Association between antibiotics use and the risk of rheumatoid arthritis: a retrospective cohort study in South Korea.

OBJECTIVES: Certain studies propose that antibiotic use may influence rheumatoid arthritis (RA) incidence, but the clear association between antibiotics and RA remains unclear. Therefore, this study aimed to examine the relationship between antibiotics and RA risk to provide additional epidemiological evidence. METHODS: This population-based retrospective cohort study was conducted with adults aged 40 years or older using the Korean National Health Insurance Service (NHIS) database. Antibiotic exposure was measured from 2003 to 2007. Study participants were followed up from January 1, 2008, to December 31, 2019. Multivariable Cox hazard regression was utilized to evaluate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the risk of RA according to accumulative days of antibiotic use and the number of antibiotic classes used, respectively. RESULTS: During 3,395 590 person-years of follow-up, 29 274 cases of RA were identified. Participants who used antibiotics for 91 or more days had a higher risk of RA (aHR, 1.79; 95% CI, 1.67-1.92) than antibiotic non-users. Additionally, individuals who used four or more kinds of antibiotic classes had a higher risk of RA (aHR, 1.61; 95% CI, 1.51-1.71) than those who did not prescribe antibiotics. The risk of RA was positively associated with both higher cumulative days of antibiotic exposure and a larger number of drug classes. These trends were maintained in sensitivity analyses, including variations in antibiotic exposure periods. CONCLUSION: Our findings suggest a possible association between the long-term use of antibiotics and RA incidence. Further studies are necessary for a clearer understanding of this association.

Association between antibiotic use and cardiovascular diseases in metabolic dysfunction-associated steatotic liver disease: A nationally representative retrospective cohort study.

AIM: Various subcategories for steatotic liver disease (SLD) were proposed globally. Previous studies suggested a heightened risk of cardiovascular diseases (CVD) with prolonged antibiotic exposure and metabolic dysfunction-associated SLD (MASLD), respectively. This study investigates the impact of antibiotic usage on CVD in MASLD patients. METHODS: From the Korean National Health Insurance Service database, 276 520 adults aged 40 and older were included. Antibiotic exposure was defined by the cumulative prescription days and the number of classes. Participants were categorized into no SLD and MASLD groups. Hepatic steatosis was defined by using the fatty liver index ≥60. From 2013 to 2019, 16 197 CVD cases were recorded. A multivariate Cox model, adjusting for covariates, assessed adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for CVD risk associated with MASLD and antibiotic prescriptions. RESULTS: The group with ≥91 days of antibiotics prescribed and MASLD showed a significantly increased risk of CVD (aHR, 1.56; 95% CI, 1.39-1.74) compared with antibiotic non-users without SLD. Furthermore, the group with ≥4 classes of antibiotics prescribed and MASLD had an elevated risk of CVD (aHR, 1.49; 95% CI, 1.34-1.66) compared with antibiotic non-users without SLD. Consistent results were observed in several sensitivity analyses. CONCLUSIONS: Our study identified prolonged antibiotic exposure may be a factor that increases the risk of CVD in MASLD patients. These findings suggest an epidemiological basis for the therapeutic application of antibiotics in MASLD patients, and emphasize the need for further studies to deepen the understanding of these intricate relationships.

Association between body composition and subsequent cardiovascular diseases among 5-year breast cancer survivors.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) remain one of the leading causes of mortality in breast cancer survivors. This study aimed to investigate the association between body composition and subsequent CVD in breast cancer survivors. METHODS AND RESULTS: A retrospective cohort study of more than 70 thousand 5-year breast cancer survivors aged 40 years or older was conducted using data from the National Health Insurance Service of South Korea. Based on the percentage of predicted lean body mass (pLBMP), appendicular skeletal muscle mass (pASMP), and body fat mass (pBFMP), which were calculated using prediction equations with anthropometric data and health habits, groups were equally divided into quartiles. The risk of CVD was evaluated using multivariate Cox proportional hazards regression. Compared to those with the lowest pLBMP and pASMP, those with the highest pLBMP and pASMP had a 38% and 42% lower risk of CVD, respectively. In contrast, those with the highest pBFMP had a 57% higher risk of CVD compared to those with the lowest pBFMP. Each 1 % increase in pLBMP and pASMP was associated with a decreased risk of CVD [pLBMP, adjusted hazard ratio (aHR): 0.96, 95% CI 0.94-0.98, p < 0.05; pASMP, aHR: 0.91, 95% CI 0.87-0.95, p < 0.05] while each 1 % increase in pBFMP was associated with the increased risk of CVD (aHR: 1.05, 95% CI 1.03-1.07, p < 0.01). CONCLUSION: In this cohort study, a high pLBMP, a high pASMP, and a low pBFMP were associated with a lower risk of CVD.

