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      Proton minibeam radiation therapy widens the therapeutic index for high-grade gliomas

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          Abstract

          Proton minibeam radiation therapy (pMBRT) is a novel strategy which has already shown a remarkable reduction in neurotoxicity as to compared with standard proton therapy. Here we report on the first evaluation of tumor control effectiveness in glioma bearing rats with highly spatially modulated proton beams. Whole brains (excluding the olfactory bulb) of Fischer 344 rats were irradiated. Four groups of animals were considered: a control group (RG2 tumor bearing rats), a second group of RG2 tumor-bearing rats and a third group of normal rats that received pMBRT (70 Gy peak dose in one fraction) with very heterogeneous dose distributions, and a control group of normal rats. The tumor-bearing and normal animals were followed-up for 6 months and one year, respectively. pMBRT leads to a significant tumor control and tumor eradication in 22% of the cases. No substantial brain damage which confirms the widening of the therapeutic window for high-grade gliomas offered by pMBRT. Additionally, the fact that large areas of the brain can be irradiated with pMBRT without significant side effects, would allow facing the infiltrative nature of gliomas.

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          Understanding survival analysis: Kaplan-Meier estimate

          Kaplan-Meier estimate is one of the best options to be used to measure the fraction of subjects living for a certain amount of time after treatment. In clinical trials or community trials, the effect of an intervention is assessed by measuring the number of subjects survived or saved after that intervention over a period of time. The time starting from a defined point to the occurrence of a given event, for example death is called as survival time and the analysis of group data as survival analysis. This can be affected by subjects under study that are uncooperative and refused to be remained in the study or when some of the subjects may not experience the event or death before the end of the study, although they would have experienced or died if observation continued, or we lose touch with them midway in the study. We label these situations as censored observations. The Kaplan-Meier estimate is the simplest way of computing the survival over time in spite of all these difficulties associated with subjects or situations. The survival curve can be created assuming various situations. It involves computing of probabilities of occurrence of event at a certain point of time and multiplying these successive probabilities by any earlier computed probabilities to get the final estimate. This can be calculated for two groups of subjects and also their statistical difference in the survivals. This can be used in Ayurveda research when they are comparing two drugs and looking for survival of subjects.
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            Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS).

            We have reviewed the studies on radiation-induced vascular changes in human and experimental tumors reported in the last several decades. Although the reported results are inconsistent, they can be generalized as follows. In the human tumors treated with conventional fractionated radiotherapy, the morphological and functional status of the vasculature is preserved, if not improved, during the early part of a treatment course and then decreases toward the end of treatment. Irradiation of human tumor xenografts or rodent tumors with 5-10 Gy in a single dose causes relatively mild vascular damages, but increasing the radiation dose to higher than 10 Gy/fraction induces severe vascular damage resulting in reduced blood perfusion. Little is known about the vascular changes in human tumors treated with high-dose hypofractionated radiation such as stereotactic body radiotherapy (SBRT) or stereotactic radiosurgery (SRS). However, the results for experimental tumors strongly indicate that SBRT or SRS of human tumors with doses higher than about 10 Gy/fraction is likely to induce considerable vascular damages and thereby damages the intratumor microenvironment, leading to indirect tumor cell death. Vascular damage may play an important role in the response of human tumors to high-dose hypofractionated SBRT or SRS.
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              Systemic effects of local radiotherapy.

              Radiotherapy is generally used to treat a localised target that includes cancer. Increasingly, evidence indicates that radiotherapy recruits biological effectors outside the treatment field and has systemic effects. We discuss the implications of such effects and the role of the immune system in standard cytotoxic treatments. Because the effects of chemotherapy and radiotherapy are sensed by the immune system, their combination with immunotherapy presents a new therapeutic opportunity. Radiotherapy directly interferes with the primary tumour and possibly reverses some immunosuppressive barriers within the tumour microenvironment-ideally, recovering the role of the primary tumour as an immunogenic hub. Local radiation also triggers systemic effects that can be used in combination with immunotherapy to induce responses outside the radiation field.
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                Author and article information

                Contributors
                prezado@imnc.in2p3.fr
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                7 November 2018
                7 November 2018
                2018
                : 8
                : 16479
                Affiliations
                [1 ]ISNI 0000 0001 2112 9282, GRID grid.4444.0, Laboratoire d’Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC), , Centre National de la Recherche Scientifique (CNRS), Universités Paris 11 and Paris 7, Campus d’Orsay, ; 91405 Orsay, France
                [2 ]ISNI 0000 0001 2353 6535, GRID grid.428999.7, Institut Pasteur, , Neuropathologie Expérimentale, Institut Pasteur, ; 28 Rue du Docteur Roux, 75015 Paris, France
                [3 ]ISNI 0000 0004 0639 6384, GRID grid.418596.7, Institut Curie, PSL Research University, Radiation Oncology Department, Centre de Protonthérapie d’Orsay, 101, ; F-91898 Orsay, France
                [4 ]ISNI 0000 0004 0639 6384, GRID grid.418596.7, Institut Curie, PSL Research University, Translational Research Department, Experimental Radiotherapy Platform, ; Orsay, France
                [5 ]Paris Sud University, Paris -Saclay University, 91405 Orsay, France
                [6 ]ISNI 0000 0001 2171 2558, GRID grid.5842.b, IR4M, UMR8081, , Université Paris Sud, CNRS, Université Paris-Saclay, ; 91405 Orsay, France
                Article
                34796
                10.1038/s41598-018-34796-8
                6220274
                30405188
                66b376a6-5a08-4706-a389-f74fa552cd76
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 11 July 2018
                : 26 October 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100006364, Institut National Du Cancer (French National Cancer Institute);
                Award ID: 2015-1-RT-06-CNRS-DR04
                Award ID: 2015-1-RT-06-CNRS-DR04
                Award ID: 2015-1-RT-06-CNRS-DR04
                Award ID: 2015-1-RT-06-CNRS-DR04
                Award ID: 2015-1-RT-06-CNRS-DR04
                Award Recipient :
                Funded by: Agence National de la REcherche, ANR-11-INBS-0006
                Funded by: FundRef https://doi.org/10.13039/501100001665, Agence Nationale de la Recherche (French National Research Agency);
                Award ID: ANR-11-INBS-0006
                Award Recipient :
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