Indications of IMRT, PRT and CIRT for HCC from comparisons of dosimetry and normal tissue complication possibility.

PURPOSE: To identify the indications for hepatocellular carcinoma (HCC) irradiated by intensity-modulated photon radiotherapy (IMRT), proton radiotherapy (PRT) or carbon-ion radiotherapy (CIRT) by comparing of dosimetric parameters and incidences of classic radiation-induced liver disease (RILD). METHODS: In all, 40 HCCs were divided into group A (tumors located > 1 cm away from gastrointestinal [GI] tract), and group B (tumors located < 1 cm away from GI tract). The prescribed curative doses were 60 Gy (relative biological effectiveness [RBE]) in 10 fractions for group A, and 67.5 Gy (RBE) in 15 fractions for group B. IMRT, PRT and CIRT plans were separately generated to reach the curative doses and coverage. Dosimetric parameters evaluated were mean dose to normal liver (MDTNL) and the volume of normal liver receiving more than 1 Gy (RBE) (V1). Lyman-Kutcher-Burman model was used to determine the incidences of classic RILD, and Power model of non-linear regression, to estimate the tumor volume that could be irradiated with the curative doses within dose constraint of MDTNL. RESULTS: With comparable target doses, the MDTNL (Gy [RBE]) were 18.8 ± 3.7, 13.5 ± 3.1 and 12.8 ± 2.7 in group A and 24.9 ± 7.1, 18.2 ± 3.7 and 17.5 ± 3.7 in group B, respectively, for IMRT, PRT and CIRT. The classic RILD incidences (%) were 22.3 ± 30.0 in IMRT, 2.3 ± 4.9 in PRT and 1.2 ± 2.4 in CIRT. V1 (%) were 89.9 ± 8.8, 43.0 ± 10.2 and 45.9 ± 8.8, respectively, for IMRT, PRT and CIRT. CONCLUSIONS: PRT and CIRT could spare the liver more than IMRT. IMRT could deliver the curative doses to HCC up to a diameter of 7.9 cm; PRT, up to 13.2 cm; and CIRT, up to 14.8 cm.

Palliative radiotherapy for multiple liver metastases: a retrospective analysis of 73 cases.

BACKGROUND: Whole-liver radiotherapy for diffuse liver metastases can improve symptoms and abnormal liver-related blood data. However, whole-liver radiotherapy is uncommonly used in clinical practice in Japan. Therefore, we aimed to clarify palliative radiotherapy outcomes in Japanese patients with liver metastases. METHODS: We retrospectively reviewed databases in our institution to identify patients treated with radiotherapy (8 Gy in a single fraction) for multiple liver metastases between December 2014 and April 2021. The endpoints included pain response, liver-related blood data and adverse effects. We investigated aspartate transaminase, alanine transaminase, lactate dehydrogenase, alkaline phosphatase, γ-glutamyl transpeptidase and albumin. The mean values at whole-liver radiotherapy and after 2-4 weeks were compared using the Wilcoxon rank-sum test. RESULTS: A total of 73 cases in 71 patients were included. The median clinical target volume was 2118 ml (range, 133-7867 ml). Fifty-seven patients (78%) had finished aggressive treatment at the time of radiotherapy. The median follow-up period was 6 weeks. The pain response rate was 64% (18/28). The mean values of five parameters significantly improved 2-4 weeks after radiotherapy compared to those at baseline: aspartate transaminase (118 vs. 83 U/l P < 0.01); alanine transaminase (84 vs. 61 U/l P < 0.01); lactate dehydrogenase (1351 vs. 1007 U/l P = 0.027); alkaline phosphatase (1624 vs. 1216 U/l P < 0.01) and γ-glutamyl transpeptidase (663 vs. 450 U/l P = 0.037). No patients experienced radiation-induced liver disease. CONCLUSIONS: Palliative radiotherapy is efficient and safe in Japanese patients with liver metastases. These findings will help encourage whole-liver radiotherapy use in Japan.

[Analysis of factors influencing radiation-induced liver injury caused by stereotactic radiotherapy in patients with primary hepatocellular carcinoma].

