Prognostic Impact of Visceral Adipose Tissue Imaging Parameters in Patients with Cholangiocarcinoma after Surgical Resection.

Visceral adiposity is known to be related to poor prognosis in patients with cholangiocarcinoma; however, the prognostic significance of the qualitative features of adipose tissue in cholangiocarcinoma has yet to be well defined. This study investigated the prognostic impact of adipose tissue imaging parameters reflecting the quantity and qualitative characteristics of subcutaneous (SAT) and visceral (VAT) adipose tissue on recurrence-free survival (RFS) and overall survival (OS) in 94 patients undergoing resection of cholangiocarcinoma. The area, mean computed tomography (CT) attenuation, and mean 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake of SAT and VAT on positron emission tomography (PET)/CT for staging work-up were measured, and the relationship of these adipose tissue imaging parameters with clinicopathological factors and survival was assessed. TNM stage, histologic grade, lymphovascular invasion, and the size of cholangiocarcinoma showed positive correlations with adipose tissue imaging parameters. Multivariate survival analysis demonstrated that the visceral-to-subcutaneous adipose tissue area ratio (VSR) (p = 0.024; hazard ratio, 1.718) and mean FDG uptake of VAT (p = 0.033; hazard ratio, 9.781) were significant predictors for RFS, but all of the adipose tissue imaging parameters failed to show statistical significance for predicting OS. In addition to visceral adiposity, FDG uptake of VAT might be a promising prognostic parameter for predicting RFS in patients with cholangiocarcinoma.

Comparative Clinical Evaluation of NeoPlex RB-8 with Seeplex PneumoBacter ACE for Simultaneous Detection of Eight Respiratory Bacterial Pathogens.

There are several convenient and accurate molecular assays to detect respiratory bacterial infection. The NeoPlex RB-8 detection kit (NeoPlex RB-8) is a new multiplex real-time PCR assay that simultaneously detects Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, Haemophilus influenzae, Bordetella pertussis, Bordetella parapertussis, and Moraxella catarrhalis in a single test. This study compared the clinical concordance of NeoPlex RB-8 with another method, Seeplex PneumoBacter ACE detection assay (Seeplex PB ACE), which simultaneously detects S. pneumoniae, M. pneumoniae, C. pneumoniae, L. pneumophila, H. influenzae, and B. pertussis We tested 2,137 nasopharyngeal swab and sputum specimens using both assays. For discordant Bordetella parapertussis and M. catarrhalis specimens, we also performed bidirectional sequencing. For S. pneumoniae, M. pneumoniae, C. pneumoniae, L. pneumophila, H. influenzae, and B. pertussis, which are detected by both NeoPlex RB-8 and Seeplex PB ACE, the positive and negative agreement between the two assays ranged from 91.7 to 100% (κ = 0.918 to 1). S. pneumoniae and H. influenzae were the most discordant targets and measured with higher sensitivity and specificity by NeoPlex RB-8 than Seeplex PB ACE. For Bordetella parapertussis and M. catarrhalis, which are not detected by Seeplex PB ACE, NeoPlex RB-8 sensitivity and specificity were >99%. Overall, NeoPlex RB-8 was highly comparable to Seeplex PB ACE, but NeoPlex RB-8 was more clinically accurate, with higher throughput and more convenience.

Triticum aestivum ethanolic extract improves non-alcoholic fatty liver disease in mice fed a choline-deficient or high-fat diet.

