Prognostic analysis of radiation-induced liver damage following carbon-ion radiotherapy for hepatocellular carcinoma.

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 (VS30 < 739 cm3) (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 VS30 < 739 cm3 or ≥ 739 cm3 were 10.3% or 51.8% and 39.6% or 9.2%, respectively. CONCLUSION: In conclusion, the pretreatment Child-Pugh score and VS30 of the liver are significant risk factors for RILD following CIRT for HCC.

Markerless liver online adaptive stereotactic radiotherapy: feasibility analysisCervantes.

Objective. Radio-opaque markers are recommended for image-guided radiotherapy in liver stereotactic ablative radiotherapy (SABR), but their implantation is invasive. We evaluate in thisin-silicostudy 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 GTVPropagatedand the GTVConventional, the vector lengths between their centres of mass (lCoM), 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 (PlanNon-adaptive) and daily-adapted plans (PlanAdaptive) were compared for each treatment fraction.Main results.The image-guided deformable registration with rigid GTV propagation was the best propagation strategy regarding tolCoM(mean: 4.3 +/- 2.1 mm), HD95 (mean 4.8 +/- 3.2 mm) and volume preservation between GTVPropagatedand GTVConventional. This resulted in a planning target volume (PTV) margin increase (+69.1% in volume on average). Online adaptation (PlanAdaptive) 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 (PlanNon-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.

The role of curcumin during pregnancy on the exposed fetuses' tissues of Wistar rats to electromagnetic field.

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.

Electromagnetic fields (EMFs) are able to penetrate and be absorbed by the body. The researchers showed that these radiations might be harmful and lead to cancers, cardiovascular diseases, mental disorders, and fetal abnormalities. Curcumin as an active component in turmeric has anti-inflammatory, antioxidant and anti-hyperlipidemia properties. It can protect the body against diseases such as arthritis, anxiety, and metabolic syndrome. This study examined the effects of curcumin as the protector against the harmful effects of EMF (50Hz) during pregnancy period. So the pregnant rats were divided into six groups. During pregnancy, a group was exposed to EMF for 30 min/day, the second group was injected a dose of curcumin 50mg/kg/daily, the third group was injected curcumin and exposed to EMF daily. The fourth group was injected a curcumin solvent dose, the sham group was placed through the field generator 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 liver, kidney, and hippocampal tissues were investigated. EMF exposure led to an outstanding increase in necrotic areas in hippocampal tissue, a notable increase in the amount of hyperemia and necrosis in kidneys, and degeneration in liver tissue(p=0.007) in the EMF group compared with the third group that was exposed to EMF and received curcumin. A single dose of curcumin daily during pregnancy can protect these tissues from injuries caused by EMF(50Hz) exposure in rat fetuses.

Partial liver irradiation in rats induces the hypertrophy of nonirradiated liver lobes through hepatocyte proliferation†.

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.

Effects of low-dose/high-dose-rate X-irradiation on oxidative stress in organs following forced swim test and its combined effects on alcohol-induced liver damage in mice.

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 protective effect of N-acetyl cysteine against selenium toxicity and gamma irradiation in rats.

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.

Effects of Radiation Dose on Liver After Free-breathing Volumetric Modulated Arc Therapy for Breast Cancer.

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.

Correlation of chemokines and growth factors with radiation-induced liver injury after interstitial high dose rate (HDR) brachytherapy of liver metastases.

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.

Prolonged Inhalation Exposure to Coal Dust on Irradiated Rats and Consequences.

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.

Hepatotoxicity and renal toxicity induced by radiation and the protective effect of quercetin in male albino rats.

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.

A new animal model of atrophy-hypertrophy complex and liver damage following Yttrium-90 lobar selective internal radiation therapy in rabbits.

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 90Y resin microspheres in rabbits is a reliable animal model to analyse the atrophy-hypertrophy complex and liver damage without toxicity.

Leveraging Blood-Based Diagnostics to Predict Tumor Biology and Extend the Application and Personalization of Radiotherapy in Liver Cancers.

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.

Occupational dose and associated factors during transarterial chemoembolization of hepatocellular carcinoma using real-time dosimetry: A simple way to reduce radiation exposure.

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 ±â€Š55.14 Gycm2 and 12.03 ±â€Š5.95 minutes, respectively. The mean radiation exposure doses were 24.8 ±â€Š19.5, 2.0 ±â€Š2.2, and 1.65 ±â€Š2.0 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.

Hepatic tumours and radiotherapy.

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.

Effect of stereotactic body radiotherapy on regional metabolic liver function investigated in patients by dynamic [18F]FDGal PET/CT.

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-[18F]fluoro-D-galactose ([18F]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 [18F]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 TD50 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: [18F]FDGal PET/CT makes it possible to determine a dose-response relationship between radiation dose and metabolic liver function, here with a TD50 of 18 Gy (95% CI 12-26 Gy). Moreover, the method makes it possible to estimate metabolic recovery in liver tissue.

Response Assessment and Prediction of Progression-Free Survival by 68Ga-PSMA-11 PET/CT Based on Tumor-to-Liver Ratio (TLR) in Patients with mCRPC Undergoing 177Lu-PSMA-617 Radioligand Therapy.

At present, little is known about the molecular imaging-based response assessment of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with 177Lutetium (177Lu-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. 68Ga-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 SUVpeak 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 (PRPSA and PRTLR) 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 SUVpeak 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 68Ga-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.

Roles of Simvastatin and Sildenafil in Modulation of Cranial Irradiation-Induced Bystander Multiple Organs Injury in Rats.

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 (Co60) 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.

Hepatic Gene Expression Changes in Rats Internally Exposed to Radioactive 56MnO2 Particles at Low Doses.

We have studied the biological effects of the internal exposure to radioactive manganese-56 dioxide (56MnO2), the major radioisotope dust found in soil after atomic bomb explosions. Our previous study of blood chemistry indicated a possible adverse effect of 56MnO2 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 56MnO2 particles (three groups with the whole-body doses of 41, 90, and 100 mGy), stable MnO2 particles, or external 60Co 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 56MnO2 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 56MnO2 and γ-rays on postexposure day 3. However, the expression of cytokine genes (interleukin-6 or chemokine ligand 2) or fibrosis-related TGF-ß/Smad genes (Tgfb1, Smad3, or Smad4) was not altered by the exposure. Our data demonstrated that the internal exposure to 56MnO2 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-ß/Smad gene expressions.

Contrasting functional responses of resident Kupffer cells and recruited liver macrophages to irradiation and liver X receptor stimulation.

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/ß 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/ß 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.

Impact of adjuvant radiotherapy on biological and clinical parameters in right-sided breast cancer.

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.