Search

Stresses caused by ionizing radiation can also damage tissues and organs through the circulatory system. In this study, we aimed to determine the radioprotective effect of propolis, a natural and powerful antioxidant product, against oxidative liver damage caused by cranial irradiation. Thirty-two male albino Sprague-Dawley rats, divided into four groups, were designed as sham group, irradiation (IR) group, propolis plus IR, control group of propolis. Biochemical parameters were measured in liver tissue of rats. While Total enzymatic superoxide scavenging activity (TSSA) and non-enzymatic superoxide scavenging activity (NSSA), glutathione peroxidase (GSH-Px) activities of all groups were statistically significantly higher than rats receiving only-irradiation, Glutathione-S-transferase (GST) activity in the IR group was significantly lower than in the sham control group and IR + propolis group. Superoxide dismutase (SOD) activity in the IR group was found to be significantly higher than both the sham control group and the propolis control group, but lower than the IR + propolis group. Malondialdehyde level and xanthine oxidase activity were higher in the IR group than in the other groups. Compared to the sham control group, in the group treated with propolis, a significant elevation in antioxidant parameters, specifically TSSA, NSSA, SOD, and GST activities, was noted, with corresponding increases of 32.3%, 23.2%, 47.6%, and 22.6%, respectively. Our findings show that propolis can be a radioprotective agent against ionized radiation damage by increasing antioxidant activity and reducing oxidant stress in liver tissue., (© 2024. The Author(s).)

Radiation exposure in a therapeutic setting or during a mass casualty event requires improved medical triaging, where the time to delivery and quantity of medical countermeasures are critical to survival. Radiation-induced liver injury (RILI) and fibrosis can lead to death, but clinical symptoms manifest late in disease pathogenesis and there is no simple diagnostic test to determine RILI. Because animal models do not completely recapitulate clinical symptoms, we used a human liver-on-a-chip model to identify biomarkers of RILI. The goals of this study were: 1. to establish a microfluidic liver-on-a-chip device as a physiologically relevant model for studying radiation-induced tissue damage; and 2. to determine acute changes in RNA expression and biological pathway regulation that identify potential biomarkers and mechanisms of RILI. To model functional human liver tissue, we used the Emulate organ-on-a-chip system to establish a co-culture of human liver sinusoidal endothelial cells (LSECs) and hepatocytes. The chips were subject to 0 Gy (sham), 1 Gy, 4 Gy, or 10 Gy irradiation and cells were collected at 6 h, 24 h, or 7 days postirradiation for RNA isolation. To identify significant expression changes in messenger RNA (mRNA) and long non-coding RNA (lncRNA), we performed RNA sequencing (RNASeq) to conduct whole transcriptome analysis. We found distinct differences in expression patterns by time, dose, and cell type, with higher doses of radiation resulting in the most pronounced expression changes, as anticipated. Ingenuity Pathway Analysis indicated significant inhibition of the cell viability pathway 24 h after 10 Gy exposure in LSECs but activation of this pathway in hepatocytes, highlighting differences between cell types despite receiving the same radiation dose. Overall, hepatocytes showed fewer gene expression changes in response to radiation, with only 3 statistically significant differentially expressed genes at 7 days: APOBEC3H, PTCHD4, and GDNF. We further highlight lncRNA of interest including DINO and PURPL in hepatocytes and TMPO-AS1 and PRC-AS1 in LSECs, identifying potential biomarkers of RILI. We demonstrated the potential utility of a human liver-on-a-chip model with primary cells to model organ-specific radiation injury, establishing a model for radiation medical countermeasure development and further biomarker validation. Furthermore, we identified biomarkers that differentiate radiation dose and defined cell-specific targets for potential radiation mitigation therapies., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a disease that causes an abnormal accumulation of fat in the liver, triggering inflammation and fibrosis, the mechanism of which is not fully understood and for which there is a lack of specific drug therapy. Far-infrared radiation (FIR) has demonstrated evident therapeutic efficacy across various diseases, and novel nanomaterial graphene patches can emit it through electric heating. This study aimed to investigate the potential protective effects of FIR against MAFLD. Mice were fed with a MCD diet to mimic MAFLD progression, and histopathology analysis, biochemical analysis, RT-qPCR, and Western blotting analysis were performed to assess the effect of FIR on MAFLD in vivo. The effect of FIR treatment on MAFLD in vitro was investigated by biochemical analysis and gene expression profiling of hepatocytes. Mice subjected to the MCD diet and treated with FIR exhibited reduced hepatic lipid deposition, inflammation, fibrosis and liver damage. The therapeutic effect exerted by FIR in mice may be caused by the enhancement of AMPK phosphorylation and inhibition of the TGFβ1-SMAD2/3 pathway. Besides, FIR intervention alleviated MAFLD in hepatocytes in vitro and the results were verified by gene expression profiling. Our results revealed a promising potential of FIR as a novel therapeutic approach for MAFLD., (© 2024. The Author(s).)

Objective. Contrast-enhanced computed tomography (CECT) is commonly used in the pre-treatment evaluation of liver Y-90 radioembolization feasibility. CECT provides detailed imaging of the liver and surrounding structures, allowing healthcare providers to assess the size, location, and characteristics of liver tumors prior to the treatment. Here we propose a method for translating CECT images to an expected dose distribution for tumor(s) and normal liver tissue. Approach. A pre-procedure CECT is used to obtain an iodine arterial-phase distribution by subtracting the non-contrast CT from the late arterial phase. The liver segments surrounding the targeted tumor are selected using Couinaud's method. The resolution of the resulting images is then degraded to match the resolution of the positron emission tomography (PET) images, which can image the Y-90 activity distribution post-treatment. The resulting images are then used in the same way as PET images to compute doses using the local deposition method. CECT images from three patients were used to test this method retrospectively and were compared with Y-90 PET-based dose distributions through dose volume histograms. Main results. Results show a concordance between predicted and delivered Y-90 dose distributions with less than 10% difference in terms of mean dose, for doses greater than 10% of the 98th percentile (D2%). Significance. CECT-derived predictions of Y-90 radioembolization dose distributions seem promising as a supplementary tool for physicians when assessing treatment feasibility. This dosimetry prediction method could provide a more comprehensive pre-treatment evaluation-offering greater insights than a basic assessment of tumor opacification on CT images., (© 2024 Institute of Physics and Engineering in Medicine.)

Image-based dosimetry-guided radiopharmaceutical therapy has the potential to personalize treatment by limiting toxicity to organs at risk and maximizing the therapeutic effect. The 177 Lu dosimetry challenge of the Society of Nuclear Medicine and Molecular Imaging consisted of 5 tasks assessing the variability in the dosimetry workflow. The fifth task investigated the variability associated with the last step, dose conversion, of the dosimetry workflow on which this study is based. Methods: Reference variability was assessed by 2 medical physicists using different software, methods, and all possible combinations of input segmentation formats and time points as provided in the challenge. General descriptive statistics for absorbed dose values from the global submissions from participants were calculated, and variability was measured using the quartile coefficient of dispersion. Results: For the liver, which included lesions with high uptake, variabilities of up to 36% were found. The baseline analysis showed a variability of 29% in absorbed dose results for the liver from datasets where lesions included and excluded were grouped, indicating that variation in how lesions in normal liver were treated was a significant source of variability. For other organs and lesions, variability was within 7%, independently of software used except for the local deposition method. Conclusion: The choice of dosimetry method or software had a small contribution to the overall variability of dose estimates., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Throughout radiotherapy, radiation of the hepatic tissue leads to damage of the hepatocytes. We designed the current study to examine how cerium oxide nanoparticles (CONPs) modulate gamma irradiation-induced hepatotoxicity in rats. Animals received CONPs (15 mg/kg body weight [BW], ip) single daily dose for 14 days, and they were exposed on the seventh day to a single dose of gamma radiation (6 Gy). Results showed that irradiation increased serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activities. Furthermore, it elevated oxidative stress biomarker; malondialdehyde (MDA) and inhibited the activities of antioxidant enzymes (superoxide dismutase and glutathione peroxidase) in hepatic tissues homogenate. Additionally, hepatic apoptotic markers; caspase-3 (Casp-3) and Casp-9 were elevated and the B-cell lymphoma-2 (Bcl-2) gene level was decreased in rats exposed to radiation dose. We observed that CONPs can modulate these changes, where CONPs reduced liver enzyme activities, MDA, and apoptotic markers levels, in addition, it elevated antioxidant enzyme activities and Bcl-2 gene levels, as well as improved histopathological changes in the irradiated animals. So our results concluded that CONPs had the ability to act as radioprotector defense against hepatotoxicity resulted during radiotherapy., (© 2024 John Wiley & Sons Ltd.)