BACKGROUND: Although non-alcoholic fatty liver disease (NAFLD) has become more prevalent with the rapid increase of obesity worldwide, no specific treatment has been developed. Several studies have shown that wheatgrass extract Triticum aestivum (TA) improves lipid metabolism. In the present study, we evaluated the efficacy of GM-T (an ethanolic TA extract) in a murine NAFLD model. Mice were separated into 12 groups (n = 10): two groups of normal diet, choline-deficient diet (CDD) or high-fat diet (HFD) with vehicle, CCD or HFD with silymarin (400 mg kg-1 day-1 ), and CCD or HFD with GM-T (100, 200 or 400 mg kg-1 day-1 ). The study was performed for 8 weeks for the CDD groups and 12 weeks for the HFD groups. RESULTS: In the CDD-fed mice, GM-T improved serum liver enzyme activities and liver inflammation score compared to vehicle. In the HFD-fed mice, GM-T improved blood lipid profiles, liver inflammation score, steatosis score and obesity compared to vehicle. CONCLUSION: The present study demonstrated that GM-T effectively improved NAFLD in mice via a mechanism that improved insulin resistance and lipid metabolism, suggesting the possibility of a functional dietary supplement to improve liver health, overall metabolic syndrome and obesity. © 2018 Society of Chemical Industry.

Hepatic FDG uptake is associated with future cardiovascular events in asymptomatic individuals with non-alcoholic fatty liver disease.

BACKGROUND: Hepatic F-18 fluoro-2-deoxyglucose (FDG) uptake is associated with non-alcoholic fatty liver disease (NAFLD) which is an independent risk factor for cardiovascular disease. However, the value of hepatic FDG uptake for predicting future cardiovascular events has not been explored. METHODS AND RESULTS: Study participants were 815 consecutive asymptomatic participants who underwent a health screening program that included FDG positron emission tomography/computed tomography (PET/CT), abdominal ultrasonography, and carotid intima-media thickness (CIMT) measurements (age 51.8 ± 6.0 year; males 93.9%). We measured hepatic FDG uptake and assessed the prognostic significance of this parameter with other cardiovascular risk factors including Framingham risk score and CIMT. Multivariate Cox proportional hazards analyses including all study participants revealed that NAFLD with high-hepatic FDG uptake was the only independent predictor for future cardiovascular events [hazard ratio (HR) 4.23; 95% CI 1.05-17.04; P = .043). Subgroup analysis conducted in the NAFLD group showed that high-hepatic FDG uptake was a significant independent predictor of cardiovascular events (HR 9.29; 95% CI 1.05-81.04; P = .045). CONCLUSIONS: This exploratory study suggests that high-hepatic FDG uptake may be a useful prognostic factor for cardiovascular events in individuals with NAFLD.

Analysis of HBV genotype, drug resistant mutations, and pre-core/basal core promoter mutations in Korean patients with acute hepatitis B.

Acute hepatitis B, caused by hepatitis B virus (HBV) strains with drug resistant mutations or pre-core/basal core promoter (PC/BCP) mutations, is a public health concern, because this infection is often associated with poor disease outcome or difficulty in therapeutic choice. The HBV genotype, the prevalence of drug resistant mutations, and PC/BCP mutations in Korean patients with acute hepatitis B were studied. From 2006 to 2008, 36 patients with acute hepatitis B were enrolled prospectively in four general hospitals. Among them, 20 showed detectable HBV DNA (median value was 4.8 log copies/mL). HBV genotyping and analysis of HBV mutations that conferred resistance against lamivudine, adefovir, or entecavir and of PC/BCP mutations were performed using highly sensitive restriction fragment mass polymorphism (RFMP) analysis. All 20 patients were infected with HBV genotype C, which causes almost all cases of chronic hepatitis B in Korea. No patient showed mutations that conferred resistance against lamivudine (L180M, M204V/I), adefovir (A181T, N236S), or entecavir (I169M, A184T/V, S202I/G, M250V/I/L). However, four patients had BCP mutations, and two had PC mutations. Platelet counts were significantly lower in the four patients with PC/BCP mutations compared to those with wild type. In this study, all acute hepatitis B patients had genotype C HBV strains with no drug resistant mutations. However, 20% showed PC/BCP mutations. This highlights the need for further study on the significance of PC/BCP mutations.

Anti-obesity effect of Triticum aestivum sprout extract in high-fat-diet-induced obese mice.