Association between antibiotic use and subsequent risk of prostate cancer: A retrospective cohort study in South Korea.

OBJECTIVES: Several studies suggest that antibiotic use may affect overall cancer incidence, but the association between antibiotics and prostate cancer is still unclear. This retrospective cohort study aimed to assess the association between antibiotics and the risk of prostate cancer. METHODS: A population-based retrospective cohort study was conducted using the Korean National Health Insurance Service (NHIS) database. 1 032 397 individuals were followed up from January 1, 2007, to December 31, 2019. Multivariable Cox hazards regression was utilized to calculate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the risk of prostate cancer according to accumulative days of antibiotic use and the number of antibiotic classes used from 2002 to 2006. RESULTS: Individuals who used antibiotics for 180 or more days had a higher risk of prostate cancer (aHR, 1.46; 95% CI, 1.11-1.91) than those who did not use antibiotics. Also, individuals who used four or more kinds of antibiotics had a higher risk of prostate cancer (aHR, 1.18; 95% CI, 1.07-1.30) than antibiotic non-users. An overall trend was observed among participants who underwent health examinations. CONCLUSIONS: Our findings suggest that long-term use of antibiotics may affect prostate cancer incidence. Further studies are needed to improve understanding of the association between antibiotic use and prostate cancer incidence.

Association of allergic disease with Parkinson's disease: A nationally representative retrospective cohort study.

BACKGROUND: The association of allergic diseases such as allergic rhinitis, asthma, and atopic dermatitis with Parkinson's disease (PD) risk is yet unclear. In the few preceding studies, a short follow-up duration was followed for a relatively small study population, and lifestyle behaviors were not adjusted for. Therefore, there is a need for large-scale observation studies on the association of allergic disease with PD risk after considering lifestyle behaviors. METHODS: The study population consisted of 398,936 participants aged 40 years or older who underwent health screening before 1 January 2005 from the Korean National Health Insurance Service database. Starting from 1 January 2005, all participants were followed up until the date of PD event, death, or 31 December 2019. The adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the risk of PD were calculated using multivariable Cox proportional hazards regression. RESULTS: Compared to non-allergic disease participants, allergic disease patients had a higher risk for PD (aHR 1.18, 95% CI 1.07-1.30) and especially, allergic rhinitis patients had a higher risk for PD (aHR 1.14, 95% CI 1.00-1.29). Allergic disease was associated with a higher risk for PD (aHR 1.24, 95% CI 1.01-1.52) among participants who were never smokers, did not consume alcohol, and exercised regularly. CONCLUSIONS: Allergic rhinitis was associated with a higher risk for PD compared to participants without allergic rhinitis. This risk-increasing association of allergic rhinitis with PD was preserved even among people with healthy lifestyle behaviors.

Changes in high-density lipoprotein cholesterol with risk of Cardiovascular Disease among initially high-density lipoprotein-high participants.