Ionizing radiation produces deleterious effects on living organisms. The present investigation has been carried out to study the prophylactic as well as the therapeutic effects of treated rats with quercetin (Quer) and curcumin (Cur), which are two medicinal herbs known for their antioxidant activities against damages induced by whole-body fractionated gamma irradiation. Exposure of rats to whole-body gamma irradiation induced a significant decrease in erythrocyte (RBC), leukocyte (WBCs), platelet count (Plt), hemoglobin concentration (Hb), hematocrit (Hct %), mean erythrocyte hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and mean erythrocyte volume (MCV); a high increase in plasma thiobarbituric acid reactive substances (TBARS); a nonsignificant statistical decrease in the mean value of serum glutathione (GSH); a significant increase in plasma alanine transferase (ALT), aspartate transferase (AST), alkaline phosphates (ALP), serum total protein, serum total cholesterol levels, total triglycerides levels, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels; and with marked histological changes and structural changes measured by Fourier transform infrared (FTIR). Applying both quercetin and curcumin pre- and postexposure to gamma radiation revealed a remarkable improvement in all the studied parameters. The cellular damage by gamma radiation is greatly mitigated by the coadministration of curcumin and quercetin before radiation exposure., (© 2024. The Author(s).)

Exposure to high, marginally lethal doses or higher of ionizing radiation, either intentional or accidental, results in injury to various organs. Currently, there is only a limited number of safe and effective radiation countermeasures approved by US Food and Drug Administration for such injuries. These approved agents are effective for only the hematopoietic component of the acute radiation syndrome and must be administered only after the exposure event: currently, there is no FDA-approved agent that can be used prophylactically. The nutraceutical, gamma-tocotrienol (GT3) has been found to be a promising radioprotector of such exposure-related injuries, especially those of a hematopoietic nature, when tested in either rodents or nonhuman primates. We investigated the nature of injuries and the possible protective effects of GT3 within select organ systems/tissues caused by both non-lethal level (4.0 Gy), as well as potentially lethal level (5.8 Gy) of ionizing radiation, delivered as total-body or partial-body exposure. Results indicated that the most severe, dose-dependent injuries occurred within those organ systems with strong self-renewing capacities (e.g., the lymphohematopoietic and gastrointestinal systems), while in other tissues (e.g., liver, kidney, lung) endowed with less self-renewal, the pathologies noted tended to be less pronounced and less dependent on the level of exposure dose or on the applied exposure regimen. The prophylactic use of the test nutraceutical, GT3, appeared to limit the extent of irradiation-associated pathology within blood forming tissues and, to some extent, within the small intestine of the gastrointestinal tract. No distinct, global pattern of bodily protection was noted with the agent's use, although a hint of a possible radioprotective benefit was suggested not only by a lessening of apparent injury within select organ systems, but also by way of noting the lack of early onset of moribundity within select GT3-treated animals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: This study aimed to construct a nomogram to predict radiation-induced hepatic toxicity in patients with hepatocellular carcinoma treated with intensity-modulated radiotherapy., Methods: This study reviewed the clinical characteristics and dose-volume parameters of 196 patients with hepatocellular carcinoma. Radiation-induced hepatic toxicity was defined as progression of the Child-Pugh score caused by intensity-modulated radiotherapy. Factors relevant to radiation-induced hepatic toxicity were selected using receiver operating characteristic and univariate logistic analysis. A risk assessment model was developed, and its discrimination was validated., Results: Eighty-eight (44.90%) and 28 (14.29%) patients had radiation-induced hepatic toxicity ≥ 1 (Child-Pugh ≥ 1) and radiation-induced hepatic toxicity ≥ 2 (Child-Pugh ≥ 2). Pre-treatment Child-Pugh, body mass index and dose-volume parameters were correlated with radiation-induced hepatic toxicity ≥ 1 using univariate logistic analysis. V15 had the best predictive effectiveness among the dose-volume parameters in both the training (area under the curve: 0.763, 95% confidence interval: 0.683-0.842, P < 0.001) and validation cohorts (area under the curve: 0.759, 95% confidence interval: 0.635-0.883, P < 0.001). The area under the curve values of the model that was constructed by pre-treatment Child-Pugh, body mass index and V15 for radiation-induced hepatic toxicity ≥1 were 0.799 (95% confidence interval: 0.719-0.878, P < 0.001) and 0.775 (95% confidence interval: 0.657-0.894, P < 0.001) in the training and validation cohorts, respectively. Patients with a body mass index ≤ 20.425, Barcelona clinic liver cancer = C, Hepatitis B Virus-positive, Eastern Cooperative Oncology Group = 1-2 and hepatic fibrosis require lower V15 dose limits., Conclusions: Risk assessment model constructed from Pre-treatment Child-Pugh, V15 and body mass index can guide individualized patient selection of toxicity minimization strategies., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: A pediatric normal tissue effects in the clinic (PENTEC) comprehensive review of patients with childhood cancer who received radiation therapy (RT) to the liver was performed to develop models that may inform RT dose constraints for the liver and improve risk forecasting of toxicities., Methods and Materials: A systematic literature search was performed to identify published data on hepatic toxicities in children. Treatment and outcome data were extracted and used to generate normal tissue complication probability (NTCP) models. Complications from both whole and partial liver irradiation were considered. For whole liver irradiation, total body irradiation and non-total body irradiation treatments were considered, but it was assumed that the entire liver received the prescribed dose. For partial liver irradiation, only Wilms tumor flank field RT could be analyzed. However, a prescribed dose assumption could not be applied, and there was a paucity of analyzable liver dosimetry data. To associate the dose-volume exposures with the partial volume complication data from flank irradiation, liver dose-volume metrics were reconstructed for Wilms tumor flank RT using age-specific computational phantoms as a function of field laterality and superior extent of the field., Results: The literature search identified 2103 investigations pertaining to hepatic sinusoidal obstructive syndrome (SOS) and liver failure in pediatric patients. All abstracts were screened, and 241 articles were reviewed in full by the study team. A model was developed to calculate the risk of developing SOS after whole liver RT. RT dose (P = .006) and receipt of nonalkylating chemotherapy (P = .01) were significant. Age <20 years at time of RT was borderline significant (P = .058). The model predicted a 2% risk of SOS with zero RT dose, 6.1% following 10 Gy, and 14.5% following 20 Gy to the whole liver (modeled as the linear-quadratic equivalent dose in 2-Gy fractions [α/β = 3 Gy]). Patients with Wilms tumor treated with right flank RT had a higher observed rate of SOS than patients receiving left flank RT, but data were insufficient to generate an NTCP model for partial liver irradiation. From the phantom-based dose reconstructions, mean liver dose was estimated to be 2.16 ± 1.15 Gy and 6.54 ± 2.50 Gy for left and right flank RT, respectively, using T10-T11 as the superior field border and a prescription dose of 10.8 Gy (based on dose reconstruction). Data were sparse regarding rates of late liver injury after RT, which suggests low rates of severe toxicity after treatment for common pediatric malignancies., Conclusions: This pediatric normal tissue effects in the clinic (PENTEC) review provides an NTCP model to estimate the risk of hepatic SOS as a function of RT dose following whole liver RT and quantifies the range of mean liver doses from typical Wilms tumor flank irradiation fields. Patients treated with right flank RT had higher rates of SOS than patients treated with left flank RT, but data were insufficient to develop a model for partial liver irradiation. Risk of SOS was estimated to be approximately ≤6% in pediatric patients receiving whole liver doses of <10 Gy., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Transarterial radioembolization or selective internal radiation therapy (SIRT) has emerged as a minimally invasive approach for the treatment of tumors. This percutaneous technique involves the local, intra-arterial delivery of radioactive microspheres directly into the tumor. Historically employed as a palliative measure for liver malignancies, SIRT has gained traction over the past decade as a potential curative option, mirroring the increasing role of radiation segmentectomy. The latest update of the BCLC hepatocellular carcinoma guidelines recognizes SIRT as an effective treatment modality comparable to other local ablative methods, particularly well-suited for patients where surgical resection or ablation is not feasible. Radiation segmentectomy is a more selective approach, aiming to deliver high-dose radiation to one to three specific hepatic segments, while minimizing damage to surrounding healthy tissue. Future research efforts in radiation segmentectomy should prioritize optimizing radiation dosimetry and refining the technique for super-selective administration of radiospheres within the designated hepatic segments., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection., Methods: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were assessed 6-8 weeks and 6 months after completing radiotherapy., Results: All 12 patients had colorectal liver metastases and received prior hepatotoxic chemotherapy; 8 patients underwent prior liver resection. Median computed tomography anatomical nontumor liver volume was 1584 cc (range = 764-2699 cc). Median SPECT functional liver volume was 1117 cc (range = 570-1928 cc). Median nontarget computed tomography and SPECT liver volumes below the volumetric dose constraint were 997 cc (range = 544-1576 cc) and 684 cc (range = 429-1244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No dose-limiting toxicities were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%., Conclusion: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process, which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function., Trial Registration: NCT02626312., (© The Author(s) 2024. Published by Oxford University Press.)

