Clinical effectiveness of combined whole body hyperthermia and external beam radiation therapy (EBRT) versus EBRT alone in patients with painful bony metastases: A phase III clinical trial study.

PURPOSE: To evaluate the response rate, pain relief duration, and time it took for pain to decline or resolve after radiation therapy (RT) with or without fever-range Whole Body Hyperthermia (WBH) in bony metastatic patients with mainly primary tumor of prostate and breast cancer leading to bone pain. MATERIALS & METHODS: Bony metastatic patients with pain score ≥4 on the Brief Pain Inventory (BPI) underwent RT of 30 Gy in 10 fractions in combination with WBH with nursing care under medical supervision versus RT-alone. WBH application time was 3-4 h in three fractions with at least 48-h intervals. All patients were stratified primary site, breast or prostate cancer vs others, BPI score, and exclusion criteria. The primary endpoint was complete response (CR) (BPI equal to zero with no increase of analgesics) within two months of follow-up. RESULTS: Based on this study, the RT-alone group showed the worst pain. The study was terminated after the enrollment of a total of 61 patients, 5 years after the first enrollment (April 2016 to February 2021). Finally, the CR rate in RT + WBH revealed the most significant difference with RT-alone, 47.4% versus 5.3% respectively within 2 months post-treatment (P-value <0.05). The time of complete pain relief was 10 days for RT + WBH, while the endpoint was not reached during the RT-alone arm. Pain progression or stable disease was observed in half of the patients in RT-alone group within 4 weeks after treatment. However, this score was near zero in RT + WBHT patients in two months post-treatment. CONCLUSIONS: WBH plus RT showed significant increases in pain relief and shorter response time in comparison with RT-alone for patients with bone metastatic lesions.

Radiotherapy Combination: Insight from Tumor Immune Microenvironment (TIME).

The view of Radiotherapy (RT) as a simple inducer of DNA damage resulting in tumor cell death has dramatically changed in recent years, and it is now widely accepted that RT can trigger an immune response which provides a sound basis for combining RT with immunotherapy. Given that, radiation can be delivered with different regimens, its effect on immune responses and Tumor Immune Microenvironment (TIME) may vary with dose and fractionation schedule. This fractional dose dependency may need to be more considered because of recent developments in RT delivery techniques making it possible to deliver precisely higher dosages per fraction (hypofractionation) while reducing exposure to normal tissues. Although combining radiotherapy with immunotherapy could be a promising strategy for synergistic enhancement of treatment efficacy, the selection of the best-matched combination of immunotherapy with each radiotherapy scheme remains to be addressed. Thus, for designing better therapeutic combinations, it is necessary to understand the immunological effects of RT. Here, we review the impact of conventional and different hypofractionation radiation schedules on the TIME. Subsequently, we highlight how knowing about these interactions may have implications for choosing a rational combination with targeted therapies.

Trends of Colorectal Cancer Incidence, Prevalence and Mortality in Worldwide From 1990 to 2017.

Background: Colorectal cancer is a major health problem both in developing and developed countries. This cancer is among the top three commonly diagnosed cancers in males and females. In this context, assessing the Incidence, Prevalence and Mortality Rate trend of this cancer is of great importance. Methods: We used the data from the GBD 2017 study to assess the global trend of 3 important indicators of colorectal cancer burden and to examine the relationship between trends of these indicators with Human Development Index (HDI). We used the multivariate mixed effects modeling framework with time and HDI as the covariates. Results: Trend analysis of colorectal cancer burden indicators showed a rather steady trend for mortality rate, while it revealed increasing slopes for both the incidence and prevalence rates. In addition, our findings showed a direct relationship between prevalence and incidence rates of this cancer and HDI level and indirect association between mortality rate and level of HDI. Conclusion: There were significant changes in indicators of colorectal cancer during the study period. The inverse relationship between mortality due to this cancer and socio-economic status of the countries indicated an urgent need for screening the patients and promoting the level of care in countries with lower levels of HDI.

Effect of a cross-linking antioxidant agent on the bond strength of adhesive resin to irradiated dentin.