BACKGROUND: High-density lipoprotein cholesterol's (HDL-C) long-held status as a cardiovascular disease (CVD) preventative has been called into question. Most of the evidence, however, focused on either the risk of death from CVD, or on single time point level of HDL-C. This study aimed to determine the association between changes in HDL-C levels and incident CVD in individuals with high baseline HDL-C levels (≥ 60 mg/dL). METHODS: 77,134 people from the Korea National Health Insurance Service-Health Screening Cohort were followed for 517,515 person-years. Cox proportional hazards regression was used to evaluate the association between change in HDL-C levels and the risk of incident CVD. All participants were followed up until 31 December 2019, CVD, or death. RESULTS: Participants with the greatest increase in their HDL-C levels had higher risks of CVD (adjusted hazard ratio [aHR], 1.15; 95% confidence interval [CI], 1.05-1.25) and CHD (aHR 1.27, CI 1.11-1.46) after adjusting for age, sex, household income, body mass index, hypertension, diabetes mellitus, dyslipidemia, smoking, alcohol consumption, moderate-to-vigorous physical activity, Charlson comorbidity index, and total cholesterol than those with the lowest increase in HDL-C levels. Such association remained significant even among participants with decreased low-density lipoprotein cholesterol (LDL-C) levels for CHD (aHR 1.26, CI 1.03-1.53). CONCLUSIONS: In people with already high HDL-C levels, additional increases in HDL-C levels may be associated with an increased risk of CVD. This finding held true irrespective of the change in their LDL-C levels. Increasing HDL-C levels may lead to unintentionally elevated risk of CVD.

Non-Alcoholic Fatty Liver Disease, Atherosclerosis, and Cardiovascular Disease in Asia.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to increase to over half of the adult population by 2040 globally. Since the final diagnosis of NAFLD is made by a liver biopsy, several non-invasive approaches have been developed and validated to define NAFLD and evaluate NAFLD-associated diseases. Presently, NAFLD has been identified as an important and independent risk factor for developing several extrahepatic diseases, including atherosclerosis, cardiovascular disease (CVD), diabetes, and dementia. This review discusses current findings of up-to-date literature regarding the effects of NAFLD on the risk of atherosclerosis and CVD in Asia along with potential underlying biological mechanisms and therapeutic approaches to lower the NAFLD-related CVD risk. We further focus on the difference between NAFLD and metabolic dysfunction-associated fatty liver disease (MAFLD) on the risk of CVD and its implication by comparing the risk of NAFLD and MAFLD.

Increased Estimated GFR Is Negatively Associated With the Risk of SARS-CoV-2 Infection and Severe COVID-19 Within Normal to Mildly Decreased Levels: Nested Case-Control Study.

BACKGROUND: While accumulating evidence indicates chronic kidney disease as a risk factor for coronavirus disease 2019 (COVID-19), the association between normal or mildly decreased kidney function and COVID-19 is unaddressed. Here, we have examined the association of an increase in estimated glomerular filtration rate (eGFR) with the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe COVID-19 outcomes among patients within normal to mildly decreased kidney function. METHODS: The patients who participated in both health screenings from period I (2017-2018) to II (2019-2020) were enrolled to our study. All participants were categorized into four groups according to the changes in eGFR stage from period I to II: 1) persistently stage G1, 2) from stage G2 to G1, 3) from stage G1 to G2, 4) persistently stage G2. In addition, the changes in eGFR value were defined by subtracting its value of period I from II. Patients were followed up for SARS-CoV-2 infection from January 1, 2021 to any diagnosis of COVID-19 or December 31, 2021, whichever happened first. In addition, those with SARS-CoV-2 infection were followed-up for one month after diagnosis to analyze severe COVID-19. Adjusted odds ratio (aOR) was calculated using multivariable-adjusted logistic regression. RESULTS: We identified 159,427 patients with and 1,804,798 patients without SARS-CoV-2 infection. The risk of SARS-CoV-2 infection decreased when eGFR stage changed from G2 to G1 (aOR, 0.957; 95% confidence interval [CI], 0.938-0.977) and persistently maintained at G1 (aOR, 0.966; 95% CI, 0.943-0.990), compared with the persistently stage G2 group. In addition, the risk showed an inverse relationship with changes in eGFR value, which was depicted by restricted cubic spline curves. For the overall risk of severe COVID-19, the persistently stage G1 showed the lowest risk (aOR, 0.897; 95% CI, 0.827-0.972), followed by those from stage G1 to G2 (aOR, 0.900; 95% CI, 0.828-0.978) and those from stage G2 to G1 (aOR, 0.931; 95% CI, 0.871-0.995), compared with the persistently stage G2 group. CONCLUSION: An increase in eGFR was negatively associated with the risk of SARS-CoV-2 infection and severe COVID-19 among normal or mildly decreased kidney function. For severe COVID-19, maintaining higher baseline eGFR may act as a protective factor against its risk.