Objective . Radio-opaque markers are recommended for image-guided radiotherapy in liver stereotactic ablative radiotherapy (SABR), but their implantation is invasive. We evaluate in this in-silico study the feasibility of cone-beam computed tomography-guided stereotactic online-adaptive radiotherapy (CBCT-STAR) to propagate the target volumes without implanting radio-opaque markers and assess its consequence on the margin that should be used in that context. Approach . An emulator of a CBCT-STAR-dedicated treatment planning system was used to generate plans for 32 liver SABR patients. Three target volume propagation strategies were compared, analysing the volume difference between the GTV Propagated and the GTV Conventional , the vector lengths between their centres of mass ( l CoM ), and the 95th percentile of the Hausdorff distance between these two volumes (HD95). These propagation strategies were: (1) structure-guided deformable registration with deformable GTV propagation; (2) rigid registration with rigid GTV propagation; and (3) image-guided deformable registration with rigid GTV propagation. Adaptive margin calculation integrated propagation errors, while interfraction position errors were removed. Scheduled plans (Plan Non-adaptive ) and daily-adapted plans (Plan Adaptive ) were compared for each treatment fraction. Main results. The image-guided deformable registration with rigid GTV propagation was the best propagation strategy regarding to l CoM (mean: 4.3 +/- 2.1 mm), HD95 (mean 4.8 +/- 3.2 mm) and volume preservation between GTV Propagated and GTV Conventional . This resulted in a planning target volume (PTV) margin increase (+69.1% in volume on average). Online adaptation (Plan Adaptive ) reduced the violation rate of the most important dose constraints ('priority 1 constraints', 4.2 versus 0.9%, respectively; p < 0.001) and even improved target volume coverage compared to non-adaptive plans (Plan Non-adaptive ). Significance . Markerless CBCT-STAR for liver tumours is feasible using Image-guided deformable registration with rigid GTV propagation. Despite the cost in terms of PTV volumes, daily adaptation reduces constraints violation and restores target volumes coverage., (© 2024 Institute of Physics and Engineering in Medicine.)

Background: Radiation-induced liver damage (RILD) occasionally occurs following carbon-ion radiotherapy (CIRT) for liver tumors, such as hepatocellular carcinoma (HCC), in patients with impaired liver function disease. However, the associated risk factors remain unknown. The present study aimed to determine the risk factors of RILD after CIRT., Methods: We retrospectively analyzed 108 patients with HCC treated with CIRT at the Osaka Heavy Ion Therapy Center between December 2018 and December 2022. RILD was defined as a worsening of two or more points in the Child-Pugh score within 12 months following CIRT. The median age of the patients was 76 years (range 47-95 years), and the median tumor diameter was 41 mm (range 5-160 mm). Based on the pretreatment liver function, 98 and 10 patients were categorized as Child-Pugh class A and B, respectively. We analyzed patients who received a radiation dose of 60 Gy (relative biological effectiveness [RBE]) in four fractions. The median follow-up period was 9.7 months (range 2.3-41.1 months), and RILD was observed in 11 patients (10.1%)., Results: Multivariate analysis showed that pretreatment Child-Pugh score B (p = 0.003, hazard ratio [HR] = 6.90) and normal liver volume spared from < 30 Gy RBE (VS 30  < 739 cm 3 ) (p = 0.009, HR = 5.22) were significant risk factors for RILD. The one-year cumulative incidences of RILD stratified by Child-Pugh class A or B and VS 30  < 739 cm 3 or ≥ 739 cm 3 were 10.3% or 51.8% and 39.6% or 9.2%, respectively., Conclusion: In conclusion, the pretreatment Child-Pugh score and VS 30 of the liver are significant risk factors for RILD following CIRT for HCC., (© 2024. The Author(s).)

To investigate curcumin (CUR) as the protector against the harmful effects of low-frequency electromagnetic field(LF- EMF, 50 Hz) during pregnancy period, 5 males and 15 females of Wistar rat mated and vaginal plaques were observed. Then, the pregnant rats were divided into six groups. During pregnancy(21 days), the EMF group was exposed to EMF for 30 min/day, the CUR group received a single dose of 50 mg/kg/daily CUR intraperitoneal, the EMF+CUR group was injected CUR and exposed to EMF daily. The DMSO(dimethyl sulfoxide) group was injected solvent of CUR (DMSO) intraperitoneal with the same volume of CUR solvent, the sham group was placed through the solenoid in the same conditions as the first group without exposure and the control group was kept in their cage in normal condition. After four weeks, babies born were divided according to the mother groups and sacrificed. Then, the three tissues injuries were investigated. EMF exposure led to an increase in outstanding necrotic areas in hippocampal tissue, an increase in the amount of hyperemia( p  = 0.017) and necrotic( p  = 0.005) in kidneys, and degeneration in liver tissue( p  = 0.007) in the EMF group compared with EMF+CUR groups. A single dose of CUR daily during pregnancy can protect these tissues from injuries caused by LF-EMF exposure in rat fetuses.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder mainly affecting joints, yet the systemic inflammation can influence other organs and tissues. The objective of this study was to unravel the ameliorative capability of Ondansetron (O) or β-sitosterol (BS) against inflammatory reactions and oxidative stress that complicates Extra-articular manifestations (EAM) in liver, kidney, lung, and heart of arthritic and arthritic irradiated rats., Methods: This was accomplished by exposing adjuvant-induced arthritis (AIA) rats to successive weekly fractions of total body γ-irradiation (2 Gray (Gy)/fraction once per week for four weeks, up to a total dose of 8 Gy). Arthritic and/or arthritic irradiated rats were either treated with BS (40 mg/kg b.wt. /day, orally) or O (2 mg/kg) was given ip) or were kept untreated as model groups., Results: Body weight changes, paw circumference, oxidative stress indices, inflammatory response biomarkers, expression of Janus kinase-2 (JAK-2), Signal transducer and activator of transcription 3 (STAT3), high mobility group box1 (HMGB1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), as well as pro- and anti-inflammatory mediators in the target organs, besides histopathological examination of ankle joints and extra-articular tissues. Treatment of arthritic and/or arthritic irradiated rats with BS or O powerfully alleviated changes in body weight gain, paw swelling, oxidative stress, inflammatory reactions, and histopathological degenerative alterations in articular and non-articular tissues., Conclusion: The obtained data imply that BS or O improved the articular and EAM by regulating oxidative and inflammatory indices in arthritic and arthritic irradiated rats., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Irradiation of the liver induces a regenerative response in the nonirradiated part of the liver. It is unclear whether this leads to actual liver enlargement. The aim of this study was to evaluate the weight of compensatory hypertrophy that occurs in nonirradiated livers and to clarify the mechanism of hypertrophy from the viewpoint of hepatocyte proliferation. The anterior liver lobes (anterior lobes) were irradiated with 60 Gy of X-rays (X60 Gy) under opening laparotomy. Body weights and liver lobe weights were measured before and at 1, 4, 8 and 12 weeks after irradiation, and serum and liver tissue samples were analyzed at each time point. The anterior lobes atrophied progressively, whereas the posterior liver lobes (posterior lobes) hypertrophied in the X-ray irradiated (X-irradiated) group. Although temporary liver damage was observed after irradiation, liver function did not decrease at any time point. Hepatocyte degeneration and loss were observed in the anterior lobes of the X-irradiated group, and significant fibrosis developed 8 weeks postirradiation. Following irradiation, the proportion of Ki-67-positive cells in the anterior lobes decreased markedly in the early postirradiation period, whereas the proportion of positive cells in the posterior lobes increased, peaking at 4 weeks postirradiation (P < 0.05). Increased tumor necrosis factor-α expression was observed only in the anterior liver lobes of the X-irradiated group at 1 and 4 weeks postirradiation. Partial liver irradiation with X60 Gy induced compensatory hypertrophy of nonirradiated liver lobes. This study suggests that liver hypertrophy after partial liver irradiation is caused by increased hepatocyte mitosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

The liver's susceptibility to oxidative stress after a combination of forced swim test (FST) and low-dose-rate γ-irradiation has been observed. Therefore, this study aims to clarify the effects of low-dose (0.1 and 0.5 Gy)/high-dose-rate (1.2 Gy/min) irradiation on combined oxidative stressors-liver damage associated with FST and alcohol administration. In addition, the effects of similar irradiation on FST-induced immobility, which induces psychomotor retardation, and antioxidative effects on the brain, lungs, liver and kidneys were investigated, and the results were compared with those of a similar previous study that utilized low-dose-rate irradiation. Low-dose/high-dose-rate (especially 0.5 Gy) irradiation temporarily worsened liver antioxidant function and hepatic function with FST- and alcohol administration-related oxidative damage; however, the damages improved soon after. In addition, the increase in total glutathione content in the liver contributed to the early improvement of hepatic functions. However, pre-irradiation did not suppress immobility during the FST. The results also suggested that the effects of low-dose/high-dose-rate irradiation on the antioxidant functions of each organ after the FST were different from those of low-dose/low-dose-rate irradiation. Overall, this study provides further insights into the effects of low-dose irradiation on exposure to a combination of different oxidative stressors. It will also contribute to the elucidation of dose rate effects on oxidative stress in the low-dose irradiation range., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