It has been shown that irradiation can cause structural changes in dentin that may reduce the bond strength of adhesives to dentin. Applying cross-linking or antioxidant agents may help reverse this detrimental effect and improve adhesion to dentin. This in vitro study aimed to evaluate the effects of epigallocatechin-3-gallate (EGCG) pretreatment and the time of adhesive bonding (24 hours vs 1 month) on the shear bond strength (SBS) of All-Bond Universal (ABU) to irradiated dentin using etch-and-rinse (ER) and self-etching (SE) modes. Flat dentin surfaces prepared from 96 extracted intact human molars were divided into 8 groups (n = 12) and bonded with ABU. In the control (CO) groups (CO/ER and CO/SE), bonding was performed on nonirradiated dentin; in the irradiated (IR) groups (IR/ER and IR/SE), bonding was performed on irradiated dentin; in the irradiated pretreated groups (IR/EGCG/ER and IR/EGCG/SE), irradiated dentin received a 0.1% EGCG pretreatment before bonding; and in the irradiated delayed bonding (DL) groups (IR/DL/ER and IR/DL/SE), bonding on irradiated dentin was performed 1 month after completion of radiotherapy. The irradiation protocol consisted of a total dose of 60 Gy with 2-Gy exposure applied 5 days per week for a period of 6 weeks. After bonding procedures were completed, the specimens were stored in 100% humidity at 37°C for 24 hours and then the SBS was tested in a universal testing machine. Data were analyzed using 1-way analysis of variance and Tukey tests. There was a statistically significant difference among the 8 groups (P < 0.001). Irradiation diminished the SBS in the IR/ER and IR/SE groups compared with their controls (P < 0.001). Pretreatment with EGCG significantly increased the SBS in the IR/EGCG/ER group only (P < 0.001). The difference between the IR/ER and IR/DL/ER groups was not statistically significant, and the difference between the IR/SE and IR/DL/SE groups was marginally significant (P = 0.056). Pretreatment with EGCG after acid etching restored the SBS of ABU to irradiated dentin, resulting in an adhesive performance equivalent to that observed with nonirradiated dentin. A 1-month delay between irradiation and bonding did not improve the SBS.

Comparison of PRIMO Monte Carlo code and Eclipse treatment planning system in calculation of dosimetric parameters in brain cancer radiotherapy.

Background: It is important to evaluate the dose calculated by treatment planning systems (TPSs) and dose distribution in tumor and organs at risk (OARs). The aim of this study is to compare dose calculated by the PRIMO Monte Carlo code and Eclipse TPS in radiotherapy of brain cancer patients. Materials and methods: PRIMO simulation code was used to simulate a Varian Clinac 600C linac. The simulations were validated for the linac by comparison of the simulation and measured results. In the case of brain cancer patients, the dosimetric parameters obtained by the PRIMO code were compared with those calculated by Eclipse TPS. Gamma function analysis with 3%, 3 mm criteria was utilized to compare the dose distributions. The evaluations were based on the dosimetric parameters for the planning target volume (PTV) and OAR including D min, D mean, and D max, homogeneity index (HI), and conformity index (CI). Results: The gamma function analysis showed a 98% agreement between the results obtained by the PRIMO code and measurement for the percent depth dose (PDD) and dose profiles. The corresponding value in comparing the dosimetric parameters from PRIMO code and Eclipse TPS for the brain patients was 94%, on average. The results of the PRIMO simulation were in good agreement with the measured data and Eclipse TPS calculations. Conclusions: Based on the results of this study, the PRIMO code can be utilized to simulate a medical linac with good accuracy and to evaluate the accuracy of treatment plans for patients with brain cancer.

Introducing new plan evaluation indices for prostate dose painting IMRT plans based on apparent diffusion coefficient images.