Exercise Frequency Reduction Is Associated With Higher Risk of Infection in Newly Diagnosed Diabetes: A Nationally Representative Cohort Study.

BACKGROUND: Exercise is an important method to control the progression of diabetes. Since diabetes compromises immune function and increases the risk of infectious diseases, we hypothesized that exercise may affect the risk of infection by its immunoprotective effects. However, population-based cohort studies regarding the association between exercise and the risk of infection are limited, especially regarding changes in exercise frequency. The aim of this study was to determine the association between the change in exercise frequency and the risk of infection among patients with newly diagnosed diabetes. METHODS: Data of 10,023 patients with newly diagnosed diabetes were extracted from the Korean National Health Insurance Service-Health Screening Cohort. Self-reported questionnaires for moderate-to-vigorous physical activity (MVPA) were used to classify changes in exercise frequency between two consecutive two-year periods of health screenings (2009-2010 and 2011-2012). The association between changes in exercise frequency and the risk of infection was evaluated using multivariable Cox proportional-hazards regression. RESULTS: Compared with engaging in ≥ 5 times of MVPA/week during both periods, a radical decrease in MVPA (from ≥ 5 times of MVPA/week to physical inactivity) was associated with a higher risk of pneumonia (adjusted hazard ratio [aHR], 1.60; 95% confidence interval [CI], 1.03-2.48) and upper respiratory tract infection (aHR, 1.15; 95% CI, 1.01-1.31). In addition, a reduction of MVPA from ≥ 5 to < 5 times of MVPA/week was associated with a higher risk of pneumonia (aHR, 1.52; 95% CI, 1.02-2.27), whereas the risk of upper respiratory tract infection was not higher. CONCLUSION: Among patients with newly diagnosed diabetes, a reduction in exercise frequency was related to an increase in the risk of pneumonia. For patients with diabetes, a modest level of physical activity may need to be maintained to reduce the risk of pneumonia.

Validity of fatty liver prediction scores for diagnosis of fatty liver by Fibroscan.

BACKGROUND: The Korea National Health and Nutrition Examination Survey nonalcoholic fatty liver disease (K-NAFLD) score was recently developed with the intent to operationally define nonalcoholic fatty liver disease (NAFLD). However, there remained an external validation that confirmed its diagnostic performance, especially in patients with alcohol consumption or hepatitis virus infection. METHODS: Diagnostic accuracy of the K-NAFLD score was evaluated in a hospital-based cohort consisting of 1388 participants who received Fibroscan®. Multivariate-adjusted logistic regression models and the contrast estimation of receiver operating characteristic curves were used for validation of the K-NAFLD score, fatty liver index (FLI), and hepatic steatosis index (HSI). RESULTS: K-NAFLD-moderate [adjusted odds ratio (aOR) = 2.53, 95% confidence interval (CI): 1.13-5.65] and K-NAFLD-high (aOR = 4.14, 95% CI: 1.69-10.13) groups showed higher risks of fatty liver compared to the K-NAFLD-low group after adjustments for demographic and clinical characteristics, and FLI-moderate and FLI-high groups revealed aORs of 2.05 (95% CI: 1.22-3.43) and 1.51 (95% CI: 0.78-2.90), respectively. In addition, the HSI was less predictive for Fibroscan®-defined fatty liver. Both K-NAFLD and FLI also demonstrated high accuracy in the prediction of fatty liver in patients with alcohol consumption and chronic hepatitis virus infection, and the adjusted area under curve values were comparable between K-NAFLD and FLI. CONCLUSIONS: Externally validation of the K-NAFLD and FLI showed that these scores may be a useful, noninvasive, and non-imaging modality for the identification of fatty liver. In addition, these scores also predicted fatty liver in patients with alcohol consumption and chronic hepatitis virus infection.

Associations between alcohol consumption and cardiovascular disease among long-term survivors of colorectal cancer: a population-based, retrospective cohort study.