Objective: To analyze the factors influencing radiation-induced liver injury after receiving Cyberknife stereotactic radiotherapy in patients with primary hepatocellular carcinoma. Methods: 278 cases with primary hepatocellular carcinoma from July 2016 to April 2019 were prospectively enrolled. Stereotactic radiosurgery with a prescription dose of 48-55gy/5-8 times were given. Liver function, coagulation function, Child-Pugh score, and liver imaging changes were dynamically observed before and after treatment to evaluate the occurrence of radiation-induced liver injury. Logistic regression model was used to analyze the factors influencing radiation-induced liver injury. Results: Among 278 cases, 3 cases of tumor progression were excluded, and a total of 275 cases were included for analysis. The overall survival rate after 8 months of treatment was 100%. Among them, 22 cases were diagnosed as radiation-induced liver injury, with an incidence rate of 8%, and all cases were recovered after symptomatic treatment. Multivariate analysis result suggested that the peripheral white blood cell count was factors influencing the occurrence of radiation-induced liver injury. Conclusion: Cyberknife stereotactic radiotherapy has a low incidence of radiation-induced liver injury in patients with liver cancer, and it is a relatively safe treatment method. Patients with low peripheral white blood cell counts before treatment should be closely monitored for early detection and treatment.

Circular RNA RSF1 promotes inflammatory and fibrotic phenotypes of irradiated hepatic stellate cell by modulating miR-146a-5p.

The role of circular RNA (circRNA) in radiation-induced liver disease (RILD) remains largely unknown. In this study, Ras-related C3 botulinum toxin substrate 1 (RAC1) was elevated in irradiated human hepatic stellate cell (HSC) line LX2, the important effector cell mediating RILD. Overexpression of RAC1 promotes cell proliferation, proinflammatory cytokines production, and α-smooth muscle actin expression, which were blocked by microRNA (miR)-146a-5p mimics. CircRNA RSF1 (circRSF1) was upregulated in irradiated LX2 cells and predicted to harbor binding site for miR-146a-5p. Biotinylated-RNA pull down and dual-luciferase reporter detection confirmed the direct interaction of circRSF1 and miR-146a-5p. Enforced expression of circRSF1 increased RAC1 expression by acting as miR-146a-5p sponge to inhibit miR-146a-5p activity, and thus enhanced the cell viability, and promoted inflammatory and fibrotic phenotype of irradiated LX2 cells. These findings indicate a functional regulatory axis composing of circRSF1, miR-146a-5p, and RAC1 in irradiated HSC, which may provide attractive therapeutic targets for RILD.

Potential of Gd-EOB-DTPA as an imaging biomarker for liver injury estimation after radiation therapy.

BACKGROUND: Hepatic radiation injury severely restricts irradiation treatment for liver carcinoma. The purpose of this study was to investigate the clinical application of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI (EOB-MRI) in the assessment of liver function after external radiation therapy and to determine the relationship between focal liver reaction (FLR) and liver function. METHODS: A total of 47 patients with liver malignancies who underwent external beam radiation therapy were enrolled. EOB-MRI was performed on each patient at approximately one month post-radiotherapy. The hepatobiliary (HPB) phase images from EOB-MRI were fused with the planning CT images, and the isodose lines from the patients' treatment plans were overlaid onto the fused images. The correlation of the EOB-MR image intensity distribution with the isodose lines was studied. We also compared liver function in patients between pre-treatment and post-treatment. RESULTS: Decreased uptake of Gd-EOB-DTPA, which was manifested by well-demarcated focal hypointensity of the liver parenchyma or FLR to high-dose radiation, was observed in the irradiated areas of 38 patients. The radiotherapy isodose line of decreased uptake area of Gd-EOB-DTPA was 30-46 Gy. The median corresponding dose curve of FLR was 34.4 Gy. Nine patients showed the absence of decreased uptake area of Gd-EOB-DTPA in the irradiated areas. Compared to the 38 patients with the presence of decreased uptake area of Gd-EOB-DTPA, 9 patients with the absence of decreased uptake area of Gd-EOB-DTPA showed significant higher levels of total bile acid, total bilirubin, direct bilirubin and alpha-fetoprotein (P < 0.05). There were no significant differences in alanine transaminase, aspartate aminotransferase, gamma-glutamyl transpeptidase or albumin levels between the two groups (P > 0.05). CONCLUSIONS: Visible uptake of Gd-EOB-DTPA by the liver parenchyma was significantly associated with liver function parameters. EOB-MRI can be a valuable imaging biomarker for the assessment of liver parenchyma function outside of radiation area.