BACKGROUND: Dose painting planning would be more complicated due to different levels of prescribed doses and more complex evaluation with conventional plan quality indices considering uniform dose prescription. Therefore, we tried to introduce new indices for evaluating the dose distribution conformity and homogeneity of treatment volumes based on the tumoral cell density and relative volumes of each lesion in prostate IMRT. METHODS: CT and MRI scans of 20 male patients having local prostate cancer were used for IMRT DP planning. Apparent diffusion coefficient (ADC) images were imported to a MATLAB program to identify lesion regions based on ADC values automatically. Regions with ADC values lower than 750 mm2/s and regions with ADC values higher than 750 and less than 1500 mm2/s were considered CTV70Gy (clinical tumor volume with 70 Gy prescribed dose), and CTV60Gy, respectively. Other regions of the prostate were considered as CTV53Gy. New plan evaluation indices based on evaluating the homogeneity (IOE(H)), and conformity (IOE(C)) were introduced, considering the relative volume of each lesion and cellular density obtained from ADC images. These indices were compared with conventional homogeneity and conformity indices and IOEs without considering cellular density. Furthermore, tumor control probability (TCP) was calculated for each patient, and the relationship of the assessed indices were evaluated with TCP values. RESULTS: IOE (H) and IOE (C) with considering cellular density had significantly lower values compared to conventional indices and IOEs without considering cellular density. (P < 0.05). TCP values had a stronger relationship with IOE(H) considering cell density (R2 = -0.415), and IOE(C) without considering cell density (R2 = 0.624). CONCLUSION: IOE plan evaluation indices proposed in this study can be used for evaluating prostate IMRT dose painting plans. We suggested to consider cell densities in the IOE(H) calculation formula and it's appropriate to calculate IOE(C) without considering cell density values.

Evaluating the relationship between dosimetric parameters and esophagitis in patients who experienced radiotherapy in the cervicothoracic region.

Purpose: Prescribing radiotherapy or concurrent chemoradiation for cervicothoracic cancers inevitably leads to esophagitis. The purpose of the current study was to evaluate the correlation between the dose-volume parameters and the esophagitis in patients who received radiotherapy in the cervicothoracic region. Materials and Methods: Forty cancerous patients whose radiotherapy fields were in the cervicothoracic region have been rolled. The correlation between the dosimetric and clinical factors with esophagitis was analyzed through binary logistic regression model and Pearson correlation tests and was quantified with receiver operating characteristic curve. Results: The patients participating in the study were selected from breast (6 cases), lymphoma (7 cases), and head-neck (27 cases) patients with prescription doses of 36-72 Gy. Increasing esophagus mean dose resulted in an increase of acute esophagitis significantly (P = 0.05). Furthermore, by one-gray increase in the esophagus median dose, the possibility of esophagitis increased by 9.3% (P = 0.02). To prevent acute esophagitis (Grade ≥2), D50 should be kept below 7 Gy. To limit acute esophagitis, V40 should be kept below 19% (P = 0.04). Conclusions: Based on the correlation analysis of the current study, concurrent chemoradiotherapy, DMean, D50, D80, and V40 are known as reliable predictive dosimetric parameters of acute esophagitis incidence in patients who experienced radiotherapy in the cervicothoracic region.

Combining ablative radiotherapy and anti CD47 monoclonal antibody improves infiltration of immune cells in tumor microenvironments.

Radiotherapy as an anti-tumor treatment can stimulate the immune system. However, irradiated tumor cells express CD47 to escape the anti-tumor immune response. Anti- CD47 Immunotherapy is a possible way to tackle this problem. This study evaluated the effect of single high dose radiotherapy combined with an anti-CD47 monoclonal antibody (αCD47 mAb) in CT26 tumor-bearing BALB/c mice. We assessed the tumors volume and survival in mice 60 days after tumor implantation. Also, immune cell changes were analyzed by flow cytometry in tumors, lymph nodes, and spleen. Combination therapy enhanced the anti-tumor response in treated mice by increasing CD8+ T cells and M1 macrophages and decreasing M2 macrophages and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME). Also, our results showed that combination therapy increased survival time in mice compared to other groups. Furthermore, tumor volumes remarkably decreased in mice that received a single high dose RT plus αCD47 mAb. In conclusion, we showed that combining RT and αCD47 mAb improved the immune cell population in TME, regressed tumor growth, and increased survival in tumor-bearing mice.