BACKGROUND: There is no evidence whether it is best to stop drinking alcohol at all or whether it is okay to drink a little in that light-to-moderate alcohol use was associated with low cardiovascular disease (CVD) compared to non-drinker among colorectal cancer (CRC) survivors, who are regarded as vulnerable to CVD. Therefore, we evaluated the association between alcohol consumption and incident CVD among long-term survivors of CRC. METHODS: This population-based, retrospective cohort study utilized data from the Korean National Insurance Service of 20,653 long-term survivors of CRC diagnosed between 2006 and 2012. Participants were followed up to the date of CVD, death, or December 31, 2018. All patients were categorized according to their daily alcohol consumption (g/day). The outcomes were incident CVD, including ischemic heart disease (IHD) and ischemic and hemorrhagic stroke, analyzed using the Cox proportional hazards regression after adjusting for cardiovascular risk factors and history of chemotherapy and radiotherapy. RESULTS: There was no association between alcohol consumption and incident CVD among long-term survivors of CRC. Additionally, hazardous alcohol consumption (≥ 40 g/day in male patients and ≥ 20 g/day in female patients) was associated with increased CVD, ischemic stroke, and hemorrhagic stroke (adjusted hazard ratio [95% confidence interval]: 1.51 [1.15-1.97], 1.60 [1.03-2.48], and 2.65 [1.25-5.62], respectively) compared with non-drinkers. CONCLUSION: No discernable protective association was found between alcohol consumption and incident CVD for even light-to-moderate drinking among long-term survivors of CRC. Alcohol consumption ≥40 g/day in male patients and ≥ 20 g/day in female patients was associated with an increased risk of stroke compared with non-drinkers. These novel results provide useful evidence when advising survivors of CRC regarding alcohol use.

Nervous system and primary liver cancer.

Recent advances have found irregular activities of the nervous system-associated factors in the development and progression of primary liver cancer. These factors contributed in the regulation of migration, proliferation, and apoptosis of cancer cells, and took a role in modulating invasion, metastasis, and recurrence after curative treatment. In clinical researches, neural-related factors were found to be significant prognostic factors, suggesting that the interactions between nervous system and primary liver cancer are indispensable in understanding underlying biological mechanisms. Herein, we reviewed up-to-date achievements in this area and the future perspectives of the interactions between the nervous system and primary liver cancer.

Differential Effectiveness of Tenofovir and Entecavir for Prophylaxis of Hepatocellular Carcinoma in Chronic Hepatitis B Patients Depending on Coexisting Cirrhosis and Prior Exposure to Antiviral Therapy: A Systematic Review and Meta-analysis.

GOALS: This meta-analysis evaluated the comparative effectiveness of tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) in reducing the risk of hepatocellular carcinoma (HCC). BACKGROUND: It is unclear whether TDF or ETV is more effective in reducing the risk of HCC in chronic hepatitis B (CHB) patients with or without underlying cirrhosis. METHODS: We searched the MEDLINE database through April 13, 2020, for studies involving CHB treated with TDF and/or ETV. Primary and secondary outcomes were the incidence of HCC and overall survival, respectively, calculated as risk ratios (RRs). Adjusted results were further evaluated by pooling propensity score matched cohorts. RESULTS: Of the 229 records identified, 17 studies were included in the quantitative analysis. TDF treatment was associated with a significantly lower risk of HCC development [RR, 0.63; 95% confidence interval (CI), 0.43-0.93; P=0.024] and mortality (RR, 0.69; 95% CI, 0.57-0.84; P=0.003) than ETV treatment. Moreover, TDF significantly lowered HCC risk in patients with cirrhosis (RR, 0.69; 95% CI, 0.56-0.84) and antiviral treatment-naive patients (RR, 0.59; 95% CI, 0.35-0.98) compared with ETV. Among treatment-naive patients, TDF significantly prolonged survival compared with ETV (RR, 0.69; 95% CI, 0.52-0.91). CONCLUSIONS: TDF likely confers a lower risk of HCC development and longer survival in patients with CHB, especially among treatment-naive patients and those with underlying cirrhosis, than ETV.