Obesity is a common disease worldwide that often results in serious conditions including hypertension, diabetes, and hyperlipidemia. Many herbal medicines have been examined with regard to ameliorating obesity. We investigated the anti-obesity effects of 50% EtOH extract of Triticum aestivum sprout (TAEE) in high-fat-diet (HFD)-induced obese mice. TAEE administration (10, 50, or 200 mg/kg) for 6 weeks significantly decreased the body weights, serum total cholesterol (TC), and low-density lipoprotein cholesterol levels in HFD-fed mice. TAEE treatment reduced lipid accumulation in epididymal white adipose tissue (EWAT) and liver. Moreover, TC and lipid levels were decreased by TAEE treatment in liver. Serum leptin and adiponectin concentrations were reduced by TAEE treatment. TAEE-treated mice showed decreases in peroxisome proliferator-activated receptor γ (PPARγ) and fatty acid synthase expression in EWAT. Furthermore, TAEE administration elevated levels of PPARα protein in the liver of HFD-induced obese mice. These results suggest that TAEE supplementation might be beneficial for the treatment and prevention of obesity and related diseases.

Adefovir and lamivudine combination therapy in patients with entecavir-resistant chronic hepatitis B: antiviral responses and evolution of mutations.

OBJECTIVE: This study was designed to prospectively evaluate the antiviral responses and evolution of resistance mutations during adefovir (ADV) plus lamivudine (LMV) therapy in patients with entecavir (ETV)-resistant hepatitis B virus (HBV) infection. METHODS: Twenty chronic hepatitis B (CHB) patients who had been receiving ETV for more than 6 months and developed virologic breakthrough due to ETV resistance were consecutively enrolled. RESULTS: Patients received ADV plus LMV therapy for 12 months. The baseline mean serum HBV DNA level was 5.59 ± 1.28 log10 IU/ml. The rtT184L/I/A/F (50%), rtS202G (25%) and mixed ETV-resistant mutations (25%) were detected at enrollment. The mean reduction in serum HBV DNA levels from baseline to 12 months was -2.3 ± 1.06 log10 IU/ml (p < 0.001). Seventeen patients were followed up for the full 12 months, and complete virologic response (HBV DNA <20 IU/ml) was observed in 4 patients (23.5%). Among the remaining 13 patients who still had detectable HBV DNA, 7 patients showed disappearance of ETV-resistant mutations or reduction of the proportion of ETV-resistant mutants. An ADV- and LMV-resistant mutant (rtA181T) emerged in 2 patients (11.7%). CONCLUSIONS: ADV plus LMV combination therapy suppresses ETV-resistant mutants in the viral population and significantly reduces serum HBV DNA levels in ETV-resistant CHB patients.

Comparison of digene hybrid capture 2, GeneMatrix PapilloScreen, and a PCR sequencing assay in detecting high-risk and probable high-risk oncogenic HPV genotypes in specimens from Korean women.

Most cervical cancers are caused by 15 high-risk (HR) and three probable high-risk (pHR) oncogenic types of human papillomavirus (HPV). However, current commercial HR HPV screening test products do not include pHR HPV genotypes. Recently, PapilloScreen has been developed to detect the 15 HR and three pHR HPV types. In this study, we evaluated the concordance levels and clinical performance of Hybrid Capture 2 (HC2), PapilloScreen, and a PCR sequencing assay in detecting HR and pHR HPV. The PapilloScreen (96.8 %) and PCR sequencing assay (96.8 %) demonstrated higher sensitivity than HC2 (80.7 %) for detecting HR and pHR HPV. The three assays showed similar specificities and positive or negative predictive values. The concordance levels were 86.5 % (κ = 0.68) and 86.5 % (κ = 0.67) between HC2 and PapilloScreen and between HC2 and PCR sequencing, respectively. A near-perfect concordance was observed between PapilloScreen and PCR sequencing (97.8 %, κ = 0.95). Overall, the agreement between the three assays suggests that the results obtained by the HC2 assay are more often discordant (12.6 %) than the PCR-based tests. In conclusion, PapilloScreen is highly sensitive for detecting high-grade CIN or cervical cancer. The PapilloScreen assay should be considered an accurate and sensitive method for detecting HR and pHR HPV infections and an epidemiological tool for prevalence studies as well as early diagnosis and intervention in HR and pHR HPV infections.