N-acetyl cysteine (NAC) is a nutritional supplement and greatly applied as an antioxidant in vivo and in vitro . Therefore, this study aimed to assess the metabolic and antioxidant protective effect of NAC against selenium (Se) toxicity and gamma irradiation in rats by measuring biochemical and molecular parameters. This study was conducted on sixty rats divided into six equal different groups; control, NAC, Rad, Se, Rad + NAC, and Se + NAC groups. Oxidative/nitrosative makers (LPO, NO, and NOS), antioxidants status markers (GSH, GPx, and SOD), liver metabolic markers (LDH, SDH, and ATP), and plasma metabolic markers (Glucose, total cholesterol, and total proteins) were measured using commercial colorimetric kits while plasma corticosterone concentration was measured using commercial ELISA kit. Also, Levels of NR3C1 and Glut-2 genes expression using reverse transcription-quantitative polymerase chain reaction were done. Our results revealed that Se toxicity and gamma irradiation induced significant increases in oxidative/nitrosative stress markers and a significant decrease in antioxidant status markers in the liver and adrenal tissues. Moreover, metabolic disorders were recorded as manifested by elevation of plasma ALT, Albumin, glucose and cholesterol, and decrease in protein levels associated with a significant increase in corticosterone concentration. This was also accompanied by a significant decrease in SDH activity and ATP production in the hepatic tissue. Molecular analysis showed a marked increase in NR3C1 mRNA and decrease in Glut-2 mRNA in liver tissue. However, NAC supplementation attenuated the changes induced by these toxins. Finally, we could conclude that, oral supplementation of NAC can modulate the metabolic disturbances and has protective effects in rats exposed to Se toxicity and gamma irradiation.

Background: Locoregional therapies, as imaging-guided tumor-directed procedures, are emerging treatment strategies in the management of primary and secondary liver malignancies such as e.g. colorectal cancer liver metastases. As one of those, irradiation-based interstitial high dose rate brachytherapy (iBT) of liver metastases bears a risk of developing focal radiation-induced liver injury (fRILI). Since little is known about biological factors involved in hepatic dysfunction after irradiation, the aim of this study was to identify factors, that may play a role in the underlying mechanism of fRILI, and that potentially may serve as biomarkers for post-therapeutic fRILI to improve specific management and treatment of patients., Methods: Twenty-two patients with hepatic malignancies (tumor patients, TP) underwent iBT with total ablative doses of radiation to the target volume ranging from e.g. 15 to 25 Gy. Hepatobiliary magnetic resonance imaging (MRI) was performed 6 weeks after iBT to quanitify fRILI. Blood samples were taken before (pre) and 6 weeks after (post) iBT from TP, and from ten healthy volunteers (HV controls) for the analyses of humoral mediators: monocyte chemoattractant protein-1 (MCP-1), chemokine (C-X3-C motif) ligand 1 (CX3CL1), vascular endothelial growth factor (VEGF) and beta-nerve growth factor (beta-NGF) using the Multi-Analyte Flow Assay via flow cytometry. Correlation analyses between the humoral mediators (pre and post iBT) with the tumor volume and fRILI were performed., Results: While MCP-1 and CX3CL1 tended to decrease in TP vs. HV, VEGF was significantly decreased in TP vs. HV pre and post iBT (p < 0.05). Beta-NGF levels were significantly increased in TP vs. HV pre and post iBT (p < 0.05). Baseline circulating levels of MCP-1, VEGF and beta-NGF have shown significant positive correlations with the hepatic tumor volume (p < 0.05). Circulating levels of humoral mediators before treatment did not correlate with fRILI, while CX3CL1 and VEGF after iBT have shown significant positive correlations with fRILI (p < 0.05)., Conclusion: Tumor volume and threshold dose of irradiation damage correlated positively with MCP-1 and VEGF as well as NGF and CX3CL, respectively. Thus, investigation of biological mediators in blood samples from tumor patients may provide an appropriate tool to predict fRILI after interstitial HDR brachytherapy of liver metastases., (© 2022. The Author(s).)

Background/aim: To evaluate the early effect of radiation dose on liver function in breast cancer patients undergoing free-breathing volumetric modulated arc therapy (FB-VMAT)., Patients and Methods: Medical records of 125 patients with breast cancer who underwent curative surgery followed by postoperative radiotherapy using FB-VMAT during 2018-2021 were reviewed. Results of the liver function test (LFT), performed within 1-week before and 6-months after radiotherapy, were collected and compared. The LFTs analyzed albumin, total and direct bilirubin, aspartate transaminase, alanine transferase, and alkaline phosphatase levels. The mean dose and relative liver volume receiving at least 10 Gy, 20 Gy, or 30 Gy were calculated., Results: Median follow-up time was 21.4 months. One patient experienced locoregional and distant failures. The mean liver irradiation dose was 325.9 centigray (cGy) for all patients. The liver irradiation dose was higher in patients with right breast cancer than in those with left breast cancer (mean, 434.1 cGy vs. 260.6 cGy, p<0.001). Direct bilirubin and aspartate transaminase levels showed significant differences after FB-VMAT. LFT results outside normal limits were noted in 31 patients at follow-up, but nobody met the criteria of radiation-induced liver disease. Underlying liver disease, breast laterality, systemic treatment, or dose-volume histogram parameters were not associated with abnormal LFT results., Conclusion: FB-VMAT can deliver radiation doses safely without adversely affecting the liver. The mean dose ≤4 Gy could be a useful dose criterium of the liver for FB-VMAT plans., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

While the incidence of primary liver cancers has been increasing worldwide over the last few decades, the mortality has remained consistently high. Most patients present with underlying liver disease and have limited treatment options. In recent years, radiotherapy has emerged as a promising approach for some patients; however, the risk of radiation induced liver disease (RILD) remains a limiting factor for some patients. Thus, the discovery and validation of biomarkers to measure treatment response and toxicity is critical to make progress in personalizing radiotherapy for liver cancers. While tissue biomarkers are optimal, hepatocellular carcinoma (HCC) is typically diagnosed radiographically, making tumor tissue not readily available. Alternatively, blood-based diagnostics may be a more practical option as blood draws are minimally invasive, widely availability and may be performed serially during treatment. Possible blood-based diagnostics include indocyanine green test, plasma or serum levels of HGF or cytokines, circulating blood cells and genomic biomarkers. The albumin-bilirubin (ALBI) score incorporates albumin and bilirubin to subdivide patients with well-compensated underlying liver dysfunction (Child-Pugh score A) into two distinct groups. This review provides an overview of the current knowledge on circulating biomarkers and blood-based scores in patients with malignant liver disease undergoing radiotherapy and outlines potential future directions.

Lobar selective internal radiation therapy (SIRT) is widely used to treat liver tumors inducing atrophy of the treated lobe and contralateral hypertrophy. The lack of animal model has precluded further investigations to improve this treatment. We developed an animal model of liver damage and atrophy-hypertrophy complex after SIRT. Three groups of 5-8 rabbits received transportal SIRT with Yttrium 90 resin microspheres of the cranial lobes with different activities (0.3, 0.6 and 1.2 GBq), corresponding to predicted absorbed radiation dose of 200, 400 and 800 Gy, respectively. Another group received non-loaded microspheres (sham group). Cranial and caudal lobes volumes were assessed using CT volumetry before, 15 and 30 days after SIRT. Liver biochemistry, histopathology and gene expression were evaluated. Four untreated rabbits were used as controls for gene expression studies. All animals receiving 1.2 GBq were euthanized due to clinical deterioration. Cranial SIRT with 0.6 GBq induced caudal lobe hypertrophy after 15 days (median increase 34% -ns-) but produced significant toxicity. Cranial SIRT with 0.3 GBq induced caudal lobe hypertrophy after 30 days (median increase 82%, p = 0.04). No volumetric changes were detected in sham group. Transient increase in serum transaminases was detected in all treated groups returning to normal values at 15 days. There was dose-dependent liver dysfunction with bilirubin elevation and albumin decrease. Histologically, 1.2 GBq group developed permanent severe liver damage with massive necrosis, 0.6 and 0.3 GBq groups developed moderate damage with inflammation and portal fibrosis at 15 days, partially recovering at 30 days. There was no difference in the expression of hepatocyte function and differentiation genes between 0.3 GBq and control groups. Cranial SIRT with 0.3 GBq of 90 Y resin microspheres in rabbits is a reliable animal model to analyse the atrophy-hypertrophy complex and liver damage without toxicity., (© 2022. The Author(s).)

