows that dual-phase FDG-PET is superior to conventional FDG-PET or MRI-CT in the evaluation of metastatic lesions in locally advanced or recurrent cervical cancer.