Hepatic glucose uptake is increased in association with elevated serum γ-glutamyl transpeptidase and triglyceride.

BACKGROUND: Subjects with fatty liver disease (FLD) can show increased hepatic 2-deoxy-2-((18)F)fluoro-D-glucose (FDG) uptake, but the role of hepatic inflammation has not been explored. AIMS: We investigated whether hepatic inflammatory response, as implicated by elevated serum markers, is associated with increased liver FDG uptake in FLD. METHODS: Liver sonography and FDG positron emission tomography was performed in 331 asymptomatic men with nonalcoholic FLD (NAFLD), 122 with alcoholic FLD (AFLD), and 349 controls. Mean standard uptake value (SUV) of liver FDG uptake was compared to cardiac risk factors and serum markers of liver injury. RESULTS: Hepatic FDG mean SUV was increased in NAFLD (2.40 ± 0.25) and AFLD groups (2.44 ± 0.25) compared to controls (2.28 ± 0.26; both P < 0.001). Both FLD groups also had higher serum γ-glutamylranspeptidase (GGT), triglyceride (TG), hepatic transaminases, and LDL. High GGT and TG levels were independent determinants of increased FDG uptake for both FLD groups. Hepatic mean SUV significantly increased with high compared to low GGT for NAFLD (2.48 ± 0.28 vs. 2.37 ± 0.24), AFLD (2.51 ± 0.27 vs. 2.39 ± 0.23), and control groups (2.39 ± 0.22 vs. 2.26 ± 0.26). High TG increased hepatic mean SUV in AFLD and control groups. Furthermore, serum GGT and TG levels significantly correlated to hepatic mean SUV in all three groups. CONCLUSIONS: Hepatic FDG uptake is closely associated with elevated TG and GGT regardless of the presence of FLD. Thus, inflammation response may play a major role in increased hepatic glucose uptake.

Prognostic value of 18F-FDG PET/CT in patients with soft tissue sarcoma: comparisons between metabolic parameters.

OBJECTIVES: To investigate the relationship between volume-based PET parameters and prognosis in patients with soft tissue sarcoma (STS). METHODS: We retrospectively reviewed 55 patients with pathologically proven STS who underwent pretreatment with (18) F-Fluorodeoxyglucose ((18)F-FDG) PET/CT. The maximum standardized uptake value (SUVmax), average SUV (SUVavg), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of primary tumors were measured using a threshold SUV as liver activity for determining the boundary of tumors. Univariate and multivariate survival analyses for overall survival were performed according to the metabolic parameters and other clinical variables. RESULTS: Cancer-related death occurred in 19 of 55 patients (35 %) during the follow-up period (29 ± 23 months). On univariate analysis, AJCC stage (stage IV vs. I-III, hazard ratio (HR) = 2.837, p = 0.028), necrosis (G2 vs. G0-G1, HR = 3.890, p = 0.004), SUVmax (1 unit - increase, HR = 1.146, p = 0.008), SUVavg (1 unit - increase, HR = 1.469, p = 0.032) and treatment modality (non-surgical therapy vs. surgery, HR = 4.467, p = 0.002) were significant predictors for overall survival. On multivariate analyses, SUVmax (HR = 1.274, p = 0.015), treatment modality (HR = 3.353, p = 0.019) and necrosis (HR = 5.985, p = 0.006) were identified as significant independent prognostic factors associated with decreased overall survival. CONCLUSIONS: The SUVmax of the primary tumor is a significant independent metabolic prognostic factor for overall survival in patients with STS. Volume-based PET parameters may not add prognostic information outside of the SUVmax.

Relationship of FDG PET/CT imaging features with tumor immune microenvironment and prognosis in colorectal cancer: a retrospective study.

