Microenvironment and radiation therapy

Dependency on tumor oxygenation is one of the major features of radiation therapy and this has led many radiation biologists and oncologists to focus on tumor hypoxia. The first approach to overcome tumor hypoxia was to improve tumor oxygenation by increasing oxygen delivery and a subsequent approach was the use of radiosensitizers in combination with radiation therapy. Clinical use of some of these approaches was promising, but they are not widely used due to several limitations. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that is activated by hypoxia and induces the expression of various genes related to the adaptation of cellular metabolism to hypoxia, invasion and metastasis of cancer cells and angiogenesis, and so forth. HIF-1 is a potent target to enhance the therapeutic effects of radiation therapy. Another approach is antiangiogenic therapy. The combination with radiation therapy is promising, but several factors including surrogate markers, timing and duration, and so forth have to be optimized before introducing it into clinics. In this review, we examined how the tumor microenvironment influences the effects of radiation and how we can enhance the antitumor effects of radiation therapy by modifying the tumor microenvironment

Pharmacological inhibition of sodium-calcium exchange activates NADPH oxidase and induces infection-independent NETotic cell death

In addition to its function of innate immunity against invading pathogens, neutrophil extracellular traps (NETs) promote thrombosis, autoimmune disease, and cancer metastasis; therefore, unnecessary exposure to the triggers of infection-independent NET generation should be avoided. We herein show that inhibition of forward-mode Na⁺/Ca²⁺ exchange by amiloride analogs, 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and 5-(N-Methyl-N-isobutyl)amiloride (MIA), triggers NETotic cell death independently of infectious stimuli. Isolated human neutrophils treated with EIPA and MIA undergo NETotic cell death by an increase of intracellular Ca²⁺ following activation of NADPH oxidase and the resultant upregulation of intracellular ROS. EIPA- and MIA-mediated intracellular Ca²⁺ increase is attributed to the competitive binding of EIPA and MIA against Na⁺ to Na⁺/Ca²⁺ exchanger 1 (NCX1). These results demonstrate a new mechanism of infection-independent NET generation and implicate NCX1 as a physiologic regulator of intracellular calcium balance and NETotic cell death

The mutual relationship between the host immune system and radiotherapy: stimulating the action of immune cells by irradiation

The effects of irradiation on tumor tissue and the host immune system are interrelated. The antitumor effect of irradiation is attenuated in the immunocompromised hosts. In addition, radiation alone positively and negatively influences the host immune system. The positive effects of radiation are summarized by the ability to help induce and enhance tumor-antigen-specific immune responses. The cancer-immunity cycle is a multistep framework that illustrates how the tumor-antigen-specific immune responses are induced and how the induced antigen-specific immune cells exert their functions in tumor tissues. Irradiation affects each step of this cancer-immunity cycle, primarily in a positive manner. In contrast, radiation also has negative effects on the immune system. The first is that irradiation has the possibility to kill irradiated effector immune cells. The second is that irradiation upregulates immunosuppressive molecules in the tumor microenvironment, whereas the third is that irradiation to the tumor condenses immunosuppressor cells in the tumor microenvironment. When used in conjunction with radiotherapy, immune checkpoint inhibitors can further leverage the positive effects of radiation on the immune system and compensate for the negative effects of irradiation, which supports the rationale for the combination of radiotherapy and immune checkpoint inhibitors. In this review, we summarize the preclinical evidence for the reciprocal effects of radiation exposure and the immune system, and up-front topics of the combination therapy of immune checkpoint inhibitors and radiotherapy

Analyses of integrated EPID images for on-treatment quality assurance to account for interfractional variations in volumetric modulated arc therapy

Purpose: To investigate the effects of interfractional variation, such as anatomical changes and setup errors, on dose delivery during treatment for prostate cancer (PC) and head and neck cancer (HNC) by courses of volumetric modulated arc therapy (VMAT) aided by on‐treatment electronic portal imaging device (EPID) images. Methods: Seven patients with PC and 20 patients with HNC who had received VMAT participated in this study. After obtaining photon fluence at the position of the EPID for each treatment arc from on‐treatment integrated EPID images, we calculated the differences between the fluence for the first fraction and each subsequent fraction for each arc. The passing rates were investigated based on a tolerance level of 3% of the maximum fluence during the treatment courses and the correlations between the passing rates and anatomical changes. Results: In PC, the median and lowest passing rates were 99.8% and 95.2%, respectively. No correlations between passing rates and interfractional variation were found. In HNC, the median passing rate of all fractions was 93.0%, and the lowest passing rate was 79.6% during the 35th fraction. Spearman’s correlation coefficients between the passing rates and changes in weight or neck volume were − 0.77 and − 0.74, respectively. Conclusions: Analyses of the on‐treatment EPID images facilitates estimates of the interfractional anatomical variation in HNC patients during VMAT and thus improves assessments of the need for re‐planning or adaptive strategies and the timing thereof

