Functional Characterization of Allelic Variations of Human Cytochrome P450 2C8 (V181I, I244V, I331T, and L361F).

The human cytochrome P450 2C8 is responsible for the metabolism of various clinical drugs as well as endogenous fatty acids. Allelic variations can significantly influence the metabolic outcomes. In this study, we characterize the functional effects of four nonsynonymous single nucleotide polymorphisms *15, *16, *17, and *18 alleles recently identified in cytochrome P450 2C8. The recombinant allelic variant enzymes V181I, I244V, I331T, and L361F were successfully expressed in Escherichia coli and purified. The steady-state kinetic analysis of paclitaxel 6-hydroxylation revealed a significant reduction in the catalytic activities of the V181I, I244V, and L361F variants. The calculated catalytic efficiency (kcat/Km) of these variants was 5-26% of that of the wild-type enzyme. The reduced activities were due to both decreased kcat values and increased Km values of the variants. The epoxidation of arachidonic acid by the variants was analyzed. The L361F variant only exhibited 4-6% of the wild-type catalytic efficiency in ω-9- and ω-6-epoxidation reactions to produce 11,12-epoxyeicosatrienoic acid (EET) and 14,15-EET, respectively. These reductions were mainly due to a decrease in the kcat value of the L361F variant. The binding titration analysis of paclitaxel and arachidonic acid showed that all variants had similar affinities to those of the wild-type (10-14 µM for paclitaxel and 20-49 µM for arachidonic acid). The constructed paclitaxel docking model of the variant enzyme suggests that the L361F substitution leads to the incorrect orientation of paclitaxel in the active site, with the 6'C of paclitaxel displaced from the productive catalytic location. This study suggests that individuals carrying the newly identified P450 2C8 allelic variations are likely to have an altered metabolism of clinical medicines and production of fatty acid-derived signal molecules.

Mesenchymal Stem Cells and Exosomes: A Novel Therapeutic Approach for Corneal Diseases.

The cornea, with its delicate structure, is vulnerable to damage from physical, chemical, and genetic factors. Corneal transplantation, including penetrating and lamellar keratoplasties, can restore the functions of the cornea in cases of severe damage. However, the process of corneal transplantation presents considerable obstacles, including a shortage of available donors, the risk of severe graft rejection, and potentially life-threatening complications. Over the past few decades, mesenchymal stem cell (MSC) therapy has become a novel alternative approach to corneal regeneration. Numerous studies have demonstrated the potential of MSCs to differentiate into different corneal cell types, such as keratocytes, epithelial cells, and endothelial cells. MSCs are considered a suitable candidate for corneal regeneration because of their promising therapeutic perspective and beneficial properties. MSCs compromise unique immunomodulation, anti-angiogenesis, and anti-inflammatory properties and secrete various growth factors, thus promoting corneal reconstruction. These effects in corneal engineering are mediated by MSCs differentiating into different lineages and paracrine action via exosomes. Early studies have proven the roles of MSC-derived exosomes in corneal regeneration by reducing inflammation, inhibiting neovascularization, and angiogenesis, and by promoting cell proliferation. This review highlights the contribution of MSCs and MSC-derived exosomes, their current usage status to overcome corneal disease, and their potential to restore different corneal layers as novel therapeutic agents. It also discusses feasible future possibilities, applications, challenges, and opportunities for future research in this field.

Chromism-Integrated Sensors and Devices for Visual Indicators.

The bifunctionality of chromism-integrated sensors and devices has been highlighted because of their reversibility, fast response, and visual indication. For example, one of the representative chromism electrochromic materials exhibits optical modulation under ion insertion/extraction by applying a potential. This operation mechanism can be integrated with various sensors (pressure, strain, biomolecules, gas, etc.) and devices (energy conversion/storage systems) as visual indicators for user-friendly operation. In this review, recent advances in the field of chromism-integrated systems for visual indicators are categorized for various chromism-integrated sensors and devices. This review can provide insights for researchers working on chromism, sensors, or devices. The integrated chromic devices are evaluated in terms of coloration-bleach operation, cycling stability, and coloration efficiency. In addition, the existing challenges and prospects for chromism-integrated sensors and devices are summarized for further research.

Concurrent and Selective Determination of Dopamine and Serotonin with Flexible WS2 /Graphene/Polyimide Electrode Using Cold Plasma.