Protective Effect of Antrodia cinnamomea Extract against Irradiation-Induced Acute Hepatitis.

Radiotherapy for treatment of hepatocellular carcinoma causes severe side effects, including acute hepatitis and chronic fibrosis. Complementary and alternative medicine (CAM) has emerged as an important part of integrative medicine in the management of diseases. Antrodia cinnamomea (AC), a valuable medicinal fungus originally found only in Taiwan, has been shown to possess anti-oxidation, vaso-relaxtation, anti-inflammation, anti-hepatitis, and anti-cancer effects. In this paper we evaluate the protective effects of ethanol extract of Antrodia cinnamomea (ACE) against radiotoxicity both in normal liver cell line CL48 and in tumor-bearing mice. In CL48, ACE protects cells by eliminating irradiation-induced reactive oxygen species (ROS) through the induction of Nrf2 and the downstream redox system enzymes. The protective effect of ACE was also demonstrated in tumor-bearing mice by alleviating irradiation-induced acute hepatitis. ACE could also protect mice from CCl4-induced hepatitis. Since both radiation and CCl4 cause free radicals, these results indicate that ACE likely contains active components that protect normal liver cells from free radical attack and can potentially benefit hepatocellular carcinoma (HCC) patients during radiotherapy.

Radiation-induced Liver Injury after 3D-conformal Radiotherapy for Hepatocellular Carcinoma: Quantitative Assessment Using Gd-EOB-DTPA-enhanced MRI.

Focal liver reaction (FLR) appears in the hepatobiliary-phase images of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) following radiotherapy (RT). We investigated the threshold dose (TD) for FLR development in 13 patients with hepatocellular carcinoma (HCC) who underwent three-dimensional conformal radiotherapy (3D-CRT) with 45 Gy in 15 fractions. FLR volumes (FLRVs) were calculated based on planning CT images by referring to fused hepatobiliary- phase images. We also calculated the TD and the irradiated volumes (IVs) of the liver parenchyma at a given dose of every 5 Gy (IVdose) based on a dose-volume histogram (DVH). The median TD was 35.2 Gy. The median IV20, IV25, IV30, IV35, IV40, and IV45 values were 371.1, 274.8, 233.4, 188.6, 145.8, and 31.0 ml, respectively. The median FLRV was 144.9 ml. There was a significant difference between the FLRV and IV20, IV25, and IV45 (p<0.05), but no significant differences between the FLRV and IV30, IV35, or IV40. These results suggest that the threshold dose of the FLR is approx. 35 Gy in HCC patients who undergo 3D-CRT in 15 fractions. The percentage of the whole liver volume receiving a dose of more than 30-40 Gy (V30-40) is a potential candidate optimal DVH parameter for this fractionation schedule.

Investigation of dosimetric variations of liver radiotherapy using deformable registration of planning CT and cone-beam CT.

