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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.

Background Lutetium-177-DOTA-octreotate ( 177 Lu-DOTATATE) significantly increases survival and response rates in patients with grade I and grade II neuroendocrine tumors (NETs). However, survival and response rates are significantly lower in patients with bulky liver metastases. Increasing the tumor-absorbed dose in liver metastases may improve response to 177 Lu-DOTATATE. The LUTIA (Lutetium Intra-Arterial) study aims to increase the tumor-absorbed dose in liver metastases by intra-arterial (IA) administration of 177 Lu-DOTATATE, compared to conventional intravenous (IV) administration. Methods A multicenter, within-patient randomized controlled trial (RCT) in 26 patients with progressive, liver-dominant, unresectable grade I or grade II NET will be conducted. Patients with bilobar bulky disease will be randomly allocated to receive IA treatment into either the left or the right hepatic artery. Using this approach, one liver lobe will be treated intra-arterially (first-pass effect), while the contralateral lobe will receive an intravenous treatment as a second-pass effect. The primary endpoint of this study is the difference in tumor-to-non-tumor ratio of 177 Lu-DOTATATE uptake between the two liver lobes on post-treatment SPECT/CT (IA versus IV). Secondary endpoints include absorbed dose in both liver lobes, tumor response, dose-response relationship, toxicity, uptake in extrahepatic lesions, and renal uptake. Discussion This multicenter, within-patient RCT will investigate whether IA administration of 177 Lu-DOTATATE results in a higher activity concentration in liver metastases compared to IV administration. Trial registration ClinicalTrials.gov, NCT03590119 . Registered on 17 July 2018.

Background There is a lack of data on the biologically effective dose and the efficacy of stereotactic body radiotherapy in hepatocellular carcinoma patients, and this study was conducted to explore the relation between BED and efficacy. Methods This study is designed as a mono-center study. The participants are randomized into three group, and received the following recommended schedule: 49Gy/7f, 54Gy/6f and 55Gy/5f with BED 10 in correspondence to 83.3Gy, 102.6Gy and 115.5Gy. The primary outcome measures are to calculate local control rates (LC), overall survival rates (OS) and progression-free survival rates (PFS). The secondary outcome measures are to observe radiation-induced liver injury (RILD) rates, Child-Pugh score and indocyanine green retention rate at 15 min (ICG-R15) value before and after CK-SBRT. Moreover, gastrointestinal toxicities are also observed. Discussion There is no uniform standard for CK-SBRT dose schedule of hepatocellular carcinoma. We propose to conduct a study determining the optimal CK-SBRT schedule of hepatocellular carcinoma patients (≤5 cm). The trial protocol has been approved by the Institutional Review Board of 302 Hospital of PLA (People’s Liberation Army). The Ethics number is 2017111D. Trail registration Clinical trails number: NCT03295500 . Date of registration: November, 2017.

Objective: We evaluated microwave-assisted liver resection for hepatocellular carcinoma. Patients and Methods: We enrolled 79 patients in this study, and microwave ablation was used for liver resection. Patients were randomized to group A (50.6%; n = 40), liver resection without microwave ablation, or group B (49.4%; n = 39), liver resection performed using microwave ablation. Data were analyzed for statistical significance. Results: Of the participants enrolled, 60 were male, and the participant’s average age was 59.32 ± 10.34 years. The mean overall tumor diameter was 4.39 (2.00) cm, and this did not differ between groups. Intraoperative blood loss in group B was significantly less than that in group A (P < .001). No differences were reported between the 2 groups regarding surgical time (P = .914), postoperative morbidity (P = .718), and late postoperative complications (P = .409). Postoperative drainage volume for group B was less than that of group A on the first (P = .005) and third (P = .019) day after surgery. The time of postoperative hospitalization in group B was significantly shorter than that in group A (P < .001). Local recurrence was noted in 18.99% of cases (n = 15) in group B, which is less than that of group A (P = 0.047), while in group B distant metastasis is less but not statistically significant (P = 0.061). The 1-year and 3-year cumulative survival rates were 57% and 93.7%, respectively. Conclusions: The curative effects of liver resection combined with microwave ablation during operation are superior to only liver resection in the treatment of primary liver cancer.