Makers of point-of-care devices and wearable diagnostics prefer flexible electrodes over conventional electrodes. In this study, a flexible electrode platform is introduced with a WS2 /graphene heterostructure on polyimide (WGP) for the concurrent and selective determination of dopamine and serotonin. The WGP is fabricated directly via plasma-enhanced chemical vapor deposition (PECVD) at 150 °C on a flexible polyimide substrate. Owing to the limitations of existing fabrication methods from physical transfer or hydrothermal methods, many studies are not conducted despite excellent graphene-based heterostructures. The PECVD synthesis method can provide an innovative WS2 /graphene heterostructure of uniform quality and sufficient size (4 in.). This unique heterostructure affords excellent electrical conductivity in graphene and numerous electrochemically active sites in WS2 . A large number of uniform qualities of WGP electrodes show reproducible and highly sensitive electrochemical results. The synergistic effect enabled well-separated voltammetric signals for dopamine and serotonin with a potential gap of 188 mV. Moreover, the practical application of the flexible sensor is successfully evaluated by using artificial cerebrospinal fluid.

Possibility of Japanese Cedar Pollen Causing False Positives in the Deep Mycosis Test.

Because Japanese cedar pollen (JCP) contains beta-1,3-d-glucan (BG), there is concern that its lingering presence in the atmosphere, especially during its scattering period, may cause false positives in the factor-G-based Limulus amebocyte lysate (LAL) assay used to test for deep mycosis (i.e., G-test). Hence, we examined whether the LAL assay would react positively with substances contained in JCP by using the G-test to measure JCP particles and extracts. BG was purified from the JCP extract on a BG-specific affinity column, and the percentage extractability was measured using three different BG-specific quantitative methods. The G-test detected 0.4 pg BG in a single JCP particle and 10 fg from a single particle in the extract. The percentage extractability of JCP-derived BG was not significantly different among the three quantitative methods. As the JCP particles should technically have been removed during serum separation, they should be less likely to be a direct false-positive factor. However, given that the LAL-assay-positive substances in the JCP extract were not distinguishable by the three BG-specific quantitative methods, we conclude that they may cause the background to rise. Therefore, in Japan false positives arising from JCP contamination should be considered when testing patients for deep mycosis.

Antibacterial rGO-CuO-Ag film with contact- and release-based inactivation properties.

To reduce the high operational costs of water treatment because of membrane biofouling, next-generation materials are being developed to counteract microbial growth. These modern anti-biofouling strategies are based on new membrane materials or membrane surface modifications. In this study, antimicrobial films comprising rGO, rGO-CuO, rGO-Ag, and rGO-CuO-Ag were synthesized, evaluated, and tested for potential biofouling control using Pseudomonas aeruginosa PAO1 as the model bacterium. The combined rGO-CuO-Ag film displayed enhanced reduction (10-log reduction) in biofouling in comparison to the rGO film (control), followed by the rGO-Ag film (8-log reduction) and rGO-CuO film (0-log reduction). This demonstrated that the use of mixed antimicrobial agents is more effective in reducing biofouling than that of a single agent. The rGO-CuO-Ag film exhibited consistent, controlled, and moderate release of silver (Ag) ions. The release of Ag ions produced a long-lasting antimicrobial effect. These results underscore the potential applications of combined antimicrobial surface-based agents in practice and further research.

Diphenylaminoarylvinyl-Substituted Diphenylanthracenes for Organic Light-Emitting Diodes.

Two blue fluorescent materials based on diphenylaminoarylvinyl-substituted diphenylanthracene have been synthesized. Multilayered organic light-emitting diodes (OLED) with the following sequence; ITO/NPB (50 nm)/Blue materials (30 nm)/Bphen (30 nm)/Liq (2 nm)/Al (100 nm) were fabricated using these materials as emitters. Two devices exhibited blue electroluminescence. Particularly, a device using 6-(4-(10-phenylanthracen-9-yl)styryl)-N,N-diphenylnaphthalen-2-amine (2) exhibited blue emission with a luminance efficiency, a power efficiency, an external quantum efficiency and CIE coordinates of 5.69 cd/A, 1.99 lm/W, 3.39% at 100 mA/cm² and (x = 0.19, y =0.31) at 8.0 V, respectively.

Highly Efficient Organic Light-Emitting Diodes Based on Naphthoanthracene Derivatives Containing Different Arylamines.

