Radiation therapy, in conjunction with surgical implant fixation, is a common combined treatment in cases of bone metastases. However, metal implants generally used in orthopedic implants perturb radiation dose distributions. Carbon‐Fiber Reinforced Polyetheretherketone (CFR‐PEEK) material has been recently introduced for production of intramedullary nails and plates. The purpose of this work was to investigate the perturbation effects of the new CFR‐PEEK screws on radiotherapy dose distributions and to evaluate these effects in comparison with traditional titanium screws. The investigation was performed by means of Monte Carlo (MC) simulations for a 6 MV photon beam. The project consisted of two main stages. First, a comparison of measured and MC calculated doses was performed to verify the validity of the MC simulation results for different materials. For this purpose, stainless steel, titanium, and CFR‐PEEK plates of various thicknesses were used for attenuation and backscatter measurements in a solid water phantom. For the same setup, MC dose calculations were performed. Next, MC dose calculations for titanium, CFR‐PEEK screws, and CFR‐PEEK screws with ultrathin titanium coating were performed. For the plates, the results of our MC calculations for all materials were found to be in good agreement with the measurements. This indicates that the MC model can be used for calculation of dose perturbation effects caused by the screws. For the CFR‐PEEK screws, the maximum dose perturbation was less than 5%, compared to more than 30% perturbation for the titanium screws. Ultrathin titanium coating had a negligible effect on the dose distribution. CFR‐PEEK implants have good prospects for use in radiotherapy because of minimal dose alteration and the potential for more accurate treatment planning. This could favorably influence treatment efficiency and decrease possible over‐ and underdose of adjacent tissues. The use of such implants has potential clinical advantages in the treatment of bone metastases.
Radiotherapy induces immune-related responses in cancer patients by various mechanisms. Here, we investigate the immunomodulatory role of tumor-derived microparticles (TMPs)-extracellular vesicles shed from tumor cells-following radiotherapy. We demonstrate that breast carcinoma cells exposed to radiation shed TMPs containing elevated levels of immune-modulating proteins, one of which is programmed death-ligand 1 (PD-L1). These TMPs inhibit cytotoxic T lymphocyte (CTL) activity both in vitro and in vivo, and thus promote tumor growth. Evidently, adoptive transfer of CTLs pre-cultured with TMPs from irradiated breast carcinoma cells increases tumor growth rates in mice recipients in comparison with control mice receiving CTLs pre-cultured with TMPs from untreated tumor cells. In addition, blocking the PD-1-PD-L1 axis, either genetically or pharmacologically, partially alleviates TMP-mediated inhibition of CTL activity, suggesting that the immunomodulatory effects of TMPs in response to radiotherapy is mediated, in part, by PD-L1. Overall, our findings provide mechanistic insights into the tumor immune surveillance state in response to radiotherapy and suggest a therapeutic synergy between radiotherapy and immune checkpoint inhibitors.
A major therapeutic obstacle in clinical oncology is intrinsic or acquired resistance to therapy, leading to subsequent relapse. We have previously shown that systemic administration of different cytotoxic drugs can induce a host response that contributes to tumor angiogenesis, regrowth and metastasis. Here we characterize the host response to a single dose of local radiation, and its contribution to tumor progression and metastasis. We show that plasma from locally irradiated mice increases the migratory and invasive properties of colon carcinoma cells. Furthermore, locally irradiated mice intravenously injected with CT26 colon carcinoma cells succumb to pulmonary metastasis earlier than their respective controls. Consequently, orthotopically implanted SW480 human colon carcinoma cells in mice that underwent radiation, exhibited increased metastasis to the lungs and liver compared to their control tumors. The irradiated tumors exhibited an increase in the colonization of macrophages compared to their respective controls; and macrophage depletion in irradiated tumor-bearing mice reduces the number of metastatic lesions. Finally, the anti-tumor agent, dequalinium-14, in addition to its anti-tumor effect, reduces macrophage motility, inhibits macrophage infiltration of irradiated tumors and reduces the extent of metastasis in locally irradiated mice. Overall, this study demonstrates the adverse effects of local radiation on the host that result in macrophage-induced metastasis.
Stem cells (SCs) play a pivotal role in fueling homeostasis and regeneration. While much focus has been given to self-renewal and differentiation pathways regulating SC fate, little is known regarding the specific mechanisms utilized for their elimination. Here, we report that the pro-apoptotic protein ARTS (a Septin4 isoform) is highly expressed in cells comprising the intestinal SC niche and that its deletion protects Lgr5+ and Paneth cells from undergoing apoptotic cell death. As a result, the Sept4/ARTS−/− crypt displays augmented proliferation and, in culture, generates massive cystic-like organoids due to enhanced Wnt/β-catenin signaling. Importantly, Sept4/ARTS−/− mice exhibit resistance against intestinal damage in a manner dependent upon Lgr5+ SCs. Finally, we show that ARTS interacts with XIAP in intestinal crypt cells and that deletion of XIAP can abrogate Sept4/ARTS−/−-dependent phenotypes. Our results indicate that intestinal SCs utilize specific apoptotic proteins for their elimination, representing a unique target for regenerative medicine.
The purpose of this study was to evaluate the feasibility of hippocampal‐sparing whole‐brain radiotherapy (HS WBRT) using the Elekta Infinity linear accelerator and Monaco treatment planning system (TPS). Ten treatment plans were created for HS‐WBRT to a dose of 30 Gy (10 fractions). RTOG 0933 recommendations were applied for treatment planning. Intensity‐modulated radiotherapy (IMRT) plans for the Elekta Infinity linear accelerator were created using Monaco 3.1 TPS‐based on a nine‐field arrangement and step‐and‐shoot delivery method. Plan evaluation was performed using D2% and D98% for the whole‐brain PTV (defined as whole brain excluding hippocampus avoidance region), D100% and maximum dose to the hippocampus, and maximum dose to optic nerves and chiasm. Homogeneity index (HI) defined as false(D2normal%−D98normal%false)/normalDmedian was used to quantify dose homogeneity in the PTV. The whole‐brain PTV D2% mean value was 37.28 Gy (range 36.95–37.49 Gy), and D98% mean value was 25.37 Gy (range 25.40–25.89 Gy). The hippocampus D100% mean value was 8.37 Gy (range 7.48–8.97 Gy) and the hippocampus maximum dose mean value was 14.35 Gy (range 13.48–15.40 Gy). The maximum dose to optic nerves and optic chiasm for all patients did not exceed 37.50 Gy. HI mean value was 0.36 (range 0.34–0.37). Mean number of segments was 105 (range 88–122) and mean number of monitor units was 1724 (range 1622–1914). Gamma evaluation showed that all plans passed 3%, 3 mm criteria with more than 99% of the measured points. These results indicate that Elekta equipment (Elekta Infinity linac and Monaco TPS) can be used for HS WBRT planning according to compliance criteria defined by the RTOG 0933 protocol.PACS numbers: 87.55D, 87.55 –v, 87.55 de
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