Many patients with technically unresectable or medically inoperable hepatocellular carcinoma (HCC) had hepatic anatomy variations as a result of interfraction deformation during fractionated radiotherapy. We conducted this retrospective study to investigate interfractional normal liver dosimetric consequences via reconstructing weekly dose in HCC patients. Twenty-three patients with HCC received conventional fractionated three-dimensional conformal radiation therapy (3DCRT) were enrolled in this retrospective investigation. Among them, seven patients had been diagnosed of radiation-induced liver disease (RILD) and the other 16 patients had good prognosis after treatment course. The cone-beam CT (CBCT) scans were acquired once weekly for each patient throughout the treatment, deformable image registration (DIR) of planning CT (pCT) and CBCT was performed to acquire modified CBCT (mCBCT), and the structural contours were propagated by the DIR. The same plan was applied to mCBCT to perform dose calculation. Weekly dose distribution was displayed on the pCT dose space and compared using dose difference, target coverage, and dose volume histograms. Statistical analysis was performed to identify the significant dosimetric variations. Among the 23 patients, the three weekly normal liver D50 increased by 0.2 Gy, 4.2 Gy, and 4.7 Gy, respectively, for patients with RILD, and 1.0 Gy, 2.7 Gy, and 3.1 Gy, respectively, for patients without RILD. Mean dose to the normal liver (Dmean) increased by 0.5 Gy, 2.6 Gy, and 4.0 Gy, respectively, for patients with RILD, and 0.4 Gy, 3.1 Gy, and 3.4 Gy, respectively, for patients without RILD. Regarding patients with RILD, the average values of the third weekly D50 and Dmean were both over hepatic radiation tolerance, while the values of patients without RILD were below. The dosimetric consequence showed that the liver dose between patients with and without RILD were different relative to the planned dose, and the RILD patients suffered from liver dose over hepatic radiation tolerance. Evaluation of routinely acquired CBCT images during radiation therapy provides biological information on the organs at risk, and dose estimation based on mCBCT could potentially form the basis for personalized response adaptive therapy.

Hepatic radiation injury mimicking metastasis in distal esophageal cancer.

INTRODUCTION: A new hypermetabolic lesion on 18FDG-PET/CT after neo-adjuvant chemoradiotherapy for distal esophageal cancer can be a hepatic metastasis and should be examined carefully before esophagectomy. CASE-REPORT: We present a case of acute and nodular radiation-induced injury of the left liver after neo-adjuvant chemoradiotherapy for distal esophageal cancer, which resembles a hepatic metastasis on 18FDG-PET/CT. Acute and nodular radiation hepatitis (RH) can be a potential cause of false-positive findings of malignancy and therefore exclude patients who could benefit from esophagectomy. CONCLUSION: 18FDG-PET/CT images should therefore carefully be interpreted and compared with the radiation beams, dose distribution and eventually clarified by DW-MR imaging.

Validation of the liver mean dose in terms of the biological effective dose for the prevention of radiation-induced liver damage.

AIM: The purpose of this study was to determine the optimal mean liver biologically effective dose (BED) to prevent radiation-induced liver disease (RILD) in stereotactic body radiation therapy (SBRT). BACKGROUND: The actual mean doses appropriate for liver irradiation in modern radiotherapy techniques have not been adequately investigated, although SBRT is sometimes alternatively performed using fractionated regimens. MATERIALS AND METHODS: SBRT treatment plans for liver tumors in 50 patients were analyzed. All distributions of the physical doses were transformed to BED2 using the linear-quadratic model. The relationship between physical doses and the BED2 for the liver were then analyzed, as was the relationship between the mean BED2 for the liver and the planning target volume (PTV). RESULTS: A significantly positive correlation was observed between the mean physical dose for the background liver and the mean BED2 for the whole liver (P < 0.0001, r = 0.9558). Using the LQ model, a mean BED2 of 73 and 16 Gy for the whole liver corresponded to the hepatic tolerable mean physical dose of 21 and 6 Gy for Child-Pugh A- and B-classified patients, respectively. Additionally, the PTV values were positively correlated with the BEDs for the whole liver (P < 0.0001, r = 0.8600), and the background liver (P < 0.0001, r = 0.7854). CONCLUSION: A mean BED2 of 73 and 16 Gy for the whole liver appeared appropriate to prevent RILD in patients with Child-Pugh classes A and B, respectively. The mean BED2 for the liver correlated well with the PTV.

Influence of liver toxicities on prognosis after stereotactic body radiation therapy for hepatocellular carcinoma.