Tumor Microenvironment, Radiology, and Artificial Intelligence: Should We Consider Tumor Periphery?

OBJECTIVES: The tumor microenvironment (TME) consists of cellular and noncellular components which enable the tumor to interact with its surroundings and plays an important role in the tumor progression and how the immune system reacts to the malignancy. In the present study, we investigate the diagnostic potential of the TME in differentiating benign and malignant lesions using image quantification and machine learning. METHODS: A total of 229 breast lesions and 220 cervical lymph nodes were included in the study. A group of expert radiologists first performed medical imaging and segmented the lesions, after which a rectangular mask was drawn, encompassing all of the contouring. The mask was extended in each axis up to 50%, and 29 radiomics features were extracted from each mask. Radiomics features that showed a significant difference in each contour were used to develop a support vector machine (SVM) classifier for benign and malignant lesions in breast and lymph node images separately. RESULTS: Single radiomics features extracted from extended contours outperformed radiologists' contours in both breast and lymph node lesions. Furthermore, when fed into the SVM model, the extended models also outperformed the radiologist's contour, achieving an area under the receiver operating characteristic curve of 0.887 and 0.970 in differentiating breast and lymph node lesions, respectively. CONCLUSIONS: Our results provide convincing evidence regarding the importance of the tumor periphery and TME in medical imaging diagnosis. We propose that the immediate tumor periphery should be considered for differentiating benign and malignant lesions in image quantification studies.

Prediction of chronic kidney disease in abdominal cancers radiation therapy using the functional assays of normal tissue complication probability models.

Aim: The purpose of this study is to predict chronic kidney disease (CKD) in the radiotherapy of abdominal cancers by evaluating clinical and functional assays of normal tissue complication probability (NTCP) models. Materials and Methods: Radiation renal damage was analyzed in 50 patients with abdominal cancers 12 months after radiotherapy through a clinical estimated glomerular filtration rate (eGFR). According to the common terminology criteria for the scoring system of adverse events, Grade 2 CKD (eGFR ≤30-59 ml/min/1.73 m2) was considered as the radiation therapy endpoint. Modeling and parameter estimation of NTCP models were performed for the Lyman-equivalent uniform dose (EUD), the logit-EUD critical volume (CV), the relative seriality, and the mean dose model. Results: The confidence interval of the fitted parameters was 95%. The parameter value of D50 was obtained 22-38 Gy, and the n and s parameters were equivalent to 0.006 -3 and 1, respectively. According to the Akaike's information criterion, the mean dose model predicts radiation-induced CKD more accurately than the other models. Conclusion: Although the renal medulla consists of many nephrons arranged in parallel, each nephron has a seriality architecture as renal functional subunits. Therefore, based on this principle and modeling results in this study, the whole kidney organs may have a serial-parallel combination or a secret architecture.

Radiation dose and schedule influence the abscopal effect in a bilateral murine CT26 tumor model.

Radiotherapy (RT) can induce immune-mediated responses in local irradiated tumors, and non-irradiated distant metastasis is termed the abscopal effect. Here, we aimed to evaluate the impact of different RT doses and fractions on anti-tumor responses within local irradiated and distance non-irradiated tumor microenvironments. In mice bearing CT26 tumors, the primary tumor was irradiated with three different RT doses (16 Gy × 1F, 10 Gy × 2F, and 3 Gy × 10F) with the same biologically effective dose. Tumor volumes and immune cells changes were assessed in irradiated and non-irradiated tumors. Survival times were evaluated over 90 days. Only 16 Gy × 1F radiation increased CD8 + T cells number in the irradiated (p = 0.043) and non-irradiated (p = 0.047) tumors compared to the untreated group. A high frequency of tumor-associated macrophages-1 (TAM-1) and low TAM-2 was found in 16 Gy × 1F irradiated mice. Moreover, 16 Gy × 1F significantly induced interferon gamma (IFNγ)-producing CD8 + cells in the spleen compared to controls (p = 0.021). Hypofraction regimens (16 Gy × 1F, 10 Gy × 2F) caused a reduction in myeloid-derived suppressor cells in the irradiated tumors. We detected A modest growth delay in both flank tumors and long-term survival after hypofraction treatments (16 Gy × 1F, 10 Gy × 2F). A single high RT dose increased CD8 + cells number in irradiated (p = 0.000) and non-irradiated (p = 0.002) tumors approximal up to 2 points along with significant induction of IFN-γ production by CD8 + cells in the spleen when combined with anti- programmed death ligand-1 (PDL-1) (p = 0.000). Combination therapy was also associated with bilateral tumor growth control and increased life span in mice. Hypofractionated RT schedules, especially single high dose, seem the most effective regimen for inducing an abscopal effect. Immune checkpoint inhibitors could promote RT-induced systemic effects.