The purposes of this study were to research immune system changes and liver and lung tissues in irradiated rats after prolonged exposure to coal dust. A study was carried out on 30 male Wistar rats that were divided into 3 groups: group I, intact animals; group II, exposure to coal dust and 0.2 Gy γ -irradiation; and group III, combined exposure to 6 Gy γ -irradiation and coal dust. The combination of a low and sublethal dose of γ -irradiation with coal dust leads to a significant change in immunity at the remote period. Particularly, the increase in radioactivity at the combined effect causes weakening of phagocytosis, and reduction in T lymphocytes by a factor of 2, immunoglobulin imbalance, and cytokine dysfunction develop secondary immune failure. During prolonged inhalation with coal dust of irradiated animals with the dose of 0.2 Gy, fibrosis and perivascular sclerosis of the bronchial wall of the lungs are formed, and perivascular fibrosis is formed in the liver. The increase in exposure dose up to 6 Gy in combination with coal, in the distant period, caused pulmonary hypertension amid hypertrophy of light arterial vessels and fibrous changes in arteriole, and destructive changes and collection necrosis develop in liver parenchyma. In the case of dust radiation synergy, the increase in doses leads to a significant immune deficiency, which occurs according to the "dose effect" principle; increases damage to animal tissues; and leads to liver tissue necrosis, pulmonary fibrosis, and pulmonary hypertension., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Laura Chulenbayeva et al.)

We present the update of the recommendations of the French society of oncological radiotherapy on hepatic tumours. Recent technological progress led to develop the concept of focused liver radiation therapy. We must distinguish primary and secondary tumours, as the indications are restricted and must be discussed as an alternative to surgical or medical treatments. The tumour volume, its liver location close to the organs at risk determine the irradiation technique (repositioning method, total dose delivered, dose fractionation regimens). Tumour (and liver) breathing related motions should be taken into account. Strict dosimetric criteria must be observed with particular attention to the dose-volume histograms of non-tumoral liver as well as of the hollow organs, particularly in case of hypofractionated high dose radiotherapy "under stereotaxic conditions". Stereotactic body radiotherapy is being evaluated and is often preferred to radiofrequency for primary or secondary tumours (usually less than 5cm). An adaptation can be proposed, with a conformal fractionated irradiation protocol with or without intensity modulation, for hepatocellular carcinomas larger than 5cm., (Copyright © 2021 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Abstract: Transarterial chemoembolization is the standard treatment option for intermediate-stage hepatocellular carcinoma (HCC). However, during the interventional procedure, occupational radiation protection is compromised. The use of real-time radiation dosimetry could provide instantaneous radiation doses. This study aimed to evaluate the occupational dose of the medical staff using a real-time radiation dosimeter during transarterial chemoembolization (TACE) for HCC, and to investigate factors affecting the radiation exposure dose.This retrospective observational study included 70 patients (mean age: 66 years; age range: 38-88 years; male: female = 59: 11) who underwent TACE using real-time radiation dosimetry systems between August 2018 and February 2019. Radiation exposure doses of operators, assistants, and technicians were evaluated. Patients' clinical, imaging, and procedural information was analyzed.The mean dose-area product (DAP) and fluoroscopy time during TACE were 66.72 ± 55.14 Gycm2 and 12.03 ± 5.95 minutes, respectively. The mean radiation exposure doses were 24.8 ± 19.5, 2.0 ± 2.2, and 1.65 ± 2.0 μSv for operators, assistants, and technicians, respectively. The radiation exposure of the operators was significantly higher than that of the assistants or technicians (P < .001). The perpendicular position of the adjustable upper-body lead protector (AULP) on the table was one factor reducing in the radiation exposure of the assistants (P < .001) and technicians (P = .040). The DAP was a risk factor for the radiation exposure of the operators (P = .003) and technicians (P < .001).Occupational doses during TACE are affected by DAP and AULP positioning. Placing the AULP in the perpendicular position during fluoroscopy could be a simple and effective way to reduce the radiation exposure of the staff. As the occupational dose influencing factors vary by region or institution, further study is needed., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Although radiation is one of the basic methods commonly used in cancer treatment, it inevitably enters the field of treatment in healthy tissues and is adversely affected by the acute and chronic side effects of radiation. This study evaluated the possible protective effects of quercetin, an antioxidant agent, against liver and kidney damage in rats exposed to a whole-body single dose of radiation (10 Gy of gamma-ray)., Materials and Methods: The study groups were formed as control, sham, quercetin, radiation, quercetin + radiation and radiation + quercetin using 60 male Wistar albino (200-250 g, 3 months old) rats, including 10 rats in each group. The gamma-ray provided by the Co60 teletherapy machine was given to the whole body as external irradiation. According to the groups, quercetin was administered to rats at 50 mg/kg/day via oral gavage before or after radiation administration. The rats were sacrificed the day after irradiation and the extracted tissue samples from all groups were compared histologically and immunohistochemically. DNA damage was determined by the neutral comet assay technique. Also, malondialdehyde (MDA) and glutathione peroxidase (GSH) were evaluated in liver and kidney tissues by the ELISA method., Results: Histopathological changes were observed altered morphology of liver and kidney tissues in the radiation groups. Sinusoidal dilatations, vacuolization, and hepatic parenchyma necrosis in the liver, while in kidneys, glomerular shrinkage, widened Bowman's space, tubular dilatation, and inflammation were evident. TNF-α, IL1-α, HIF1-α, and caspase 3 immunoreactivities in tissues were determined by immunohistochemistry. High caspase 3 positive cell number confirmed apoptosis, the comet parameters were decreased in the quercetin + radiation group. When compared to the control group, the exposure to radiation showed a marked elevation in MDA which was accompanied by high GSH. This damage was reduced in the quercetin + radiation group., Conclusions: With the results obtained from the study; Quercetin is thought to have a protective potential against radiation-induced liver and kidney damage due to its radioprotective effect.

In radiobiology and radiation oncology fields, the observation of a phenomenon called radiation-induced bystander effect (RIBE) has introduced the prospect of remotely located tissues' affection. This phenomenon has been broadly developed to involve the concept of RIBE, which are relevant to the radiation-induced response of a distant tissue other than the irradiated one. The current study aimed at investigating each of the RIBE of cranial irradiation on oxidative and inflammatory status in different organs such as liver, kidney, heart, lung, and spleen. Being a vital target of the cholinergic anti-inflammatory response to an inflammatory stimulus, the splenic α-7-nicotinic acetylcholine receptor (α-7nAchR) was evaluated and the hepatic contents of thioredoxin, peroxisome proliferator-activated receptor-alpha and paraoxinase-1 (Trx/PPAR-α/PON) were also assessed as indicators for the liver oxidative stress and inflammatory responses. Being reported to act as antioxidant and anti-inflammatory agents, simvastatin (SV) and/or sildenafil (SD) were investigated for their effects against RIBE on these organs. These objectives were achieved via the biochemical assessments and the histopathological tissues examinations. Five experimental groups, one sham irradiated and four irradiated groups, were exposed to cranial irradiation at dose level of 25 Gy using an experimental irradiator with a Cobalt (Co 60 ) source, RIBE, RIBE + SV (20 mg.(kg.bw) -1  day -1 ), RIBE + SD (75 mg.(kg.bw) -1  day -1 ), and RIBE + SV + SD. Cranial irradiation induced structural, biochemical, and functional dys-regulations in non-targeted organs. RIBE-induced organs' injuries have been significantly corrected by the administration of SV and/or SD. Our results suggest the possibility of a potentiated interaction between SV and SD in the modulation of the RIBE associated with head and neck radiotherapy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The present study was aimed to explore the potential ameliorating effects of N-acetyl cysteine (NAC) against radioiodine (RAI)-induced early liver damage., Methods: Thirty Wistar Albino male rats were arbitrarily allocated into three groups each containing 10 rats: the control group (group 1); the RAI group (group 2), oral 111 MBq/kg radioiodine was administered to rats; the RAI + NAC group (group 3), 150 mg/kg/day intraperitoneal NAC treatment was initiated 3 days prior to the RAI administration and continued for 10 days. Liver samples were obtained 24 h after the last dose of NAC therapy for biochemical and histopathologic evaluation., Results: In the RAI + NAC group, the histopathologic damage was found significantly less than in the RAI group for whole parameters except inflammatory cell infiltration (P < 0.05). Unlike the RAI group which had marked histopathologic damage, the RAI + NAC group had only mild histologic activity index scores with no granuloma formation observed. Oxidative stress parameters were demonstrated that the NAC treatment significantly decreased the tissue malondialdehyde (MDA) and catalase levels and increased the total sulfhydryl (total sulfhydryl) levels when compared to the RAI group (P < 0.01)., Conclusion: The outcomes of the study exhibited that the NAC treatment improved RAI-induced early liver damage. This improving effect considered to be caused by its antioxidant, anti-inflammatory, and likely vasodilator properties of NAC. Having advantages such as inexpensive, easy access, and tolerability, the NAC can be used as a radioprotective agent, especially in patients with liver diseases and requiring RAI treatment., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Stereotactic body radiotherapy (SBRT) is increasingly used for treatment of liver tumors but the effect on metabolic liver function in surrounding tissue is largely unknown. Using 2-deoxy-2-[ 18 F]fluoro-D-galactose ([ 18 F]FDGal) positron emission tomography (PET)/computed tomography (CT), we aimed to determine a dose-response relationship between radiation dose and metabolic liver function as well as recovery., Procedures: One male subject with intrahepatic cholangiocarcinoma and five subjects (1 female, 4 male) with liver metastases from colorectal cancer (mCRC) underwent [ 18 F]FDGal PET/CT before SBRT and after 1 and 3 months. The dose response was calculated using the data after 1 month and the relative recovery was evaluated after 3 months. All patients had normal liver function at time of inclusion., Results: A linear dose-response relationship for the individual liver voxel dose was seen until approximately 30 Gy. By fitting a polynomial curve to data, a mean TD 50 of 18 Gy was determined with a 95% CI from 12 to 26 Gy. After 3 months, a substantial recovery was observed except in tissue receiving more than 25 Gy., Conclusions: [ 18 F]FDGal PET/CT makes it possible to determine a dose-response relationship between radiation dose and metabolic liver function, here with a TD 50 of 18 Gy (95% CI 12-26 Gy). Moreover, the method makes it possible to estimate metabolic recovery in liver tissue., (© 2021. The Author(s).)