Herein, we designed and synthesized emitting materials based on naphthoanthracene with the different arylamino-substituents. Organic Light Emitting-Diodes (OLEDs) devices using these materials were fabricated in the following sequence; ITO/N,N'-diphenyl-N,N'-(2-napthyl)-(1,1'-phenyl)-4,4'- diamine (NPB) (500 Å)/Emitters (400 Å)/Alumium quinolate (Alq3) (150 Å)/lithium quinolate (Liq) (20 Å)/Al (1000 Å). All devices showed efficient emissions. In particular, a device using 4-((5,5-dimethyl-9-phenyl-5H-naphtho[3,2,1-de]anthracen-3-yl)(phenyl)amino)benzonitrile as an emitter exhibited the luminous efficiency, power efficiency, and external quantum efficiency of 9.15 cd/A, 6.36 lm/W, 2.72% at 20 mA/cm², respectively, with the Commission Internationale d'Énclairage (CIE) coordinates of (0.30, 0.62) at 6.0 V.

Highly Efficient CO2 Utilization via Aqueous Zinc- or Aluminum-CO2 Systems for Hydrogen Gas Evolution and Electricity Production.

Atmospheric carbon dioxide (CO2 ) has increased from 278 to 408 parts per million (ppm) over the industrial period and has critically impacted climate change. In response to this crisis, carbon capture, utilization, and storage/sequestration technologies have been studied. So far, however, the economic feasibility of the existing conversion technologies is still inadequate owing to sluggish CO2 conversion. Herein, we report an aqueous zinc- and aluminum-CO2 system that utilizes acidity from spontaneous dissolution of CO2 in aqueous solution to generate electrical energy and hydrogen (H2 ). The system has a positively shifted onset potential of hydrogen evolution reaction (HER) by 0.4 V compared to a typical HER under alkaline conditions and facile HER kinetics with low Tafel slope of 34 mV dec-1 . The Al-CO2 system has a maximum power density of 125 mW cm-2 which is the highest value among CO2 utilization electrochemical system.

Defect-Free Encapsulation of Fe0 in 2D Fused Organic Networks as a Durable Oxygen Reduction Electrocatalyst.

Because they provide lower cost but comparable activity to precious platinum (Pt)-based catalysts, nonprecious iron (Fe)-based materials, such as Fe/Fe3C and Fe-N-C, have gained considerable attention as electrocatalysts for the oxygen reduction reaction (ORR). However, their practical application is hindered by their poor stability, which is attributed to the defective protection of extremely unstable Fe nanoparticles. Here, we introduce a synthesis strategy for a stable Fe-based electrocatalyst, which was realized by defect-free encapsulation of Fe nanoparticles using a two-dimensional (2D) phenazine-based fused aromatic porous organic network (Aza-PON). The resulting Fe@Aza-PON catalyst showed electrocatalytic activity (half-wave potential, 0.839 V; Tafel slope, 60 mV decade-1) comparable to commercial Pt on activated carbon (Pt/C, 0.826 V and 90 mV decade-1). More importantly, the Fe@Aza-PON displayed outstanding stability (zero current loss even after 100 000 cycles) and tolerance against contamination (methanol and CO poisoning). In a hybrid Li-air battery test, the Fe@Aza-PON demonstrated performance superior to Pt/C.

Scoring system for risk stratification of viral reactivation during prophylactic antiviral treatment in Korean patients with hepatitis B undergoing anticancer chemotherapy: A multicenter study.

Prophylactic antiviral therapy is recommended for hepatitis B virus (HBV)-infected patients with malignancies who are undergoing systemic chemotherapy. In the current study, we aimed to develop a risk scoring system to guide the selection of prophylactic antiviral agents. In this retrospective analysis, we included consecutive chronic hepatitis B patients who received antiviral prophylaxis for chemotherapy of solid or hematologic malignancies at three large-volume hospitals in Korea. The primary endpoint was HBV reactivation. The inverse probability treatment weighting method was used to minimize selection bias in terms of antiviral assignments. A total of 419 patients were enrolled: 129 patients received lamivudine (LAM), 216 received telbivudine (LdT), and 74 received entecavir (ETV), respectively. Of these, 36 patients developed on-treatment HBV reactivation (LAM, 17; LdT, 18; ETV, 1). Multivariate analysis identified three independent predictors for reactivation: hepatitis B e-antigen positivity, HBV DNA level, and type of malignancy. Accordingly, a risk scoring system was developed wherein one point was assigned for each of the risk factors. HBV reactivation occurred more frequently in the high-risk group (score ≥ 2) than in the low-risk group (hazards ratio, 14.17; P < 0.001). ETV exhibited superior prophylactic efficacy over LdT or LAM in the high-risk group, whereas no significant difference was noted in the low-risk group. The prognostic scoring system was useful for risk stratification of chemotherapy-related HBV reactivation. High genetic barrier agents appear to be vital for high-risk patients, whereas cost-effectiveness may be more relevant for low-risk patients.