Estimating cancer risks due to whole lungs low dose radiotherapy with different techniques for treating COVID-19 pneumonia.

BACKGROUND: Low dose radiotherapy (LDRT) of whole lungs with photon beams is a novel method for treating COVID-19 pneumonia. This study aimed to estimate cancer risks induced by lung LDRT for different radiotherapy delivery techniques. METHOD: Four different radiotherapy techniques, including 3D-conformal with anterior and posterior fields (3D-CRT AP-PA), 3D-conformal with 8 coplanar fields (3D-CRT 8 fields), eight fields intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy using 2 full arcs (VMAT) were planned on the CT images of 32 COVID-19 patients with the prescribed dose of 1 Gy to the lungs. Organ average and maximum doses, and PTV dose distribution indexes were compared between different techniques. The radiation-induced cancer incidence and cancer-specific mortality, and cardiac heart disease risks were estimated for the assessed techniques. RESULTS: In IMRT and VMAT techniques, heart (mean and max), breast (mean, and max), and stomach (mean) doses and also maximum dose in the body were significantly lower than the 3D-CRT techniques. The calculated conformity indexes were similar in all the techniques. However, the homogeneity indexes were lower (i.e., better) in intensity-modulated techniques (P < 0.03) with no significant differences between IMRT and VMAT plans. Lung cancer incident risks for all the delivery techniques were similar (P > 0.4). Cancer incidence and mortality risks for organs located closer to lungs like breast and stomach were higher in 3D-CRT techniques than IMRT or VMAT techniques (excess solid tumor cancer incidence risks for a 30 years man: 1.94 ± 0.22% Vs. 1.68 ± 0.17%; and women: 6.66 ± 0.81% Vs. 4.60 ± 0.43%: cancer mortality risks for 30 years men: 1.63 ± 0.19% Vs. 1.45 ± 0.15%; and women: 3.63 ± 0.44% Vs. 2.94 ± 0.23%). CONCLUSION: All the radiotherapy techniques had low cancer risks. However, the overall estimated risks induced by IMRT and VMAT radiotherapy techniques were lower than the 3D-CRT techniques and can be used clinically in younger patients or patients having greater concerns about radiation induced cancers.

The feasibility of a dose painting procedure to treat prostate cancer based on mpMR images and hierarchical clustering.