Preparative hepatic irradiation (HIR), together with mitotic stimulation of hepatocytes, permits extensive hepatic repopulation by transplanted hepatocytes in rats and mice. However, whole liver HIR is associated with radiation-induced liver disease (RILD), which limits its potential therapeutic application. In clinical experience, restricting HIR to a fraction of the liver reduces the susceptibility to RILD. Here we test the hypothesis that repopulation of selected liver lobes by regional HIR should be sufficient to correct some inherited metabolic disorders. Hepatocytes (10(7)) isolated from wildtype F344 rats or Wistar-RHA rats were engrafted into the livers of congeneic dipeptidylpeptidase IV deficient (DPPIV(-)) rats or uridinediphosphoglucuronateglucuronosyltransferase-1A1-deficient jaundiced Gunn rats respectively by intrasplenic injection 24 hr after HIR (50 Gy) targeted to the median lobe, or median plus left liver lobes. An adenovector expressing hepatocyte growth factor (10(11) particles) was injected intravenously 24 hr after transplantation. Three months after hepatocyte transplantation in DPPIV(-) rats, 30-60% of the recipient hepatocytes were replaced by donor cells in the irradiated lobe, but not in the nonirradiated lobes. In Gunn rats receiving median lobe HIR, serum bilirubin declined from pretreatment levels of 5.17 ± 0.78 mg/dl to 0.96 ± 0.30 mg/dl in 8 weeks and remained at this level throughout the 16 week observation period. A similar effect was observed in the group, receiving median plus left lobe irradiation. As little as 20% repopulation of 30% of the liver volume was sufficient to correct hyperbilirubinemia in Gunn rats, highlighting the potential of regiospecific HIR in hepatocyte transplantation-based therapy of inherited metabolic liver diseases.

In quantitative PET measurements, the analysis of radiometabolites in plasma is essential for determining the exact arterial input function. Diphenyl sulfide compounds are promising PET and SPECT radioligands for in vivo quantification of the serotonin transporter (SERT) and it is therefore important to investigate their radiometabolism. We have chosen to explore the radiometabolic profile of [11C]MADAM, one of these radioligands widely used for in vivo PET-SERT studies. The metabolism of [11C]MADAM/MADAM was investigated using rat and human liver microsomes (RLM and HLM) in combination with radio-HPLC or UHPLC/Q-ToF-MS for their identification. The effect of carrier on the radiometabolic rate of the radioligand [11C]MADAM in vitro and in vivo was examined by radio-HPLC. RLM and HLM incubations were carried out at two different carrier concentrations of 1 and 10 μM. Urine samples after perfusion of [11C]MADAM/MADAM in rats were also analysed by radio-HPLC. Analysis by UHPLC/Q-ToF-MS identified the metabolites produced in vitro to be results of N-demethylation, S-oxidation and benzylic hydroxylation. The presence of carrier greatly affected the radiometabolism rate of [11C]MADAM in both RLM/HLM experiments and in vivo rat studies. The good concordance between the results predicted by RLM and HLM experiments and the in vivo data obtained in rat studies indicate that the kinetics of the radiometabolism of the radioligand [11C]MADAM is dose-dependent. This issue needs to be addressed when the diarylsulfide class of compounds are used in PET quantifications of SERT.

Although radiotherapy (RT) is used for the treatment of cancers, including liver cancer, radiation-induced liver disease (RILD) has emerged as a major limitation of RT. Radiation-induced toxicities in nontumorous liver tissues are associated with the development of numerous symptoms that may limit the course of therapy or have serious chronic side effects, including late fibrosis. Although the clinical characteristics of RILD patients have been relatively well described, the understanding of RILD pathogenesis has been hampered by a lack of reliable animal models for RILD. Despite efforts to develop suitable experimental animal models for RILD, current animal models rarely present hepatic veno-occlusive disease, the pathological hallmark of human RILD patients, resulting in highly variable results in RILD-related studies. Therefore, we introduce the concept and clinical characteristics of RILD and propose a feasible explanation for RILD pathogenesis. In addition, currently available animal models of RILD are reviewed, focusing on similarities with human RILD and clues to understanding the mechanisms of RILD progression. Based on these findings from RILD research, we present potential therapeutic strategies for RILD and prospects for future RILD studies. Therefore, this review helps broaden our understanding for developing effective treatment strategies for RILD. Radiotherapy: Animal models needed for radiation-induced liver disease Radiation-induced liver disease (RILD) remains poorly understood and treated because of the lack of suitable animal models. There are no effective treatments for liver cancer patients who experience this life-threatening complication of radiotherapy, partly because the precise mechanisms of disease development remain largely unknown. In a review article, Jieun Kim and Youngmi Jung from Pusan National University, South Korea, describe the insights into RILD pathology that have come from clinical observations and patient-derived tissue samples. The researchers describe existing mouse, rat, rabbit, dog and monkey models for RILD, but these animals rarely develop obstructed small veins in the liver, the hallmark symptom of the human disease. Animal models that more closely mirror human RILD, the authors argue, should reveal new insights into disease mechanisms and provide a pre-clinical platform for drug screening.