AIM: To better define clinically relevant non-classic radiation-induced liver disease (RILD) following stereotactic body radiotherapy (SBRT) in patients with small hepatocellular carcinoma (HCC). METHODS: We retrospectively evaluated the influence of acute liver toxicities on fatal hepatic failure in HCC patients treated with SBRT. Between April 2006 and February 2012, 194 HCC were treated with SBRT. Among them, patients followed up for more than 6 months were eligible. Laboratory results and Child-Pugh (CP) scores were obtained before treatment and at monthly follow-up visits. Toxicities were evaluated by the Common Terminology Criteria for Adverse Events version 4.0. Possible definitions of RILD were evaluated with respect to fatal hepatic failure within 12 months. RESULTS: One hundred and eighty HCC were evaluated with a median follow-up of 28.2 months. Fatal hepatic failure within 12 months occurred in eight patients (4%). On univariate analysis, grade 3 or more elevated transaminases, CP score of 8 or more, and/or grade 3 or more decreased platelet count significantly predicted fatal hepatic failure within 12 months. Combinations of these factors (i.e. having at least one criterion) also predicted fatal hepatic failure within 12 months (16% with criteria vs 1% without criteria). Two-year overall survival rates for patients with and without RILD was 64.9% and 83.8% (P < 0.001), respectively. CONCLUSION: We identified three criteria that affected overall survival in HCC patients treated with SBRT. Further prospective studies are warranted to validate the safety and effect of SBRT for HCC.

Risk factors for hepatitis B virus reactivation after conformal radiotherapy in patients with hepatocellular carcinoma.

This study investigated whether conformal radiotherapy affects hepatitis B virus (HBV) reactivation, and the risk factors for HBV reactivation in patients with HBV-related hepatocellular carcinoma (HCC). Sixty-nine patients with HCC were included in this retrospective study. Before radiotherapy (RT), all patients underwent imaging examinations and some baseline examinations, including CBC, liver function test, renal function test, α-fetoprotein level, hepatitis B (HB) surface antigen, HB surface Ab, HB e antigen, HB e Ab, and serum HBV DNA quantification. During the period of RT and at least 16 weeks after the end of RT, CBCs were carried out weekly and the other tests were monitored monthly or more frequently if necessary. The clinical features and dosimetric parameters of RT were recorded. Univariate and multivariate logistic regression algorithms were used to analyze the risk factors of HBV reactivation. The incidence of complications in the study population was as follows: radiation-induced liver disease, 17.4%; HBV reactivation, 24.6%; and HBV reactivation-induced hepatitis, 21.7%. The HBV DNA level and dose volume parameters including normal liver volume, V20, and mean dose were associated with HBV reactivation. There was a relatively high incidence of HBV reactivation in HCC patients after the end of conformal RT. The serum HBV DNA level and some dosimetric parameters related to normal liver, including normal liver volume, V20, and mean dose, were the prognosis factors of HBV reactivation and should be carefully considered before conformal RT.

False Liver Metastasis by Positron Emission Tomography/Computed Tomography Scan after Chemoradiotherapy for Esophageal Cancer-Potential Overstaged Pitfalls of Treatment.

In patients with esophageal cancer undergoing neoadjuvant chemoradiotherapy (nCRT), subsequent restaging with F-18-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) can reveal the presence of interval metastases, such as liver metastases, in approximately 10% of cases. Nevertheless, it is not uncommon in clinical practice to observe focal FDG uptake in the liver that is not associated with liver metastases but rather with radiation-induced liver injury (RILI), which can result in the overstaging of the disease. Liver radiation damage is also a concern during distal esophageal cancer radiotherapy due to its proximity to the left liver lobe, typically included in the radiation field. Post-CRT, if FDG activity appears in the left or caudate liver lobes, a thorough investigation is needed to confirm or rule out distant metastases. The increased FDG uptake in liver lobes post-CRT often presents a diagnostic dilemma. Distinguishing between radiation-induced liver disease and metastasis is vital for appropriate patient management, necessitating a combination of imaging techniques and an understanding of the factors influencing the radiation response. Diagnosis involves identifying new foci of hepatic FDG avidity on PET/CT scans. Geographic regions of hypoattenuation on CT and well-demarcated regions with specific enhancement patterns on contrast-enhanced CT scans and MRI are characteristic of radiation-induced liver disease (RILD). Lack of mass effect on all three modalities (CT, MRI, PET) indicates RILD. Resolution of abnormalities on subsequent examinations also helps in diagnosing RILD. Moreover, it can also help to rule out occult metastases, thereby excluding those patients from further surgery who will not benefit from esophagectomy with curative intent.