PLK1 blockade enhances therapeutic effects of radiation by inducing cell cycle arrest at the mitotic phase

The cytotoxicity of ionizing radiation depends on the cell cycle phase; therefore, its pharmacological manipulation, especially the induction of cell cycle arrest at the radiosensitive mitotic-phase (M-phase), has been attempted for effective radiation therapy. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that functions in mitotic progression, and is now recognized as a potential target for radiosensitization. We herein investigated whether PLK1 blockade enhanced the cytotoxic effects of radiation by modulating cell cycle phases of cancer cells using the novel small molecule inhibitor of PLK1, TAK-960. The TAK-960 treatment exhibited radiosensitizing effects in vitro, especially when it increased the proportion of M-phase cells. TAK-960 did not sensitize cancer cells to radiation when an insufficient amount of time was provided to induce mitotic arrest. The overexpression of a PLK1 mutant, PLK1-R136G&T210D, which was confirmed to cancel the TAK-960-mediated increase in the proportion of mitotic cells, abrogated the radiosensitizing effects of TAK-960. A tumor growth delay assay also demonstrated that the radiosensitizing effects of TAK-960 depended on an increase in the proportion of M-phase cells. These results provide a rational basis for targeting PLK1 for radiosensitization when considering the therapeutic time window for M-phase arrest as the best timing for radiation treatments

Appropriate margin for planning target volume for breast radiotherapy during deep inspiration breath-hold by variance component analysis

BACKGROUND: This study aimed to quantify errors by using a cine electronic portal imaging device (cine EPID) during deep inspiration breath-hold (DIBH) for left-sided breast cancer and to estimate the planning target volume (PTV) by variance component analysis. METHODS: This study included 25 consecutive left-sided breast cancer patients treated with whole-breast irradiation (WBI) using DIBH. Breath-holding was performed while monitoring abdominal anterior-posterior (AP) motion using the Real-time Position Management (RPM) system. Cine EPID was used to evaluate the chest wall displacements in patients. Cine EPID images of the patients (309, 609 frames) were analyzed to detect the edges of the chest wall using a Canny filter. The errors that occurred during DIBH included differences between the chest wall position detected by digitally reconstructed radiographs and that of all cine EPID images. The inter-patient, inter-fraction, and intra-fractional standard deviations (SDs) in the DIBH were calculated, and the PTV margin was estimated by variance component analysis. RESULTS: The median patient age was 55 (35-79) years, and the mean irradiation time was 20.4 ± 1.7 s. The abdominal AP motion was 1.36 ± 0.94 (0.14-5.28) mm. The overall mean of the errors was 0.30 mm (95% confidence interval: - 0.05-0.65). The inter-patient, inter-fraction, and intra-fractional SDs in the DIBH were 0.82 mm, 1.19 mm, and 1.63 mm, respectively, and the PTV margin was calculated as 3.59 mm. CONCLUSIONS: Errors during DIBH for breast radiotherapy were monitored using EPID images and appropriate PTV margins were estimated by variance component analysis

Activation of STAT3 by the Hepatitis C Virus Core Protein Leads to Cellular Transformation

The signal transducer and activator of transcription (STAT) family proteins are transcription factors critical in mediating cytokine signaling. Among them, STAT3 is often constitutively phosphorylated and activated in human cancers and in transformed cell lines and is implicated in tumorigenesis. However, cause of the persistent activation of STAT3 in human tumor cells is largely unknown. The hepatitis C virus (HCV) is a major etiological agent of non-A and non-B hepatitis, and chronic infection by HCV is associated with development of liver cirrhosis and hepatocellular carcinoma. HCV core protein is proposed to be responsible for the virus-induced transformation. We now report that HCV core protein directly interacts with and activates STAT3 through phosphorylation of the critical tyrosine residue. Activation of STAT3 by the HCV core in NIH-3T3 cells resulted in rapid proliferation and up-regulation of Bcl-XL and cyclin-D1. Additional expression of STAT3 in HCV core-expressing cells resulted in anchorage-independent growth and tumorigenesis. We propose that the HCV core protein cooperates with STAT3, which leads to cellular transformation

Estimation of Dietary Intake of Radionuclides and Effectiveness of Regulation after the Fukushima Accident and in Virtual Nuclear Power Plant Accident Scenarios