BACKGROUND: We aimed to assess the feasibility of a dose painting (DP) procedure, known as simultaneous integrated boost intensity modulated radiation Therapy (SIB-IMRT), for treating prostate cancer with dominant intraprostatic lesions (DILs) based on multi-parametric magnetic resonance (mpMR) images and hierarchical clustering with a machine learning technique. METHODS: The mpMR images of 120 patients were used to create hierarchical clustering and draw a dendrogram. Three clusters were selected for performing agglomerative clustering. Then, the DIL acquired from the mpMR images of 20 patients were categorized into three groups to have them treated with a DP procedure being composed of three planning target volumes (PTVs) determined as PTV1, PTV2, and PTV3 in treatment plans. The DP procedure was carried out on the patients wherein a total dose of 80, 85 and 91 Gy were delivered to the PTV1, PTV2, and PTV3, respectively. Dosimetric and radiobiologic parameters [Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP)] of the DP procedure were compared with those of the conventional IMRT and Three-Dimensional Conformal Radiation Therapy (3DCRT) procedures carried out on another group of 20 patients. A post-treatment follow-up was also made four months after the radiotherapy procedures. RESULTS: All the dosimetric variables and the NTCPs of the organs at risks (OARs) revealed no significant difference between the DP and IMRT procedures. Regarding the TCP of three investigated PTVs, significant differences were observed between the DP versus IMRT and also DP versus 3DCRT procedures. At post-treatment follow-up, the DIL volumes and apparent diffusion coefficient (ADC) values in the DP group differed significantly (p-value < 0.001) from those of the IMRT. However, the whole prostate ADC and prostate-specific antigen (PSA) indicated no significant difference (p-value > 0.05) between the DP versus IMRT. CONCLUSIONS: The results of this comprehensive clinical trial illustrated the feasibility of our DP procedure for treating prostate cancer based on mpMR images validated with acquired patients' dosimetric and radiobiologic assessment and their follow-ups. This study confirms significant potential of the proposed DP procedure as a promising treatment planning to achieve effective dose escalation and treatment for prostate cancer. TRIAL REGISTRATION: IRCT20181006041257N1; Iranian Registry of Clinical Trials, Registered: 23 October 2019, https://en.irct.ir/trial/34305 .

Low-dose radiotherapy (LD-RT) for COVID-19-induced pneumopathy: a worth considering approach.

PURPOSE: It seems that 2020 would be always remembered by the name of novel coronavirus (designated as SARS-CoV-2), which exerted its deteriorating effects on the health care, economy, education, and political relationships. In August 2020 more than eight hundred thousand patients lost their lives due to acute respiratory syndrome. In the limited list of therapeutic approaches, the effectiveness of low-dose radiation therapy (LD-RT) for curing inflammatory-related diseases have sparkled a light that probably this approach would bring promising advantages for COVID-19 patients. LD-RT owns its reputation from its ability to modulate the host inflammatory responses by blocking the production of pro-inflammatory cytokines and hampering the activity of leukocytes. Moreover, the cost-effective and availability of this method allow it to be applied to a large number of patients, especially those who could not receive anti-IL-6 treatments in low-income countries. But enthusiasm for applying LD-RT for the treatment of COVID-19 patients has been muted yet. CONCLUSION: In this review, we take a look at LD-RT mechanisms of action in the treatment of nonmalignant diseases, and then through studying both the dark and bright sides of this approach, we provide a thorough discussion if LD-RT might be a promising therapeutic approach in COVID-19 patients.

The effect of dual-frequency ultrasound waves on B16F10 melanoma cells: Sonodynamic therapy using nanoliposomes containing methylene blue.

BACKGROUND: We investigated the effect of dual-frequency sonication on the viability of B16F10 melanoma cells in the presence of methylene blue (MB) encapsulated in nanoliposomes. METHODS: Treatment protocols were studied: sonication groups (40 kHz, 1 MHz and dual-frequency), the same sonication groups with nanoliposomes containing MB, MB free and nanoliposomes containing MB groups, and so sham and control groups. The nanoliposomes were prepared by the lipid film hydration method. The cell viability of the different treatment groups was evaluated by the MTT assay. RESULTS: The dual-frequency protocols caused higher viability losses compared to the kHz and MHz sonications (P < .05). In presence of the nanoliposomes containing MB, dual frequency led to 6% and 3% viability for 600 and 1200 seconds, respectively, while the corresponding values were 10% and 4% for the 40 kHz protocols and 22% and 9% for the 1 MHz, as compared to the control group (100%). The result of KI dosimetry showed that the cavitation activity of the dual-frequency protocol was about 1.23, as compared to sonication at 40 kHz and 1 MHz. CONCLUSION: Enhancement of inertial cavitation induction by dual-frequency sonication may be the primary effective mechanism, which causes increased sonochemical processes and drug release from nanocarriers.

The protective effect of oleuropein against radiation-induced cytotoxicity, apoptosis, and genetic damage in cultured human lymphocytes.