Naphthalene Derivatives End-Capped with 2-(Diphenylamino)-9,9-Diethylfluorenes for Blue Organic Light-Emitting Diodes.

To investigate the electroluminescent (EL) properties of fluorescent materials based on fluorene-substituted naphthalene, multilayered OLEDs with the following sequence; indium- tin-oxide (ITO)/N,N'-di(1-naphthyl)-N,N'-diphenyl-(1,1'-biphenyl)-4,4'-diamine (NPB) (50 nm)/Blue emitting materials (30 nm)/4,7-diphenyl-1,10-phenanthroline (Bphen) (30 nm)/lithium quinolate (Liq) (2 nm)/Al (100 nm) were fabricated using these materials as emitters. These devices exhibited blue emissions. Particularly, a device using 7-(1-(1-(2-(diphenylamino)-9,9-diethyl-9H-fluoren-7- yl)naphthalen-4-yl)naphthalen-4-yl)-9,9-diethyl-N,N-diphenyl-9H-fluoren-2-amine as a blue emitting material exhibited blue emission with a luminous efficiency, a power efficiency, an external quantum efficiency, and CIE coordinates of 2.79 cd/A, 1.19 lm/W, 2.30% at 1,000 cd/m2, and (0.14, 0.12) at 8.0 V, respectively. This study demonstrates that 2-(Diphenylamino)-9,9-diethylfluorenes endcapped naphthalene derivatives have the excellent properties for blue emitting materials for OLEDs.

Synthesis and Electroluminescent Properties of Quinoline-Substituted Anthracene Derivatives for Organic Light-Emitting Diodes.

In this study, two anthracene derivatives with quinoline moieties were synthesized. To investigate their electroluminescent (EL) properties, multilayered OLEDs with the following sequence; indiumtin-oxide (ITO)/N, N'-di(1-naphthyl)-N, N'-diphenyl-(1,1'-biphenyl)-4,4'-diamine (NPB) (20 nm)/Blue emitting materials (30 nm)/bathophenanthroline (Bphen) (30 nm)/lithium quinolate (Liq) (2 nm)/Al (100 nm) were fabricated using these materials as emitters. Two devices exhibited EL in blue to sky-blue regions. Especially, a device using 2,3-diphenyl-6-(10-(naphthalen-7-yl)anthracen-9-yl)quinoline (1) as an emitting material exhibited blue emission with a luminous efficiency, a power efficiency, an external quantum efficiency, and Commission International de L'Eclairage (CIE) coordinates of 1.01 cd/A, 0.43 lm/W, 0.80% at 20 mA/cm2, and (0.17, 0.22) at 6.0 V, respectively.

Efficient Organic Light-Emitting Diodes Based on Naphthoanthracene Derivatives.

In this study, we designed and synthesized emitting materials based on naphthoanthracene derivatives. Organic Light Emitting-Diodes (OLEDs) devices using each four materials were fabricated. All devices showed efficient emissions. In particular, a device using 1-(5,5-Dimethyl-9-phenyl-[5H-naphth[3,2,1-de]anthracen-3-yl])-1H-indole as an emitter at 20 mA/cm2 exhibited luminous efficiency, power efficiency, and external quantum efficiency of 6.51 cd/A, 4.19 lm/W, and 2.48%, respectively, with Commission Internationale d'Énclairage (CIE) coordinates of (0.19, 0.49) at 7.0 V.

Activation of ER Stress-Dependent miR-216b Has a Critical Role in Salviamiltiorrhiza Ethanol-Extract-Induced Apoptosis in U266 and U937 Cells.