Immune modulation is a very modern medical field for targeting viral infections. In the race to develop the best immune modulator against viruses, curcumin, as a natural product, is inexpensive, without side effects, and can stimulate very well certain areas of the human immune system. As a bright yellow component of turmeric spice, curcumin has been the subject of thousands of scientific and clinical studies in recent decades to prove its powerful antioxidant properties and anticancer effects. Curcumin has been shown to influence inter- and intracellular signaling pathways, with direct effects on gene expression of the antioxidant proteins and those that regulate the immunity. Experimental studies have shown that curcumin modulates several enzyme systems, reduces nitrosative stress, increases the antioxidant capacity, and decreases the lipid peroxidation, protecting against fatty liver pathogenesis and fibrotic changes. Hepatitis B virus (HBV) affects millions of people worldwide, having sometimes a dramatic evolution to chronic aggressive infection, cirrhosis, and hepatocellular carcinoma. All up-to-date treatments are limited, there is still a gap in the scientific knowledge, and a sterilization cure may not yet be possible with the removal of both covalently closed circular DNA (cccDNA) and the embedded HBV DNA. With a maximum light absorption at 420 nm, the cytotoxicity of curcumin as photosensitizer could be expanded by the intravenous blue laser blood irradiation (IVBLBI) or photobiomodulation in patients with chronic hepatitis B infection, Hepatitis B e-antigen (HBeAg)-positive, noncirrhotic, but nonresponsive to classical therapy. Photobiomodulation increases DNA repair by the biosynthesis of complex molecules with antioxidant properties, the outset of repairing enzyme systems and new phospholipids for regenerating the cell membranes. UltraBioavailable Curcumin and blue laser photobiomodulation could suppress the virus and control better the disease by reducing inflammation/fibrosis and stopping the progression of chronic hepatitis, reversing fibrosis, and diminishing the progression of cirrhosis, and decreasing the incidence of hepatocellular carcinoma. Photodynamic therapy with blue light and curcumin opens new avenues for the effective prevention and cure of chronic liver infections and hepatocellular carcinoma. Blue laser light and UltraBioavailable Curcumin could be a new valuable alternative for medical applications in chronic B viral hepatitis and hepatocarcinoma, saving millions of lives.

Different tissues exhibit differential sensitivity to ionizing radiation exposure and display different time courses of pathologies that are not well understood. Ionizing radiation causes hemolysis of red blood cells, causing the release of iron that is taken up by a variety of tissues. The increased iron has been associated with altered expression of iron binding proteins and, in some cases, markers of ferroptosis. Here we examined the time course of iron uptake in murine liver following 60 Co total body irradiation (TBI) at 7.9 Gy (LD 90/30 ) and 6.85 Gy (LD 0/30 ). 7.9 Gy induced hydropic degeneration, micro-vesicular steatosis, and inflammatory cell infiltration, whereas at 6.85 Gy the livers displayed only inflammatory cell infiltration. In both cases, iron levels increased significantly, maximal at ~21 days post-TBI. Increased iron was associated with altered expression of ferritin, heme oxygenase, an enzyme required for iron recycling, and the pro-inflammatory cytokine serum amyloid A, maximal ~16–21 days. 7.9 Gy induced liver caspase-3 activation consistent with apoptosis. In contrast, 6.85 Gy induced markers of ferroptosis but not of apoptosis. Our data indicate that iron is deposited in the liver at a delayed time point following radiation and is associated with increased ferritin, HO-1, and inflammatory cytokine production.

Both cancer patients receiving radiotherapy and civilians in a mass casualty nuclear event may suffer from radiation induced damage to organ systems. Radiation induced liver disease (RILD) can cause acute and long-term organ dysfunction that potentially leads to death. The objective of this study was to ascertain the validity of a liver quad-culture chip, a micro-physiological system comprising primary human hepatocytes and non-parenchymal cells (NPCs), including liver sinusoidal endothelial cells, hepatic stellate cells (HSCs), and Kupffer cells, as a model for RILD. The radiation exposure to the chip model resulted in DNA damage and cellular senescence of hepatocytes and NPCs. We observed metabolic dysfunction, inflammation, endothelial dysfunction, and HSCs activation. Whole genome sequencing revealed gene alterations in pathways relevant to RILD, as well as the potential efficacy of N -acetylcysteine amide (NACA) against RILD. NACA exhibited the capacity to mitigate DNA damage and cellular senescence and decreased the impact of radiation exposure on other pathophysiological changes. CDKN1A and miR-34a-5p were validated as useful radiation response and treatment efficacy biomarkers. These findings highlight the potential of the liver quad-culture chip as an effective model for investigating the microenvironment in RILD and for evaluating the efficacy of therapeutic countermeasures and biomarkers.