PURPOSE: The aim of this study was to evaluate the effects of oleuropein radiation protection and to find an effective radioprotector. MATERIALS AND METHOD: Human mononuclear cells were treated with oleuropein at the concentration of 100 µM (optimum concentration), incubated for 24 h, and then exposed to 2 Gy gamma-rays. The anti-radiation effect of oleuropein was assessed by MTT assay, flow cytometry, comet assay, and micronucleus (MN) assay. RESULTS: It was found that pretreatment with oleuropein (25, 50, 75, 100, 200, 400, and 800 nM, and 1, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, and 200 µM) significantly increased the percentage of cell viability compared to the irradiated group (p < .001). Moreover, oleuropein treatment with the above concentrations defined without gamma-ray did not show any cytotoxicity effect in human mononuclear cells. The LD50/24h dose was calculated as 2.9 Gy, whereas by 200, 150, 50, and 100 µM oleuropein prior to radiation (1, 2,and 4 Gy), radiation LD50/24h increased to 3.36, 3.54, 3.81, and >4 Gy, in that order. A very noticeable dose-modifying factor (DMF) of 1.16, 1.23, 1.31, and 1.72 was observed for 200, 150, 50, and 100 µM, in order. Therefore, 100 µM of oleuropein was selected as the desirable dose for radio-protection trial, and 2 Gy gamma-rays were used for further research. Human mononuclear cells treatment with oleuropein (100 µM) prior to 2 Gy gamma-rays significantly decreased apoptosis, genomic damage, and MN occurrence in human mononuclear caused by gamma-radiation (p < .001). Furthermore, treatment with oleuropein (100 µM) without radiation did not lead to apoptosis, genotoxicity, or clastogenic effects caused by oleuropein in human mononuclear cells. CONCLUSION: The results revealed that oleuropein is able to significantly reduce cytotoxicity, apoptosis, genotoxic, and clastogenic effects of gamma-rays.

Low-intensity ultrasound combined with allogenic adipose-derived mesenchymal stem cells (AdMSCs) in radiation-induced skin injury treatment.

Mesenchymal stem cells are mechano-sensitive cells with the potential to restore the function of damaged tissues. Low-intensity ultrasound has been increasingly considered as a bioactive therapeutic apparatus. Optimizing transplantation conditions is a critical aim for radiation-induced skin tissue injury. Therefore, the therapeutic function of adipose-derived mesenchymal stem cells to ultrasound stimulus was examined based on the mechanical index (MI). Mesenchymal stem cells were isolated from the adipose tissues of mature guinea pigs. An ultrasound system (US) was constructed with a 40 kHz frequency. The radiation-induced skin injury model was produced on the abdominal skin of guinea pigs by 60 Gy of radiation. Then, they were divided to 7 groups (n = 42): control, sham, US (MI = 0.7), AdMSCs injection, US AdMSCs (AdMSCs, under US with MI = 0.2), AdMSCs + US (AdMSCs transplantation and US with MI = 0.7) and US AdMSCs + US (combining the last two groups). The homing of stem cells was verified with fluorescence imaging. The groups were followed with serial photography, ultrasound imaging, tensiometry, and histology. The thickness of the skin was analyzed. Functional changes in skin tissue were evaluated with Young's modulus (kPa). One-way ANOVA tests were performed to analyze differences between treatment protocols (p < 0.05). The results of Kumar's score showed that radiation injury was significantly lower in the treatment groups of US AdMSCs and US AdMSCs + US than other groups after 14 days (p < 0.05). There was a significant difference in skin thickness between treatment groups with control, sham, and US groups after 60 Gy radiation and were closer to the thickness of healthy skin. Young's modulus in US AdMSCs + US, US AdMSCs, and AdMSCs + US groups demonstrated a significant difference with the other groups (p < 0.05). Young's modulus in US AdMSCs + US and US AdMSCs treatment groups were closer to Young's modulus of the healthy skin. The histological results confirmed the improvement of acute radiation damage in the combined treatment method, especially in US AdMSCs + US and US AdMSCs groups with increasing the epithelialization and formation of collagen. An ultrasonic treatment plan based on a mechanical index of the target medium could be used to enhance stem cell therapy.