BACKGROUND: Imaging features of colorectal cancers on 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) have been considered to be affected by tumor characteristics and tumor immune microenvironment. However, the relationship between PET/CT imaging features and immune reactions in tumor tissue has not yet been fully evaluated. This study investigated the association of FDG PET/CT imaging features in the tumor, bone marrow, and spleen with immunohistochemical results of cancer tissue and recurrence-free survival (RFS) in patients with colorectal cancer. METHODS: A total of 119 patients with colorectal cancer who underwent FDG PET/CT for staging work-up and received curative surgical resection were retrospectively enrolled. From PET/CT images, 10 first-order imaging features of primary tumors, including intensity of FDG uptake, volumetric metabolic parameters, and metabolic heterogeneity parameters, as well as FDG uptake in the bone marrow and spleen were measured. The degrees of CD4+, CD8+, and CD163 + cell infiltration and interleukin-6 (IL-6) and matrix metalloproteinase-11 (MMP-11) expression were graded through immunohistochemical analysis of surgical specimens. The relationship between FDG PET/CT imaging features and immunohistochemical results was assessed, and prognostic significance of PET/CT imaging features in predicting RFS was evaluated. RESULTS: Correlation analysis with immunohistochemistry findings showed that the degrees of CD4 + and CD163 + cell infiltration and IL-6 and MMP-11 expression were correlated with cancer imaging features on PET/CT. Patients with enhanced inflammatory response in cancer tissue demonstrated increased FDG uptake, volumetric metabolic parameters, and metabolic heterogeneity. FDG uptake in the bone marrow and spleen was positively correlated with the degree of CD163 + cell infiltration and IL-6 expression, respectively. In multivariate survival analysis, the coefficient of variation of FDG uptake in the tumor (p = 0.019; hazard ratio, 0.484 for 0.10 increase) and spleen-to-liver uptake ratio (p = 0.020; hazard ratio, 24.901 for 1.0 increase) were significant independent predictors of RFS. CONCLUSIONS: The metabolic heterogeneity of tumors and FDG uptake in the spleen were correlated with tumor immune microenvironment and showed prognostic significance in predicting RFS in patients with colorectal cancer.

Prognostic Significance of the Bone Marrow-to-Aorta Uptake Ratio on 2-Deoxy-2-[18F]fluoro-d-glucose Positron Emission Tomography/Computed Tomography in Patients with Cholangiocarcinoma.

2-Deoxy-2-[18F]fluoro-d-glucose (FDG) uptake of the reticuloendothelial system on positron emission tomography/computed tomography (PET/CT) is known to be related to systemic inflammatory response to cancer cells in patients with diverse malignancies. This retrospective study aimed to investigate whether FDG uptake by the reticuloendothelial system had a prognostic value in predicting progression-free survival (PFS) and overall survival (OS) in 138 cholangiocarcinoma patients. Quantifying FDG uptake of the aorta, bone marrow (BM), liver, and spleen from staging FDG PET/CT images, we found significant correlations between the BM-to-aorta uptake ratio (BAR), spleen-to-aorta uptake ratio, and BM-to-liver uptake ratio with tumor stage and serum inflammatory markers. In the multivariate survival analysis, BAR was an independent predictor of PFS (p = 0.016; hazard ratio, 2.308) and OS (p = 0.030; hazard ratio, 2.645). Patients with stages III-IV of the disease and a high BAR exhibited low 1-year PFS (35.8%) and OS (60.2%) rates, while those with stages I-II of the disease and low BAR showed robust rates of 90.0% and 96.7%, respectively. BAR measured on staging FDG PET/CT might be a potential imaging biomarker offering insights into the systemic inflammatory response and predicting prognosis in cholangiocarcinoma. This study highlights BAR as a promising, independent predictor with potential for personalized prognostication and treatment strategies.

Multidrug-resistant hepatitis B virus resulting from sequential monotherapy with lamivudine, adefovir, and entecavir: clonal evolution during lamivudine plus adefovir therapy.