At present, little is known about the molecular imaging-based response assessment of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with 177 Lutetium ( 177 Lu-PSMA-617 RLT) in metastatic castration-resistant prostate cancer (mCRPC). Our study evaluated the response to RLT using both molecular imaging and biochemical response assessments, and their potential prediction of progression-free survival (PFS). Fifty-one consecutive patients given two cycles of RLT at 6-week intervals were analyzed retrospectively. 68 Ga-PSMA-11 PET/CT was obtained about 2 weeks prior to the first and 4-6 weeks after the second cycle. Molecular imaging-based response using SUV peak and tumor-to-liver ratio (TLR) was determined by modified PERCIST criteria. ∆TLR and ∆SUV were significantly correlated with ∆PSA ( p < 0.001, each). After a median follow-up of 49 months, the median PFS (95% CI) was 8.0 (5.9-10.1) months. In univariate analysis, responders showing partial remission (PR PSA and PR TLR ) had significantly ( p < 0.001, each) longer PFS (median: 10.5 and 9.3 months) than non-responders showing either stable or progressive disease (median: 4.0 and 3.5 months). Response assessment using SUV peak failed to predict survival. In multivariable analysis, response assessment using TLR was independently associated with PFS ( p < 0.001), as was good performance status ( p = 0.002). Molecular imaging-based response assessment with 68 Ga-PSMA-11 PET/CT using normalization of the total lesion PSMA over healthy liver tissue uptake (TLR) could be an appropriate biomarker to monitor RLT in mCRPC patients and to predict progression-free survival (PFS) of this treatment modality.

In the murine liver, there are two major macrophage populations, namely resident Kupffer cells (resKCs) with phagocytic activity and recruited macrophages (recMφs) with cytokine-producing capacity. This study was performed to clarify the functional differences between these two populations, focusing on their susceptibility to radiation and response to stimulation via liver X receptors (LXRs), which are implicated in cholesterol metabolism and immune regulation. Liver mononuclear cells (MNCs) were obtained from C57BL/6 (WT) mice with or without 2 Gy irradiation, and the phagocytic activity against Escherichia coli (E. coli) as well as TNF-α production were compared between the two macrophage populations. To assess LXR functions, phagocytosis, TNF-α production, and endocytosis of acetylated low-density lipoprotein (LDL) were compared after synthetic LXR ligand stimulation. Furthermore, LXRα/β knockout (KO) mice and LXRα KO mice were compared with WT mice. Irradiation decreased intracellular TNF-α production by recMφs but did not affect the phagocytic activity of resKCs. In vitro LXR stimulation enhanced E. coli phagocytosis by resKCs but decreased E. coli-stimulated TNF-α production by recMφs. Phagocytic activity and acetylated LDL endocytosis were decreased in both LXRα/β KO mice and LXRα KO mice, with serum TNF-α levels after E. coli injection in the former being higher than those in WT mice. In conclusion, resKCs and recMφs exhibited different functional features in response to radiation and LXR stimulation, highlighting their distinct roles liver immunity and lipid metabolism., Competing Interests: The authors have declared that no competing interests exist.

We have studied the biological effects of the internal exposure to radioactive manganese-56 dioxide ( 56 MnO 2 ), the major radioisotope dust found in soil after atomic bomb explosions. Our previous study of blood chemistry indicated a possible adverse effect of 56 MnO 2 on the liver. In the present study, we further examined the effects on the liver by determining changes in hepatic gene expressions. Male Wistar rats were exposed to 56 MnO 2 particles (three groups with the whole-body doses of 41, 90, and 100 mGy), stable MnO 2 particles, or external 60 Co γ-rays (2 Gy), and were examined together with the non-treated control group on postexposure day 3 and day 61. No histopathological changes were observed in the liver. The mRNA expression of a p53-related gene, the cyclin-dependent kinase inhibitor 1A, increased in 56 MnO 2 as well as in γ-ray irradiated groups on postexposure day 3 and day 61. The expression of a stress-responsive gene, nuclear factor κB, was also increased by 56 MnO 2 and γ-rays on postexposure day 3. However, the expression of cytokine genes (interleukin-6 or chemokine ligand 2) or fibrosis-related TGF-β/Smad genes ( Tgfb1 , Smad3 , or Smad4 ) was not altered by the exposure. Our data demonstrated that the internal exposure to 56 MnO 2 particles at less than 0.1 Gy significantly affected the short-term gene expressions in the liver in a similar manner with 2 Gy of external γ-irradiation. These changes may be adaptive responses because no changes occurred in cytokine or TGF-β/Smad gene expressions.