Although Salviamiltiorrhiza has been reported to have anti-cancer mechanisms, such as caspase activation, cell cycle arrest, an anti-angiogenesis effect, and Bcl-2 family regulation, its underlying mechanism of endoplasmic reticulum (ER) stress-mediated apoptosis has never been demonstrated. Thus, in this current study, ER stress-related apoptosis via miR-216b of the ethanol extract of Salviamiltiorrhiza (SM) is elucidated for the first time. SM treatment inhibited the viability of U266 and U937 cells in a concentration-dependent manner. However, SM-exposed Raw264.7 cells were intact compared to U266 or U937 cells. Treatment with SM significantly elevated the generation of reactive oxygen species (ROS). The anti-proliferative effect of SM was reversed by pretreatment with the ROS scavenger, N-acetyl-l-cysteine (NAC), compared to cells treated only with SM. Also, SM treatment increased the ER stress by elevation of phosphorylated activating transcription factor 4 (p-ATF4), phosphorylated eukaryotic Initiation Factor 2 (p-eIF2), and phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK) expression. Caspase-3 and Poly (ADP-ribose) polymerase (PARP) were cleaved and CCAAT-enhancer-binding protein homologous protein (CHOP) was activated by SM treatment. PARP cleavage and CHOP activation were attenuated by NAC pretreatment. Furthermore, SM increased the tumor suppressor, miR-216b, and suppressed its target, c-Jun. miR-216b inhibitor attenuated the apoptotic effect of SM. Taken together, SM treatment induced apoptosis through regulation of miR-216b and ROS/ER stress pathways. SM could be a potential drug for treatment of multiple myeloma and myeloid leukemia.

The Suppressive Effects of Cinnamomi Cortex and Its Phytocompound Coumarin on Oxaliplatin-Induced Neuropathic Cold Allodynia in Rats.

Oxaliplatin, a chemotherapy drug, induces acute peripheral neuropathy characterized by cold allodynia, spinal glial activation and increased levels of pro-inflammatory cytokines. Herein, we determined whether Cinnamomi Cortex (C. Cortex), a widely used medicinal herb in East Asia for cold-related diseases, could attenuate oxaliplatin-induced cold allodynia in rats and the mechanisms involved. A single oxaliplatin injection (6 mg/kg, i.p.) induced significant cold allodynia signs based on tail immersion tests using cold water (4 °C). Daily oral administration of water extract of C. Cortex (WECC) (100, 200, and 400 mg/kg) for five consecutive days following an oxaliplatin injection dose-dependently alleviated cold allodynia with only a slight difference in efficacies between the middle dose at 200 mg/kg and the highest dose at 400 mg/kg. WECC at 200 mg/kg significantly suppressed the activation of astrocytes and microglia and decreased the expression levels of IL-1ß and TNF in the spinal cord after injection with oxaliplatin. Furthermore, oral administration of coumarin (10 mg/kg), a major phytocompound of C. Cortex, markedly reduced cold allodynia. These results indicate that C. Cortex has a potent anti-allodynic effect in oxaliplatin-injected rats through inhibiting spinal glial cells and pro-inflammatory cytokines. We also suggest that coumarin might play a role in the anti-allodynic effect of C. Cortex.

Tenofovir monotherapy versus tenofovir plus lamivudine or telbivudine combination therapy in treatment of lamivudine-resistant chronic hepatitis B.

Tenofovir disoproxil fumarate (TDF) monotherapy is a therapeutic option for chronic hepatitis B (CHB) patients infected with hepatitis B virus (HBV) variants resistant to lamivudine (LAM). We evaluated the antiviral efficacy and safety of TDF alone compared to those of TDF plus LAM or telbivudine (LdT) combination in patients harboring HBV variants with genotypic resistance to LAM. This multicenter retrospective study included consecutive patients who had LAM-resistant HBV variants and were treated with TDF alone (monotherapy group) or TDF combined with LAM or LdT (combination therapy group) for at least 6 months. Inverse probability of treatment weighting (IPTW) for the entire cohort was applied to control for treatment selection bias. Overall, 153 patients (33 in the monotherapy group and 120 in the combination therapy group) were analyzed. The overall probability of achieving complete virologic suppression at month 12 was 91.6%: 88.6% in the monotherapy group and 92.6% in the combination therapy group. Combination therapy was not superior to monotherapy in viral suppression before and after IPTW (P=0.562 and P=0.194, respectively). Hepatitis B e antigen (HBeAg) loss, biochemical response, and virologic breakthrough did not differ between treatment groups. The probabilities of complete virologic suppression were comparable between treatment groups in the subsets according to HBeAg status and HBV DNA levels at baseline. No patient experienced any significant renal dysfunction during the treatment period. In conclusion, TDF monotherapy has antiviral efficacy comparable to that of TDF plus LAM or LdT combination therapy, with a favorable safety profile in CHB patients with LAM-resistant HBV variants.

Prognostic indicators for radiotherapy of abdominal lymph node metastases from hepatocellular carcinoma.