Whether multidrug-resistant (MDR) hepatitis B virus (HBV) harbors mutations co-located in the same HBV clones that confer reduced sensitivity to antiviral therapy remains uncertain. This study investigated the evolution of MDR HBV strains developed from sequential monotherapy with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) during LAM plus ADV salvage therapy. Sera were obtained from six patients who had developed sequential resistance to LAM, ADV, and ETV before and during LAM plus ADV therapy. The HBV genomes from each patient were amplified, cloned, and sequenced. Among 6 sets of 20 clones obtained before salvage therapy, all clones harbored the rtM204V mutation, and ETV-resistant mutations were detected with the rtM204V in 108 clones. The rtA181 mutation was not detected at baseline, but emerged in five patients during therapy. Among 9 sets of 20 clones obtained during salvage therapy, 39 clones harbored rtA181T/V ± rtN236T mutations, which were detected in the absence of rtM204 and ETV-resistant mutations in 37 clones (94.9%). Only two clones (5.1%) harbored both rtA181T/V and ETV-resistant mutations. The rtA181T/V mutation emerged after reversion from ETV-resistant mutants to wild-type HBV. Five patients achieved a partial virologic response to LAM plus ADV therapy. In conclusion, the majority of MDR mutations existed in different genomes. Suboptimal response to LAM plus ADV therapy may not result from the co-localization of MDR HBV mutations in the same genome, but instead the low antiviral potency of these drugs. Thus, more potent antiviral drug combinations may be an effective salvage therapy for patients infected with MDR HBV.

Adding adefovir vs. switching to entecavir for lamivudine-resistant chronic hepatitis B (ACE study): a 2-year follow-up randomized controlled trial.

BACKGROUND: Management of lamivudine-resistant chronic hepatitis B (CHB) remains challenging, as inappropriate choice of treatment may cause multidrug resistance. Until now, randomized trials directly comparing adding adefovir and switching to entecavir monotherapy have not been reported. AIMS: This multicentre prospective randomized study was designed to compare the efficacy of these two strategies. METHODS: Two hundred and nineteen lamivudine-resistant CHB patients were randomized to either adefovir-lamivudine combination group or entecavir monotherapy group (n = 110 vs. 109), and followed up for 24 months. RESULTS: One hundred and eighty patients completed this study. At month 24, virological response rate [hepatitis B virus (HBV) DNA <60 IU/ml] was higher in the adefovir-lamivudine combination group compared with entecavir group (56.7% vs. 40%, P = 0.025), although biochemical and serological response rates were not significantly different. Genotypic resistance (9.2% vs. 24.6%, P = 0.005) and combined viral breakthrough (2.0% vs. 17.6%, P < 0.001) were more frequent in the entecavir group. However, by subgroup analysis, virological response rates were not significantly different between the two therapies in HBeAg-positive patients (44.9% vs. 35.7%, P = 0.268) or in patients with high baseline HBV DNA (≥7 log IU/ml) (40.7% vs. 31.3%, P = 0.320) at month 24. CONCLUSION: This study showed that adefovir-lamivudine combination provides significantly higher antiviral efficacy and the lower resistance rate compared with the entecavir monotherapy in the management of lamivudine-resistant CHB. However, it had limited efficacy in HBeAg-positive patients or in patients with high baseline HBV DNA.

Treatment of lamivudine-resistant chronic hepatitis B infection: a multicenter retrospective study.

OBJECTIVES: To compare the efficacy of rescue therapies in lamivudine (LAM)-resistant chronic hepatitis B (CHB) infections including: (1) adefovir dipivoxil (ADV) monotherapy, (2) ADV plus LAM combination therapy and (3) entecavir (ETV) 1.0 mg monotherapy. MATERIALS AND METHODS: The authors designed a multicenter-retrospective study. Eight institutions participated in the study from Korea. RESULTS: A total of 343 LAM-resistant CHB patients were enrolled. The proportion of patients with undetectable serum hepatitis B virus (HBV) DNA levels at month 24 after the initiation of rescue therapy was higher in the ADV plus LAM combination therapy group (39/64, 60.9%) than in the ADV monotherapy (50/126, 39.7%) and ETV 1.0 mg monotherapy (19/48, 39.6%) groups (p = 0.014). Mean serum HBV DNA levels at 24 months were 2.07 ± 1.21 log(10) IU/ml in the ADV plus LAM combination therapy group, 2.74 ± 1.74 log(10) IU/ml in the ADV monotherapy group and 3.08 ± 1.97 log(10) IU/ml in the ETV 1.0 mg monotherapy group (p = 0.014). In multivariate analysis, a finding of undetectable serum HBV DNA level at 6 months and ADV plus LAM combination therapy (vs. ADV) was an independent factor for predicting undetectable serum HBV DNA at month 24 (odds ratio, 1.003; 95% confidence interval, 1.000-1.006; p = 0.026). CONCLUSIONS: ADV plus LAM combination therapy is more effective in reducing viral load than switching to ADV or ETV 1.0 mg in patients with LAM-resistant CHB.