Impact of EBV infection and immune function assay for lymphoproliferative disorder in pediatric patients after liver transplantation: A single-center experience.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a lethal complication after pediatric liver transplantation, but information regarding risk factors for the development of PTLD remains unclear. This study was to identify characteristics and risk factors of PTLD. METHODS: A total of 705 pediatric patients who underwent liver transplantation between January 2017 and October 2018 were studied. Impact of clinical characteristics and Epstein-Barr virus (EBV) infection on the development of PTLD was evaluated. In addition, ImmuKnow assay was adopted in partial patients to analyze the immune status. RESULTS: Twenty-five (3.5%) patients suffered from PLTD with a median time of 6 months (3-14 months) after transplantation. Extremely high tacrolimus (TAC) level was found in 2 fatal cases at PTLD onset. EBV infection was found in 468 (66.4%) patients. A higher peak EBV DNA loads (>9590 copies/mL) within 3 months was a significant indicator for the onset of PTLD. In addition, the ImmuKnow assay demonstrated that overall immune response was significantly lower in patients with EBV infection and PTLD (P<0.0001). The cumulative incidence of PTLD was also higher in patients with lower ATP value (≤187 ng/mL, P<0.05). CONCLUSIONS: A careful monitoring of EBV DNA loads and tacrolimus concentration might be supportive in prevention of PTLD in pediatric patients after liver transplantation. In addition, application of the ImmuKnow assay may provide guidance in reducing immunosuppressive agents in treatment of PTLD.

Transarterial chemoembolization versus percutaneous microwave coagulation therapy for recurrent unresectable intrahepatic cholangiocarcinoma: Development of a prognostic nomogram.

BACKGROUND: Transarterial chemoembolization (TACE) and percutaneous microwave coagulation therapy (PMCT) are commonly used to treat intrahepatic recurrent liver cancers. However, there is no information regarding their effectiveness in patients with recurrent intrahepatic cholangiocarcinoma (ICC) after resection. METHODS: A total of 275 patients with localized recurrent ICC who received either TACE (n = 183) or PMCT (n = 92) were studied. A propensity score matching analysis was performed to compare prognostic impact of TACE and PMCT. Prognostic factors for TACE and PMCT were identified respectively. Predictive nomograms for each TACE and PMCT were developed using the Cox independent prognostic factors and were validated in independent patient groups by receiver operating characteristic curves and area under curve values. RESULTS: Both TACE and PMCT provided curativeness in partial patients (5-year overall survival: 21.4% and 6.1%, respectively), but TACE provided better survival benefit in both overall patients (hazard ratio [HR] = 0.71; 95% confidence interval [CI]: 0.50-0.97; P = 0.034) and propensity score matching analysis (HR = 0.69; 95% CI: 0.47-0.98; P = 0.041). Independent prognostic factors for TACE were tumor size >5 cm, poor differentiation, and major resection, whereas poor differentiation, hepatitis B virus infection, cholelithiasis, and lymph node metastasis were identified for PMCT. Both predictive nomograms for TACE and PMCT were validated to be effective with area under curve values of 0.77 and 0.70, respectively. CONCLUSIONS: TACE provided better survival benefits compared to PMCT. However, there was a disparity in prognostic factors, suggesting evaluation of the two nomograms may be supportive in modality selection. Further prospective validation studies are required for the results to be applied in clinical medicine.

Tumor-associated lymphangiogenesis predicts unfavorable prognosis of intrahepatic cholangiocarcinoma.

BACKGROUND: Tumor-associated lymphangiogenesis is considered significant in number of solid malignancies. However, its impact on prognosis of intrahepatic cholangiocarcinoma (ICC) after resection remains further confirmation. Herein, we conducted this study to evaluate prognostic impact of tumor-associated lymphangiogenesis in patients with ICC. METHODS: Extent of tumor-associated lymphangiogenesis of ICC was evaluated by quantifying microlymphatic vessel density (MLVD) from immunohistochemical staining of a lymphatic endothelial-specific antibody (podoplanin). Clinicopathological characteristics were comprehensively analyzed to identify MLVD-associated factors. The patients were stratified into high and low MLVD groups according to the distinctive correlation between the MLVD and overall survival using the Spearman's correlation test. Kaplan-Meier estimation was performed to confirm prognostic impact of MLVD in patients with ICC. Univariate and multivariate analyses were performed using the Cox proportional hazard model. RESULTS: The MLVD between 4 to 12 counts showed inverse proportion to the overall survival (Spearman's r = - 0.66; 95% confidence interval [CI], - 0.82 to - 0.39; p <  0.0001), which was set as a cut-off for the high MLVD group, whereas the MLVD between 13 to 25 showed no correlation to the overall survival (r = - 0.11; 95% CI, - 0.38 to 0.19; p = 0.4791). The high MLVD group showed more frequent lymph node metastasis (p <  0.001) and were more likely to suffer from recurrence of the tumor compared to the low MLVD group (p <  0.001). The high MLVD was found to be independently associated with reduced overall and recurrence-free survival. The 5-year overall survival of the patients with high MLVD was significantly lower compared to those with low MLVD (0% vs 48%). CONCLUSIONS: Our study reveals that tumor-associated lymphangiogenesis is significantly associated with increased lymphatic metastasis, recurrence of the tumor, and reduced overall survival in patients with ICC, thus providing guidance when estimating postresection prognosis.