Radiotherapy plus anti-PD1 versus radiotherapy for hepatic toxicity in patients with hepatocellular carcinoma.

PURPOSE: In this study, we aimed to compare the radiation-induced hepatic toxicity (RIHT) outcomes of radiotherapy (RT) plus antibodies against programmed cell death protein 1 (anti-PD1) versus RT alone in patients with hepatocellular carcinoma (HCC), evaluate prognostic factors of non-classic radiation-induced liver disease (ncRILD), and establish a nomogram for predicting the probability of ncRILD. PATIENTS AND METHODS: Patients with unresectable HCC treated with RT and anti-PD1 (RT + PD1, n = 30) or RT alone (n = 66) were enrolled retrospectively. Patients (n = 30) in each group were placed in a matched cohort using propensity score matching (PSM). Treatment-related hepatotoxicity was evaluated and analyzed before and after PSM. The prognostic factors affecting ncRILD were identified by univariable logistic analysis and Spearman's rank test in the matched cohort to generate a nomogram. RESULTS: There were no differences in RIHT except for increased aspartate aminotransferase (AST) ≥ grade 1 and increased total bilirubin ≥ grade 1 between the two groups before PSM. After PSM, AST ≥ grade 1 occurred more frequently in the RT + PD1 group (p = 0.020), and there were no significant differences in other hepatotoxicity metrics between the two groups. In the matched cohort, V25, tumor number, age, and prothrombin time (PT) were the optimal prognostic factors for ncRILD modeling. A nomogram revealed a good predictive performance (area under the curve = 0.82). CONCLUSIONS: The incidence of RIHT in patients with HCC treated with RT + PD1 was acceptable and similar to that of RT treatment. The nomogram based on V25, tumor number, age, and PT robustly predicted the probability of ncRILD.

Non-classic radiation-induced liver disease after intensity-modulated radiotherapy for Child-Pugh grade B patients with locally advanced hepatocellular carcinoma.

BACKGROUND: The incidence of classic radiation-induced liver disease (cRILD) has been significantly reduced. However, non-classic radiation-induced liver disease (ncRILD) remains a major concern following radiotherapy in patients with hepatocellular carcinoma (HCC). This study evaluated the incidence of ncRILD following intensity-modulated radiotherapy (IMRT) for Child-Pugh grade B (CP-B) patients with locally advanced HCC and established a nomogram for predicting ncRILD probability. METHODS: Seventy-five CP-B patients with locally advanced HCC treated with IMRT between September 2014 and July 2021 were included. The max tumor size was 8.39 cm ± 5.06, and the median prescribed dose was 53.24 Gy ± 7.26. Treatment-related hepatotoxicity was evaluated within three months of completing IMRT. A nomogram model was formulated to predict the probability of ncRILD, using univariate and multivariate analysis. RESULTS: Among CP-B patients with locally advanced HCC, ncRILD occurred in 17 (22.7%) patients. Two patients (2.7%) exhibited a transaminase elevation of ≥ G3, fourteen (18.7%) exhibited a Child-Pugh score increase of ≥ 2, and one (1.3%) demonstrated both a transaminase elevation of ≥ G3 and a Child-Pugh score increase of ≥ 2. No cRILD cases were observed. A mean dose to the normal liver of ≥ 15.1 Gy was used as the cutoff for ncRILD. Multivariate analysis revealed that the prothrombin time before IMRT, tumour number, and mean dose to the normal liver were independent risk factors for ncRILD. The nomogram established on the basis of these risk factors displayed exceptional predictive performance (AUC = 0.800, 95% CI 0.674-0.926). CONCLUSIONS: The incidence of ncRILD following IMRT for CP-B patients with locally advanced HCC was acceptable. A nomogram based on prothrombin time before IMRT, tumour number, and mean dose to the normal liver accurately predicted the probability of ncRILD in these patients.

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.

Prevention of radiation-induced liver toxicity after interstitial HDR brachytherapy by pentoxifylline and ursodeoxycholic acid: patient compliance and outcome in a randomized trial.