Evaluating the Necessity of Adaptive RT and the Role of Deformable Image Registration in Lung Cancer with Different Pathologic Classifications.

BACKGROUND: This study aimed to analyze differential radiotherapy (RT) responses according to the pathological type of lung cancer to see the possibility of applying adaptive radiotherapy (ART). METHODS: ART planning with resampled-computed tomography was conducted for a total of 30 patients (20 non-small-cell lung cancer patients and 10 small-cell lung cancer patients) using a deformable image registration technique to reveal gross tumor volume (GTV) changes according to the duration of RT. RESULTS: The small-cell lung cancer group demonstrated an average GTV reduction of 20.95% after the first week of initial treatment (p = 0.001), whereas the adenocarcinoma and squamous cell carcinoma groups showed an average volume reduction of 20.47% (p = 0.015) and 12.68% in the second week. The application of ART according to the timing of GTV reduction has been shown to affect changes in radiation dose irradiated to normal tissues. This suggests that ART applications may have to be different depending on pathological differences in lung cancer. CONCLUSION: Through these results, the present study proposes the possibility of personalized treatment options for individual patients by individualizing ART based on specific radiation responses by pathologic types of lung cancer.

Mutational complex genotype of the hepatitis B virus X /precore regions as a novel predictive marker for hepatocellular carcinoma.

This study explored the combined effect of number and pattern of mutations in the X/precore regions of the hepatitis B virus (HBV) genome, mutational complex genotype (MCG), on hepatocellular carcinoma (HCC) development. Sequence variations were determined by direct sequencing and multiplex restriction fragment mass polymorphism analysis in 150 age-, sex- and hepatitis B e antigen (HBeAg) status-matched patients with and without HCC. In addition, a longitudinal study and an external validation of MCG were conducted. All were HBV subgenotype C2. Eight high-frequency mutations (G1613A, C1653T, T1753V, A1762T, G1764A, A1846T, G1896A and G1899A) were significantly associated with HCC. Whereas C1653T, T1753V, G1764A and A1846T were independent mutational factors for HCC, the significance of these individual mutations was negligible when analyzed with all clinico-virological variables. The total number of mutations was the only independent viral factor for HCC, irrespective of HBeAg status. There was a significant dose-risk relationship between the number of mutations and HCC, in which high risks for HCC were associated with mutation numbers ≥ 6. Pattern analysis of the mutations revealed disparity in distribution among the top seven high-risk mutation combination patterns, which accounted for 40 and 2.7% of HCC and non-HCC cases, respectively. The predictive accuracy of the high-risk mutations for HCC was similar to that of α-fetoprotein. Longitudinal and external validation studies also supported the association of mutation number with HCC development. MCG in the HBV X/precore regions is a risk indicator for HCC, and might serve as a new guide to the HCC screening scheme for chronic HBV carriers.

Adefovir-based combination therapy with entecavir or lamivudine for patients with entecavir-refractory chronic hepatitis B.