Apelin-13 and APJ are implicated in different key physiological processes. This work aims at exploring the radioprotective effect of fucoxanthin (FX) on γ-radiation (RAD)-induced changes in the apelin-13/APJ pathway, which causes damage in the liver, kidney, lung and spleen of mice. Mice were administered FX (10 mg kg-1 day-1, i.p) and exposed to γ-radiation (2.5 Gy week-1) for four consecutive weeks. The treatment of irradiated mice by FX resulted in a significant amendment in protein expression of the apelin-13/APJ/NF-κB signalling pathway concurrently with reduced hypoxia (hypoxia-inducible factor-1α), suppressed oxidative stress marker (malondialdehyde), enhanced antioxidant defence mechanisms (reduced glutathione and glutathione peroxidase), a modulated inflammatory response [interleukin-6 (IL-6), monocyte chemoattractant protein-1, IL-10 and α-7-nicotinic acetylcholine receptor) and ameliorated angiogenic regulators [matrix metalloproteinase (MMP-2), MMP-9 and tissue inhibitor of metalloproteinase-1), as well as the tissue damage indicator (lactate dehydrogenase) in organ tissues. In addition, there were significant improvement in serum inflammatory markers tumour necrosis factor-α, IL-10, IL-1β and C-reactive protein compared with irradiated mice. The histopathological investigation of the FX + RAD organ tissues support the biochemical findings where the improvements in the tissues' architecture were obvious when compared with those of RAD. FX was thus shown to have a noticeable radioprotective action mediated through its regulatory effect on the apelin-13/APJ/NF-κB signalling pathway attributed to its antioxidant and anti-inflammatory activity that was reflected in different physiological processes. It could be recommended to use FX in cases of radiation exposure to protect normal tissues., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: In patients with right-sided breast cancer (BC) the liver might be partially irradiated during adjuvant radiotherapy (RT). Thus, we performed a prospective observational study to evaluate the dose delivered to the liver, and its potential biological impact., Patients and Methods: We enrolled 34 patients with right-sided BC treated with adjuvant RT. The RT schedules were either the Canadian (42.5Gy in 16 fx) or standard fractionated (50Gy in 25 fx) regimen respectively with 9 (26.5%) and 25 (73.5%) patients each, ± a boost of 10-16Gy. Each patient had a complete blood count and liver enzymes analysis, before starting and during the last week of treatment., Results: A significant decrease in white blood cells and thrombocytes counts was observed during RT. We observed a significant correlation between certain hepatic parameters and the volume of the irradiated liver and/or the mean liver dose. A significant correlation between the volume of the right lung and the liver mean dose was found (P=0.008). In the bivariate analysis, a significant correlation between fatigue and the white blood cell count's evolution was observed (P<0.025)., Conclusion: With the standard RT technique, incidental irradiation of the liver was documented in a large number of patients, and some significant hepatic parameters alterations were observed, without an apparent clinical impact, but this study cannot exclude them. The liver mean dose was correlated with the right lung volume suggesting that deep inspiration breath hold (DIBH) techniques may represent a way to decrease the liver dose. These findings need to be evaluated in further larger studies., (Copyright © 2021 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Background: Due to the importance of choosing the applicable dosimetry method in radionuclide therapy, the present study was conducted to investigate the efficiency of the implementation of Dose Point Kernel (DPK) for dose optimization of 177 Lu/ 90 Y Cocktail Radionuclides in internal Dosimetry., Methods: In this study, simulations and calculations of DPK were performed using the GATE/GEANT4 Monte Carlo code. For specific liver dosimetry, the NCAT phantom and convolution algorithm-based Fast Fourier Transform method was used by MATLAB software., Results: The self-dose of 177 Lu and 90 Y radionuclides in the liver of NCAT phantom were 1.1708E-13, and 4.8420E-11 (Gy/Bq), respectively, and the cross-dose of 177 Lu and 90 Y radionuclides out of the liver of NCAT phantom were 2.03615E-16, and 0.8422E-13 (Gy/Bq) respectively. Overall results showed that with an increase the value of 90 Y with quarter steps in a cocktail, the amount of the self-dose increase 1.5, 6, and 29 times respectively, and with an increase the value of 177 Lu in quarter step in a cocktail, the amount of the cross dose decrease 3, 15 and 68 percent respectively., Conclusion: Generally, the present results indicate that the calculated DPK functions of 177 Lu and 90 Y cocktails can play an important role in choosing the best combination of radionuclide to optimize treatment planning in cocktail radionuclide therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Abstract: In the nuclear industry, wound contamination with americium is expected to increase with decommissioning and waste management. Treatment of workers with diethylenetriaminepentaacetic acid (DTPA) requires optimization to reduce internal contamination and radiation exposure. This work aimed at evaluating and comparing different DTPA protocol efficacies after wound contamination of rats with americium. Wound contamination was simulated in rats by depositing americium nitrate in an incision in the hind limb. Different routes, times, and frequencies of DTPA administration were evaluated. Individual daily urinary americium excretion and tissue retention were analyzed using the statistical tool STATBIODIS. Urinary profiles, urinary enhancement factors, and inhibition percentages of tissue retention were calculated. A single DTPA administration the day of contamination induced a rapid increase in americium urinary excretion that decreased exponentially over 7 d, indicating that the first DTPA administration should be delivered as early as possible. DTPA treatment limited americium uptake in systemic tissues irrespective of the protocol. Liver and skeleton burdens were markedly reduced, which would drive reduction of radiation dose. Local or intravenous injections were equally effective. Inherent difficulties in wound site activity measurements did not allow identification of a significant decorporating effect at the wound site. Repeated intravenous injections of DTPA also increased americium urinary excretion, which supports the use of multiple DTPA administrations shortly after wound contamination. Results from these statistical analyses will contribute to a better understanding of americium behavior in the presence or absence of DTPA and may aid optimization of treatment for workers., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Health Physics Society.)

Background: In unresectable hepatocellular carcinoma several local ablative treatments are available. Among others, radiation based treatments such as stereotactic body radiotherapy (SBRT) and high-dose rate interstitial brachytherapy (HDR BT) have shown good local control rates., Methods: We conducted a dose comparison between actually performed HDR BT versus virtually planned SBRT to evaluate the respective clinically relevant radiation exposure to uninvolved liver tissue. Moreover, dose coverage and conformity indices were assessed., Results: Overall, 46 treatment sessions (71 lesions, 38 patients) were evaluated. HDR BT was applied in a single fraction with a dose prescription of 1 × 15 Gy. D98 was 17.9 ± 1.3 Gy, D50 was 41.8 ± 8.1 Gy. The SBRT was planned with a prescribed dose of 3 × 12.5 Gy (65%-Isodose), D98 was 50.7 ± 3.1 Gy, D2 was 57.0 ± 2.3 Gy, and D50 was 55.2 ± 2.3 Gy. Regarding liver exposure Vliver10Gy BT was compared to Vliver15.9Gy SBRT , Vliver16.2Gy SBRT (EQD2 equivalent doses), and Vliver20Gy SBRT (clinically relevant dose), all results showed significant differences (p < .001). In a case by case analysis Vliver10Gy BT was smaller than Vliver20Gy SBRT in 38/46 cases (83%). Dmean of the liver was significantly smaller in BT compared to SBRT (p < .001). GTV volume was correlated to the liver exposure and showed an advantage of HDR BT over SBRT in comparison of clinically relevant doses, and for EQD2 equivalent doses. The advantage was more pronounced for greater liver lesions The Conformity Index (CI) was significantly better for BT, while Healthy Tissue Conformity Index (HTCI) and Conformation Number (CN) showed an advantage for SBRT (p < .001)., Conclusion: HDR BT can be advantageous in respect of sparing of normal liver tissue as compared to SBRT, while providing excellent target conformity.

Stereotactic body radiation therapy (SBRT) has emerged as an effective, noninvasive treatment option for primary liver cancer and metastatic disease occurring in the liver. Although SBRT can be highly effective for establishing local control in hepatic malignancies, a tradeoff exists between tumor control and normal tissue complications. The objective of the present study was to review the normal tissue dose-volume effects for SBRT-induced liver and gastrointestinal toxicities and derive normal tissue complication probability models., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: We report long-term outcomes from our phase 1 dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR pooled with our subsequent single institutional experience with patients treated postprotocol at the highest dose level (40 Gy) established from the phase 1 study., Methods and Materials: Patients with liver metastases from solid tumors located outside of the central liver zone were treated with single-fraction SABR on a phase 1 dose escalation trial. At least 700 cc of normal liver had to receive <9.1 Gy. Seven patients with 10 liver metastases received the initial prescription dose of 35 Gy, and dose was then escalated to 40 Gy for 7 more patients with 7 liver metastases. An additional 19 postprotocol patients with 22 liver metastases were treated to 40 Gy in a single fraction. Patients were followed for toxicity and underwent serial imaging to assess local control., Results: Median imaging follow-up for the combined cohort (n = 33, 39 lesions) was 25.9 months; 38.9 months for protocol patients and 20.2 months for postprotocol patients. Median lesion size was 2.0 cm (range, 0.5-5.0 cm). There were no dose-limiting toxicities observed for protocol patients, and only 3 grade 2 toxicities were observed in the entire cohort, with no grade ≥3 toxicities attributable to treatment. Four-year actuarial local control of irradiated lesions in the entire cohort was 96.6%, 100% in the protocol group and 92.9% in the subsequent patients. Two-year overall survival for all treated patients was 82.0%., Conclusions: For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy was safe and well-tolerated, and shows excellent local control with long-term follow-up; results in subsequent patients treated with single-fraction SABR doses of 40 Gy confirmed our earlier results., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Sono-photodynamic therapy is a promising anticancer technique based on the combination of sonodynamic and photodynamic therapy to improve the cancer treatment effectiveness. This study was aimed at analyzing the effects of the sono-photodynamic (SPD) activity on protoporphyrin IX (PpIX) solution and PpIX-loaded rat liver. In vitro, PpIX 5 μM solutions were irradiated with light (635 nm, 30-50 mW/cm 2 ), ultrasound (1 MHz, 1-2 W/cm 2 ) and both. The PpIX absorption spectra recorded over exposure time revealed that the PpIX decay rate induced by SPD activity (combined irradiation) was approximately the sum of those induced by photodynamic and sonodynamic activity. In vivo, rats were intraperitoneally injected with 5-aminolevulinic acid at the dose of 500 mg/kg weight. After 3 h of injection, the PpIX-loaded livers were irradiated with light (635 nm, 180 ± 9 J/cm 2 ), ultrasound (1.0 MHz, 770 ± 40 J/cm 2 ) and both using a single probe capable of illuminating and sonicating the liver simultaneously. After 30 h, the liver damage induced by each protocol was analyzed histologically. It was found that a greater necrosis depth was induced by the SPD activity. These results suggest that the SPD activity could improve the PpIX decay rate and have greater scope than photodynamic or sonodynamic activity. Further studies should be performed to gain a better understanding of this protocol., Competing Interests: Conflict of interest disclosure The authors declare that they have no conflict of interest., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to compare three different heat transfer models for radiofrequency ablation of in vivo liver tissue using a cooled electrode and three different voltage levels. The comparison was between the simplest but less realistic Pennes' equation and two porous media-based models, i.e. the Local Thermal Non-Equilibrium (LTNE) equations and Local Thermal Equilibrium (LTE) equation, both modified to take into account two-phase water vaporization (tissue and blood). Different blood volume fractions in liver were considered and the blood velocity was modeled to simulate a vascular network. Governing equations with the appropriate boundary conditions were solved with Comsol Multiphysics finite-element code. The results in terms of coagulation transverse diameters and temperature distributions at the end of the application showed significant differences, especially between Pennes and the modified LTNE and LTE models. The new modified porous media-based models covered the ranges found in the few in vivo experimental studies in the literature and they were closer to the published results with similar in vivo protocol. The outcomes highlight the importance of considering the three models in the future in order to improve thermal ablation protocols and devices and adapt the model to different organs and patient profiles.