PURPOSE: To identify prognostic indicators in patients treated with radiotherapy (RT) for metastases from hepatocellular carcinoma (HCC) in abdominal lymph nodes (LNs). PATIENTS AND METHODS: RT was used to treat 65 patients for metastases from HCC in abdominal LNs. Total radiation dose was 30-60 Gy (median 52.8 Gy), with fraction size 1.8-3 Gy. RT was administered five times per week to an equivalent dose in 2-Gy fractions (EQD2; Gy10) of 32.5-65 Gy10 (median 54 Gy10) and an α/ßratio for tumor and acute effects of normal tissue of 10. RESULTS: Median overall survival (OS) in all patients was 8.1 months. LN responders had significantly higher median OS than nonresponders (14.5 vs. 3.7 months, p < 0.05). Multivariate analysis showed that Child-Pugh classification, status of intrahepatic tumor, number of metastatic LNs, and LN response were independently predictive of OS (p < 0.05 each). Based on results of multivariate analysis, patients were prognostically stratified according to pretreatment risk factors, including Child-Pugh classification, intrahepatic tumor status, and number of metastatic LNs; with the expected median OS in patients with ≥ 2, 1, and 0 risk factors being 2.9, 9.8, and 27.6 months, respectively (p < 0.05). CONCLUSION: Our data showed that LN response to RT was an independent prognostic factor for OS in advanced HCC patients with abdominal LN metastases, and suggested that RT for metastatic LNs might improve OS in these patients. In addition, our data suggest that Child-Pugh classification, intrahepatic tumor status, and number of metastatic LNs may be useful prognostic and therapeutic indicators for selecting treatment strategies.

Use of rhamnolipid biosurfactant for membrane biofouling prevention and cleaning.

Rhamnolipids were evaluated as biofouling reducing agents in this study. The permeability of the bacterial outer membrane was increased by rhamnolipids while the growth rate of Pseudomonas aeruginosa was not affected. The surface hydrophobicity was increased through the release of lipopolysaccharides and extracellular polymeric substances from the outer cell membrane. Rhamnolipids were evaluated as agents for the prevention and cleaning of biofilms. A high degree of biofilm detachment was observed when the rhamnolipids were used as a cleaning agent. In addition, effective biofilm reduction occurred when rhamnolipids were applied to various species of Gram-negative bacteria isolated from seawater samples. Biofilm reduction using rhamnolipids was comparable to commercially available surfactants. In addition, 20% of the water flux was increased after rhamnolipid treatment (300 µg ml(-1), 6 h exposure time) in a dead-end filtration system. Rhamnolipids appear to have promise as biological agents for reducing membrane biofouling.

Simultaneous integrated boost-intensity modulated radiation therapy for inoperable hepatocellular carcinoma.

PURPOSE: The aim of this work was to evaluate the clinical efficacy and safety of simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) in patients with inoperable hepatocellular carcinoma (HCC). METHODS AND MATERIALS: A total of 53 patients with inoperable HCC underwent SIB-IMRT using two dose-fractionation schemes, depending on the proximity of gastrointestinal structures. The 41 patients in the low dose-fractionation (LD) group, with internal target volume (ITV) < 1 cm from gastrointestinal structures, received total doses of 55 and 44 Gy in 22 fractions to planning target volume 1 (PTV1) and 2 (PTV2), respectively. The 12 patients in the high dose-fractionation (HD) group, with ITV ≥ 1 cm from gastrointestinal structures, received total doses of 66 and 55 Gy in 22 fractions to the PTV1 and PTV2, respectively. RESULTS: Overall, treatment was well tolerated, with no grade > 3 toxicity. The LD group had larger sized tumors (median: 6 vs. 3.4 cm) and greater frequencies of vascular invasion (80.6 vs. 16.7 %) than patients in the HD group (p < 0.05 each). The median overall survival (OS) was 25.1 mKonzept ist machbar und sicheronths and the actuarial 2-year local progression-free survival (LPFS), relapse-free survival (RFS), and OS rates were 67.3, 14.7, and 54.7 %, respectively. The HD group tended to show better tumor response (100 vs. 62.2 %, p = 0.039) and 2-year LPFS (85.7 vs. 59 %, p = 0.119), RFS (38.1 vs. 7.3 %, p = 0.063), and OS (83.3 vs. 44.3 %, p = 0.037) rates than the LD group. Multivariate analysis showed that tumor response was significantly associated with OS. CONCLUSION: SIB-IMRT is feasible and safe for patients with inoperable HCC.