Evaluation of radiation exposure from diet is necessary under the assumption of a virtual accident as a part of emergency preparedness. Here, we developed a model with complete consideration of the regional food trade using deposition data simulated by a transport model, and estimated the dietary intake of radionuclides and the effectiveness of regulation (e.g., restrictions on the distribution of foods) after the Fukushima accident and in virtual accident scenarios. We also evaluated the dilution factors (i.e., ratios of contaminated foods to consumed foods) and cost-effectiveness of regulation as basic information for setting regulatory values. The doses estimated under actual emission conditions were generally consistent with those observed in food-duplicate and market-basket surveys within a factor of three. Regulation of restricted food distribution resulted in reductions in the doses of 54–65% in the nearest large city to the nuclear power plant. The dilution factors under actual emission conditions were 4.4% for radioiodine and 2.7% for radiocesium, which are ~20 times lower than those used in the Japanese provisional regulation values after the Fukushima accident. Strict regulation worsened the cost-effectiveness for both radionuclides. This study highlights the significance and utility of the developed model for a risk analysis of emergency preparedness and regulation

Development of AI-driven prediction models to realize real-time tumor tracking during radiotherapy

[Background] In infrared reflective (IR) marker-based hybrid real-time tumor tracking (RTTT), the internal target position is predicted with the positions of IR markers attached on the patient’s body surface using a prediction model. In this work, we developed two artificial intelligence (AI)-driven prediction models to improve RTTT radiotherapy, namely, a convolutional neural network (CNN) and an adaptive neuro-fuzzy inference system (ANFIS) model. The models aim to improve the accuracy in predicting three-dimensional tumor motion. [Methods] From patients whose respiration-induced motion of the tumor, indicated by the fiducial markers, exceeded 8 mm, 1079 logfiles of IR marker-based hybrid RTTT (IR Tracking) with the gimbal-head radiotherapy system were acquired and randomly divided into two datasets. All the included patients were breathing freely with more than four external IR markers. The historical dataset for the CNN model contained 1003 logfiles, while the remaining 76 logfiles complemented the evaluation dataset. The logfiles recorded the external IR marker positions at a frequency of 60 Hz and fiducial markers as surrogates for the detected target positions every 80-640 ms for 20-40 s. For each logfile in the evaluation dataset, the prediction models were trained based on the data in the first three quarters of the recording period. In the last quarter, the performance of the patient-specific prediction models was tested and evaluated. The overall performance of the AI-driven prediction models was ranked by the percentage of predicted target position within 2 mm of the detected target position. Moreover, the performance of the AI-driven models was compared to a regression prediction model currently implemented in gimbal-head radiotherapy systems. [Results] The percentage of the predicted target position within 2 mm of the detected target position was 95.1%, 92.6% and 85.6% for the CNN, ANFIS, and regression model, respectively. In the evaluation dataset, the CNN, ANFIS, and regression model performed best in 43, 28 and 5 logfiles, respectively. [Conclusions] The proposed AI-driven prediction models outperformed the regression prediction model, and the overall performance of the CNN model was slightly better than that of the ANFIS model on the evaluation dataset

Reducing variability among treatment machines using knowledge‐based planning for head and neck, pancreatic, and rectal cancer

PURPOSE: This study aimed to assess dosimetric indices of RapidPlan model-based plans for different energies (6, 8, 10, and 15 MV; 6- and 10-MV flattening filter-free), multileaf collimator (MLC) types (Millennium 120, High Definition 120, dual-layer MLC), and disease sites (head and neck, pancreatic, and rectal cancer) and compare these parameters with those of clinical plans. METHODS: RapidPlan models in the Eclipse version 15.6 were used with the data of 28, 42, and 20 patients with head and neck, pancreatic, and rectal cancer, respectively. RapidPlan models of head and neck, pancreatic, and rectal cancer were created for TrueBeam STx (High Definition 120) with 6 MV, TrueBeam STx with 10-MV flattening filter-free, and Clinac iX (Millennium 120) with 15 MV, respectively. The models were used to create volumetric-modulated arc therapy plans for a 10-patient test dataset using all energy and MLC types at all disease sites. The Holm test was used to compare multiple dosimetric indices in different treatment machines and energy types. RESULTS: The dosimetric indices for planning target volume and organs at risk in RapidPlan model-based plans were comparable to those in the clinical plan. Furthermore, no dose difference was observed among the RapidPlan models. The variability among RapidPlan models was consistent regardless of the treatment machines, MLC types, and energy. CONCLUSIONS: Dosimetric indices of RapidPlan model-based plans appear to be comparable to the ones based on clinical plans regardless of energies, MLC types, and disease sites. The results suggest that the RapidPlan model can generate treatment plans independent of the type of treatment machine