AIM: To investigate the impact of pentoxifylline (PTX, 3 × 400 mg per day) and ursodeoxycholic acid (UDCA, 3 × 250 mg per day) administered for 12 weeks on radiation-induced liver toxicity. MATERIALS AND METHODS: Inclusion criteria were liver metastases of extrahepatic malignancies undergoing HDR-BT. 36 patients were prospectively randomized to the medication (N = 18) or control arm (N = 18) and follow-up by hepatobiliary magnetic resonance imaging (MRI) was scheduled 6 and 12 weeks after local ablation by HDR-BT. We determined the threshold doses of fRILI by image fusion of MRI with the dosimetry data. RESULTS: 32 patients completed the study schedule. Per-protocol treatment was limited to 8 patients in the medication group and 16 patients in the control group. 22 adverse events of any grade likely or certainly related to PTX were recorded in 12 patients leading to the discontinuation of the study medication in 7 patients and to a dose reduction of PTX in 2 patients. In the per-protocol population, statistical analysis failed to prove a reduction of fRILI 6 and 12 weeks after HDR-BT. The incidence of adverse effects attributed to PTX (70.6%) was well above the data found in the literature for its approved indication. CONCLUSION: The study endpoint was not met mainly attributed to the low statistical power of the small per-protocol cohort. Independently, PTX cannot be recommended for the reduction of radiation-induced liver toxicity in oncologic patients undergoing HDR-BT of liver metastases. Further studies might focus on a combination of UDCA with other potential drugs to help establish a preventive and tolerable regimen.

A Rare Case of Radiation-Induced Liver Disease in Treated Abdominal Lymphoma Showing High [18F]FDG Avidity and Low EOB Uptake Proportional to the Irradiation Dose.

A 44-year-old woman presented with high [18F]FDG uptake liver lesion after six courses of R-CHOP and radiotherapy for abdominal DLBCL, which was misdiagnosed as a hepatic invasion. EOB-MRI showed slight T2 hyperintensity, low-intensity DWI, and decreased EOB uptake in the hepatocellular phase. Compared with the pretreatment planning CT, the liver lesion coincided with the area of >40.5 Gy, resulting in the diagnosis of RILD. At the follow-up [18F]FDG PET/CT 7 months after irradiation, the abnormal liver uptake disappeared. Comparing [18F]FDG PET/CT, EOB-MRI, and planning CT can lead to the correct diagnosis of RILD and avoid unnecessary biopsies and treatment changes.

Pentadecapeptide BPC 157 efficiently reduces radiation-induced liver injury and lipid accumulation through Kruppel-like factor 4 upregulation both in vivo and in vitro.

AIMS: Radiation-induced liver disease (RILD) is the major complication for cancer patients after radiation therapy. We investigated the protective effects of BPC 157 peptide in reducing RILD. MATERIALS AND METHODS: Mice were irradiated with a single dose of 12 Gy to induce acute liver injury with or without oral BPC 157. Plasma levels of AST and ALT were determined. In vitro rat liver clone 9 cells and in vivo liver tissues were harvested for MTT assay, TUNEL assay, lipid staining, polypoid cell counts, Western blotting of caspase-3, PCNA, KLF-4 and HIF-2α, and immunocytochemistry for PCNA, KLF-4 and HIF-2α. SiRNAs were used to knockdown KLF-4. KEY FINDINGS: BPC 157 was firstly demonstrated to reduce RILD by decreasing plasma levels of AST and ALT, and inhibiting hydropic degeneration of liver. BPC 157 significantly decreased radiation-induced cell apoptosis, increased PCNA expression, promoted the expression of KLF4, decreased the radiation-induced hepatic lipid accumulation and HIF-2α expression both in mice liver and in clone 9 liver cells. The knockdown of KLF4 abolished the protective effect of BPC 157 on radiation-induced apoptosis and lipid accumulation in clone 9 liver cells, indicating that the protective effect of BPC 157 was mediated by KLF4 in liver cells. SIGNIFICANCE: The present study provided a good model for molecular mechanism underlying the acute RILD. BPC 157, as a stable pentadecapeptide that can be chemically synthesized and purified easily for research, together with its in vivo markedly protective effect made it worth of being investigated for future clinical application for RILD.