Expression of IL-26 predicts prognosis of patients with hepatocellular carcinoma after surgical resection.

BACKGROUND: There is no data regarding prognostic impact of interleukin (IL)-26 on outcomes of patients with hepatocellular carcinoma (HCC). The present study aimed to evaluate the prognostic impact of IL-26 on HCC patients undergoing liver resection. METHODS: From 2003 to 2008, 122 patients with HCC who received surgical curative resection were enrolled. Patients were stratified into IL-26-upper and -lower groups according to the median expression level from immunohistochemical staining of resected specimens. Prognostic impact of IL-26 was estimated using Kaplan-Meier curves. Univariate and multivariate analyses were performed to evaluate time-dependent prognostic impact and independency of IL-26. Demographic and clinical factors that were associated with IL-26 were comprehensively identified. RESULTS: Prognosis of the patients with high level of IL-26 revealed to be significantly unfavorable in both cumulative recurrence-free survival (P < 0.001) and overall survival (P = 0.002). Upper expression of IL-26 (HR: 1.643; 95% CI: 1.021 to 2.644; P = 0.041) and microvascular invasion (HR: 3.303; 95% CI: 1.255 to 8.696; P = 0.016) were identified as significant independent prognostic factors for overall survival in the multivariable analysis. CONCLUSIONS: IL-26 is a novel prognostic factor for HCC after resection. Evaluation of IL-26 expression may be potentially valuable in clinical therapy when planning individualized follow-up schedule and evaluating candidates for prophylactic adjuvant treatment to prevent recurrence.

Rictor Deficiency Aggravates Hepatic Ischemia/Reperfusion Injury in Mice by Suppressing Autophagy and Regulating MAPK Signaling.

BACKGROUND/AIMS: The role of Rictor in hepatic ischemia/reperfusion (I/R) injury remains unknown. Here, we comprehensively examined the role of Rictor in hepatic I/R injury. METHODS: We studied the expression of Rictor during hepatic I/R injury. The regulatory effects of Rictor on inflammatory responses, cytokine and chemokine release, apoptotic and anti-apoptotic responses, and autophagy induction during hepatic I/R injury were identified via the shRNA-mediated knockdown of Rictor. Subsequently, we collected the liver and blood samples of these mice to evaluate liver injury, mRNA and protein levels. Additionally, the signaling pathways induced by Rictor were investigated. Furthermore, the extent of activation of MAPKs in response to Rictor deficiency was investigated in lipopolysaccharide (LPS)-treated RAW264.7 cells. The mRNA expression levels were analyzed by real-time PCR, and the protein expression levels were analyzed using Western blot, immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). RESULTS: The expression of Rictor was increased during hepatic I/R injury in vivo and hypoxia/reoxygenation (H/R) injury in vitro. Rictor deficiency enhanced the extent of liver injury by increasing macrophage and neutrophil infiltration, promoting cytokine and chemokine release, aggravating hepatocyte apoptosis, suppressing anti-apoptotic responses, and inhibiting autophagy induction during both hepatic I/R and H/R injury. Rictor was associated with the activation of hepatic I/R injury-induced MAPK signaling. In addition, Rictor deficiency affected MAPK activation in LPS-treated RAW264.7 cells. CONCLUSION: Rictor can substantially ameliorate I/R-induced liver injury. Therefore, our findings strongly suggest a therapeutic value of the Rictor/mTORC2 axis in hepatic I/R injury.