This study evaluated the efficacy of adefovir (ADV) plus lamivudine (LAM) or ADV add-on therapy for patients with entecavir (ETV)-refractory hepatitis B infection. Twenty-nine ETV-resistant and 8 patients with suboptimal response to ETV were enrolled. Twenty-seven patients received ADV + LAM therapy and 10 patients received ADV + ETV therapy for >24 weeks. In 29 patients who were ETV-resistant, the mean reduction in HBV DNA levels at 24 weeks was not different between the ADV + LAM and ADV + ETV groups (-1.98 log(10) IU/ml vs. -2.16 log(10) IU/ml; P = 0.792). Primary non-response was observed in 52.2% (12/23) of ADV + LAM group and 33.3% (2/6) of ADV + ETV group (P = 0.651). Initial virologic response (IVR) was observed in 17.4% (4/23) of ADV + LAM group and 33.3% (2/6) of ETV + ADV group (P = 0.362). In eight patients with suboptimal response to ETV, the ADV + ETV group had a greater reduction in HBV DNA at 24 and 48 weeks than the ADV + LAM group (-2.29 log(10) IU/ml vs. -0.09 log(10) IU/ml and -2.04 log(10) IU/ml vs. -0.72 log(10) IU/ml; P = 0.020 and P = 0.012, respectively). Primary non-response and IVR did not significantly differ between the two groups [100% (4/4) vs. 50% (2/4) and 0% (0/4) vs. 50% (2/4); P = 0.429 and P = 0.429, respectively]. The antiviral efficacies of ADV-based therapy with ETV or LAM for patients with ETV-resistant hepatitis B were limited and did not differ between the two groups. However, adding ADV to ETV may be more effective than ADV + LAM therapy in patients with suboptimal virologic response to ETV.

Simultaneous emergence of entecavir resistance mutations in a nucleoside-naive chronic hepatitis B patient.

BACKGROUND: Entecavir (ETV) has potent antiviral activity against hepatitis B virus (HBV), and the emergence of drug resistance is rare in nucleoside-naive patients. Resistance requires simultaneous appearance of three mutations which account for the very low resistance profile of ETV. We experienced one case of genotypic ETV resistance with viral rebound during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB). CASE: A 50-year-old HBV e antigen-positive man received ETV 0.5 mg/day for 120 weeks. The level of HBV DNA was 9.0 log(10) copies/ml at baseline, declined to a nadir of 2.7 at week 60 and then rebounded to 6.0 at week 108 and 7.5 at week 120. The serum alanine aminotransferase level did not increase during ETV treatment. The ETV resistance-related substitution (T184A) and lamivudine resistance-related substitutions (L180M and M204V) were detected by sequence analysis at week 96. CONCLUSIONS: The three substitutions associated with ETV and lamivudine resistance developed simultaneously without complete suppression in a nucleoside-naive CHB patient after extended therapy. In spite of the extremely rare chance of viral mutation during ETV treatment, treatment-naive patients with high pretreatment viral loads and detectable HBV DNA during treatment should be carefully monitored or undergo targeted surveillance for resistance.

Analytical and clinical performances of a restriction fragment mass polymorphism assay for detection and genotyping of a wide spectrum of human papillomaviruses.

Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry-based restriction fragment mass polymorphism (RFMP) assay was adapted to human papillomavirus (HPV) genotyping. The analytical sensitivity and the clinical utility were evaluated by testing defined HPV genome equivalents and a total of 426 specimens composed of normal cytology, atypical squamous cells of undetermined significance, low grade squamous intraepithelial lesion, high grade squamous intraepithelial lesion and invasive squamous cell carcinoma. The RFMP assay was able to detect 38.4-114.6 genomic equivalents of a wide variety of HPV types. The RFMP assay detected 34 different HPV genotypes in cervical samples of which 8% were found to be multiple-type infections. The high-risk HPV positivity rate according to the histological diagnosis was 7.9% (8/101), 31.7% (38/120), 50% (55/110), 86% (37/43), 96.2% (50/52) in normal, atypical squamous cells of undetermined significance, low grade squamous intraepithelial lesion, high grade squamous intraepithelial lesion and squamous cell carcinoma subgroups, respectively. Diagnostic sensitivities/specificities for the cervical lesions of squamous cell carcinoma and high grade squamous intraepithelial lesion or worse histology were found to be 96.2%/92.1% and 91.6%/92.1%, respectively. The sensitivity, accuracy, wide range of genotype identification and high-throughput capacity with cost-effectiveness of the test consumables make the RFMP assay suitable for mass screening and monitoring of HPV-associated cervical cancer.