Assessing the out-of-field dose calculation accuracy by eclipse treatment planning system in sliding window IMRT of prostate cancer patients.

AIM: The objective of this study was to evaluate out-of-field dose distribution calculation accuracy by the Anisotropic Analytical Algorithm (AAA), version 13.0.26, in Eclipse TPS, (Varian Medical Systems, Palo Alto, Ca, USA) for sliding window IMRT delivery technique in prostate cancer patients. MATERIALS AND METHODS: Prostate IMRT plans with nine coplanar were calculated with the AAA Eclipse treatment planning system. To assess the accuracy of dose calculation predicted by the Eclipse in normal tissue and OARs located out of radiation field areas, including the rectum, bladder, right and left head of the femur, absolute organ dose value, and dose distribution were measured using the Delta4+ IMRT phantom. RESULTS: In the out-of-field areas, underestimation of -0.66% in organs near the field edge to -39.63% in organs far from the field edge (2.5 and 7.3 cm respectively) occurred in the TPS calculations. The percentage of dose deviation for the femoral heads was 95.7 on average while for the organ closer to the target (rectum) it was 79.81. CONCLUSIONS: AAA dosimetry algorithm (used in Eclipse TPS) showed poor dose calculation in areas beyond the treatment fields border where underestimation varies with the distance from the field edges. A significant underestimation was found for the AAA algorithm in the sliding window IMRT technique (P-value > 0.05).

Comparison of radiation and chemoradiation-induced sensorineural hearing loss in head and neck cancer patients.

AIM: The purpose of this study was to assess and compare the incidence and severity of sensorineural hearing loss (SNHL) in head-and-neck patients undergoing radiotherapy (RT) and concurrent cisplatin-based chemoradiotherapy (CRT). MATERIALS AND METHODS: Pure tone audiometry (PTA) was performed at 0.25-12 kHz on 35 RT and 25 CRT patients after 12-month followed up. The hearing loss was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. RESULTS: SNHL increased to 84% in patients who had received CRT, compared with 26% increasing in patients who had treated with RT. There was an increased risk of SNHL at all frequencies for ears received a cochlear mean dose >50 Gy in RT group, compared to those receiving cochlear mean dose >30 Gy in CRT group. SNHL was more severe at higher frequencies in both patient groups. CONCLUSION: Characteristic of radiation-induced SNHL is different from CRT-induced SNHL, especially in threshold radiation dose and PTA frequency.

Synergistic effects of anti-PDL-1 with ablative radiation comparing to other regimens with same biological effect dose based on different immunogenic response.

INTRODUCTION: Irradiation can induce multiple inhibitory and stimulatory effects on the immune system. In recent studies, it has been noted that administration of radiation with various doses and fractionation plans may influence on immune responses in microenvironment of tumor. But in radiobiology, the Biologically Effective Dose (BED) formula has been designed for calculating isoeffect doses in different regimens of daily clinical practice. In other words, BED has also been used to predict the effects of fractionation schedules on tumor cells. METHODS: In our study, three different regimens with BEDs of 40 gray (Gy) were analyzed in BALB/c mice. These included conventional fractionated radiotherapy (RT) (3Gyx10), high-dose hypofractionated RT (10Gyx2), and single ablative high-dose RT (15Gyx1). RESULTS: As BED predicts, all three similarly decreased tumor volumes and increased survival times relative to controls, but after high dose exposure in ablative group, the expression of IFNγ was increased following high infiltration of CD8 cells into the tumor microenvironment. When anti-PDL-1 was combined with RT, single ablative high-dose radiation enhanced antitumor activity by increasing IFNγ in tumors and CD8+ tumor-infiltrating lymphocytes; as a result, this combining therapy had enhanced antitumor activity and lead to control tumor volume effectively and improve significantly survival rate and finally the recurrence of tumor was not observed. CONCLUSION: Results show distinct radiation doses and fractionation schemes with same BED have different immunogenic response and these findings can provide data helping to design regimens of radiation combined with immune checkpoint blockers (ICBs).