Obesity, a growing health concern, is associated with an increased risk of morbidity and mortality. Chronic low-grade inflammation is implicated in obesity-driven metabolic complications. Peripheral focused ultrasound stimulation (pFUS) is an emerging non-invasive technology that modulates inflammation. Here, we reasoned that focused ultrasound stimulation of the liver may alleviate obesity-related inflammation and other comorbidities. After 8 weeks on a high-fat high-carbohydrate "Western" diet, C57BL/6J mice were subjected to either sham stimulation or focused ultrasound stimulation at the porta hepatis. Daily liver-focused ultrasound stimulation for 8 weeks significantly decreased body weight, circulating lipids and mitigated dysregulation of adipokines. In addition, liver-focused ultrasound stimulation significantly reduced hepatic cytokine levels and leukocyte infiltration. Our findings demonstrate the efficacy of hepatic focused ultrasound for alleviating obesity and obesity-associated complications in mice. These findings suggest a previously unrecognized potential of hepatic focused ultrasound as a possible novel noninvasive approach in the context of obesity.

Purpose: The objective of this study was to determine whether pretreatment neutrophil-to-lymphocyte ratio (NLR) could predict survival outcomes and liver toxicity in hepatocellular carcinoma (HCC) patients treated with stereotactic ablative radiation therapy (SABR)., Methods and Materials: In this retrospective study we collected pretreatment NLR of HCC patients treated with SABR between December 2007 and August 2018 and determined its association with overall survival (OS), progression-free survival, and radiation-related liver toxicity defined as an increase in the Child-Turcotte-Pugh score by ≥2 within 3 months after SABR in the absence of disease progression., Results: A total of 153 patients with a median follow-up of 13.3 months were included. Receiver operating characteristic curve analysis found that an NLR ≥2.4 was optimum (area under the curve, 0.762; 95% confidence interval [CI], 0.682-0.841, P < .001) for predicting poor 1-year OS (38.2% vs 83.6%, P < .001). Multivariable analysis demonstrated that NLR was significantly associated with OS, both as a continuous (P = .006) and a binary variable (NLR set at 2.4; P = .003). Multiple tumors (P = .003), macrovascular invasion (P = .024), extrahepatic spread (P = .002), and albumin-bilirubin score (P = .020) were also significant predictors of OS. Elevated NLR independently prognosticated poor progression-free survival (P = .016). Liver toxicity was seen in 22 evaluable patients (15.4%). Receiver operating characteristic curve analysis found NLR ≥4.0 was optimum at predicting liver toxicity (31.4% vs 10.2%, P = .005). A higher NLR (P = .049) and albumin-bilirubin score (P = .002) were independent risk factors for liver toxicity., Conclusions: NLR is an objective and ubiquitous inflammatory marker that can predict OS and liver toxicity in HCC patients undergoing SABR. NLR could be a useful biomarker for patient risk stratification and therapeutic decision-making., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Evidence for the efficacy of radiation therapy for primary liver cancer is growing. In this context, proton therapy (PT) can potentially improve the therapeutic ratio, as demonstrated by recent clinical studies. Here we report the first European clinical experience on the use of PT for primary liver cancer., Methods: All patients treated for primary liver cancer in our center entered the analysis. Patients were simulated during deep expiration breath-hold. A 15-fraction treatment schedule was adopted using active scanning PT. Clinical outcome and toxicity were retrospectively analyzed., Results: Between January 2018 and December 2019, 18 patients were treated. Fourteen patients had hepatocellular carcinoma (HCC), three patients had intrahepatic cholangiocarcinoma (ICC), and one patient had synchronous ICC-HCC. The Child-Pugh score was A5 in the majority of patients with HCC (71.4%). Median prescription dose was 58.05 Gy (range, 50.31-67.5). Median follow-up was 10 months (range, 1-19). The majority of deaths occurred from liver tumor progression. One-year overall survival (OS) was 63%. A significant correlation between worse OS and patient performance status, vascular invasion, and tumor stage was recorded. One-year local control was 90%. Toxicity was low, with a decrease in Child-Pugh score ⩾2 points detected in one patient. No cases of classic radiation-induced liver disease occurred., Conclusions: Our initial results of active scanning PT for primary liver cancer demonstrated the feasibility, safety, and effectiveness of this advanced technique in this setting. The potential of the combination of PT with other locoregional therapies is under evaluation.

The biological effects of extremely low-frequency electromagnetic fields (ELF-EMF) exposure are not fully clarified. We conducted this investigation to explore the effects of ELF-EMF on hematologic and biochemical indexes in adult rats. Thirty adult male Sprague-Dawley rats were exposed to ELF-EMF at 1 mT for 24 weeks, while another 30 SD rats were sham exposed. During the exposure, peripheral blood was collected every 4 weeks to analyze the hematologic parameters and biochemical indexes. The morphology of liver and kidney was detected by hematoxylin-eosin staining at the end of the experiment. Exposed to ELF-EMF at 1 mT did not exert any statistic difference on hematologic parameters including total white blood cell count, neutrophil ratio, lymphocyte ratio, red blood cells, hemoglobin concentration and platelets count, compared to the control group. Similarly, biochemical indexes, such as glucose, lipid profile, liver function and renal function, were not affected by ELF-EMF exposure. In addition, no morphological change was observed in the liver and kidney from the exposure group. The exposure to ELF-EMF at the intensity of 1 mT for 24 weeks did not affect hematologic and biochemical indexes in adult rats.

Radiotherapy (RT) represents one of the major treatment methods for cancers. However, many studies have observed that in descendant surviving tumor cells, sublethal irradiation can promote metastatic ability, which is closely related to the tumor microenvironment. We therefore investigated the functions and mechanisms of sublethal irradiated liver nonparenchymal cells (NPCs) in hepatocellular carcinoma (HCC). In this study, primary rat NPCs and McA-RH7777 hepatoma cells were irradiated with 6 Gy X-ray. Conditioned media (CM) from nonirradiated (SnonR), irradiated (SR), or irradiated plus radiosensitizer celecoxib-treated (S[R + D]) NPCs were collected and added to sublethal irradiated McA-RH7777 cells. We showed that CM from sublethal irradiated NPCs significantly promoted the migration and invasion ability of sublethal irradiated McA-RH7777 cells, which was reversed by celecoxib. The differentially expressed genes in differently treated McA-RH7777 cells were enriched mostly in the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. SR increased the migration and invasion ability of HCC cells by inhibiting AMPK/mTOR signaling, which was enhanced by the AMPK inhibitor compound C and blocked by the AMPK activator GSK-621. Analyses of HCC tissues after neoadjuvant radiotherapy confirmed the effects of radiation on the AMPK/mTOR pathway. Cytokine antibody arrays and further functional investigations showed that matrix metalloproteinase-8 (MMP-8) partly mediates the promotion effects of SR on the migration and invasion ability of HCC cells by regulating AMPK/mTOR signaling. In summary, our data indicate that MMP-8 secreted by irradiated NPCs enhanced the migration and invasion of HCC by regulating AMPK/mTOR signaling, revealing a novel mechanism mediating sublethal irradiation-induced HCC metastasis at the level of the tumor microenvironment., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Ultraviolet (UV) radiation-induced chronic inflammation contributes to all stages of skin tumor development. In addition, gender plays an important role in inflammatory diseases or cancer. In this study, histopathology changes, hematology, oxidative stress and inflammatory response were used to evaluate sex differences in UV-induced chronic inflammation-associated cancer development. The results showed that the male and female mice had photoaging damage at the 9th week. However, skin tumors only appeared in male mice at 31st week. Furthermore, UV increased ROS production, p65, p-p65, IL-6 and TNF-α protein expressions in skin, and these factors elevated more in male mouse model. Hematology results showed that the parameters of blood systemic inflammation were changed in different degrees in model groups, while the pathological results showed inflammatory cell infiltration in the internal organs of both model groups in varying degrees. These results indicate that there are gender differences in UV-induced skin inflammation, carcinogenesis and systemic damage. Moreover, male mice are more sensitive to UV irradiation, which may be responsible to greater oxidative stress and inflammatory damage., (Copyright © 2020 Elsevier B.V. All rights reserved.)