Impact of the Early COVID-19 Pandemic on Emergency Department Visits of Adult Cancer Patients With Fever or Respiratory Symptoms: A Korean Nationwide Population-Based Study, 2016-2020.

BACKGROUND: We performed a nationwide analysis to evaluate the impact of the early coronavirus disease 2019 (COVID-19) pandemic on emergency department (ED) visits by adult cancer patients having COVID-like symptoms. METHODS: We analyzed the National Emergency Department Information System (NEDIS) data on ED visits by adult cancer patients who presented with chief complaints of fever or respiratory symptoms (FRS) indicative of COVID-19, from 2016 to 2020. An interrupted time series analysis with a quasi-Poisson regression model was performed, adjusting for seasonality and time, to evaluate whether underlying trends for monthly ED visits and the in-hospital mortality rate (%) per month changed with the pandemic among these patients. We also estimated the adjusted odds ratio (aOR) of in-hospital deaths among cancer patients using multivariable logistic regression analysis. RESULTS: ED visits by cancer patients with FRS decreased during the COVID-19 pandemic (relative risk [RR] with 95% confidence interval [CI]: slope change, 0.99 [0.98-1.00] and step change, 0.84 [0.76-0.92]). However, the in-hospital mortality rate (%) for these patients was increased (slope change, 1.14 [1.04-1.25] and step change, 0.99 [0.98-1.01]). Factors such as urgent triage status, ambulance use, and treatment in hospitals with fewer than 300 staffed beds significantly contributed to increased aOR of in-hospital deaths during the COVID-19 pandemic compared to the pre-pandemic period. CONCLUSION: Further studies are needed to highlight the importance of ED service preparation in planning and managing resources for cancer patients during future pandemics.

Impact of the early phase of the COVID-19 pandemic on emergency department-to-intensive care unit admissions in Korea: an interrupted time-series analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic resulted in significant disruptions to critical care systems globally. However, research on the impact of the COVID-19 pandemic on intensive care unit (ICU) admissions via the emergency department (ED) is limited. Therefore, this study evaluated the changes in the number of ED-to-ICU admissions and clinical outcomes in the periods before and during the pandemic. METHODS: We identified all adult patients admitted to the ICU through level 1 or 2 EDs in Korea between February 2018 and January 2021. February 2020 was considered the onset point of the COVID-19 pandemic. The monthly changes in the number of ED-to-ICU admissions and the in-hospital mortality rates before and during the COVID-19 pandemic were evaluated using interrupted time-series analysis. RESULTS: Among the 555,793 adult ED-to-ICU admissions, the number of ED-to-ICU admissions during the pandemic decreased compared to that before the pandemic (step change, 0.916; 95% confidence interval [CI] 0.869-0.966], although the trend did not attain statistical significance (slope change, 0.997; 95% CI 0.991-1.003). The proportion of patients who arrived by emergency medical services, those transferred from other hospitals, and those with injuries declined significantly among the number of ED-to-ICU admissions during the pandemic. The proportion of in-hospital deaths significantly increased during the pandemic (step change, 1.054; 95% CI 1.003-1.108); however, the trend did not attain statistical significance (slope change, 1.001; 95% CI 0.996-1.007). Mortality rates in patients with an ED length of stay of ≥ 6 h until admission to the ICU rose abruptly following the onset of the pandemic (step change, 1.169; 95% CI 1.021-1.339). CONCLUSIONS: The COVID-19 pandemic significantly affected ED-to-ICU admission and in-hospital mortality rates in Korea. This study's findings have important implications for healthcare providers and policymakers planning the management of future outbreaks of infectious diseases. Strategies are needed to address the challenges posed by pandemics and improve the outcomes in critically ill patients.

Role of NADPH Oxidases in Renal Aging.

INTRODUCTION: Aging of the kidney is associated with complex molecular, histological, and functional changes. Although the aging process itself does not induce renal damage, underlying disease such as diabetes mellitus can aggravate kidney injury during aging. Although oxidative stress is considered an important mediator in age-related renal fibrosis, it is unclear how oxidative stress increases during normal and diabetic aging. METHODS: In this study, we investigated molecular changes in the kidney in normal and diabetic aging mice. C57BL/6 mice were studied at 2, 12, and 24 months of age, and leptin receptor-deficient db/db mice were studied at 8, 12, 16, 20, 24, and 38 weeks of age. We measured renal functional parameters, fibrotic and inflammatory markers, and oxidative stress markers at all the above time points. RESULTS: Both nondiabetic and diabetic mice exhibited progressive microalbuminuria during their lifespan. Interestingly, both diabetic aging and normal aging mice showed progressive increases in oxidative stress markers such as plasma and urinary 8-isoprostane, as well as renal lipid hydroperoxide content. In renal tissues, proinflammatory and profibrotic molecules were significantly upregulated in an age-dependent manner. Expression of three NADPH oxidase (Nox) isoforms, namely, Nox1, Nox2, and Nox4, was significantly increased during aging. Compared with normal aging mice, diabetic db/db mice demonstrated more dramatic changes during aging process. CONCLUSIONS: Our findings suggest that NADPH oxidases play an important role in the aging kidney under both normal and diabetic conditions. Targeting of these oxidases might be a new promising therapy to treat issues associated with aging kidneys.

Temporal Trends and Characteristics of Adult Patients in Emergency Department Related to Suicide Attempt or Self-Harm in Korea, 2016-2020.

BACKGROUND: The implementation of an effective suicide prevention program requires the identification and monitoring of subpopulations with elevated risks for suicide in consideration of demographic characteristics, to facilitate the development of tailored countermeasures for tackling the risk factors of suicide. We examined the annual trends in emergency department (ED) visits for suicide attempts (SAs) or self-harm and investigated the sex- and age-specific characteristics of individuals who visited the ED for SA and self-harm. METHODS: Data on ED visits for SAs or self-harm in Korea from 2016 to 2020 were extracted from the National Emergency Department Information System and assessed. We evaluated the age-standardized incidence rate of ED visits for SAs or self-harm, and hospital mortality among individuals who visited the ED for SAs or self-harm. In addition, the characteristics of the individuals were compared according to sex and age. RESULTS: We identified 145,963 ED visits for SAs or self-harm (0.42% of the total ED visits) during the study period. The rate of ED visits increased in the youngest age group (19-29 years old), and was more prominent among women (increased by an annual average of 22.5%), despite the coronavirus disease pandemic. The middle-aged group (45-64 years old) had a higher rate of mortality than other age groups, and the highest proportion of individuals on Medical Aid. CONCLUSION: It is necessary to plan age- and gender-specific suicide prevention programs that focus on improving the limited public mental health resources for the vulnerable populations.

Trend of Women's Health Research in Korea, 2012-2020: Topic and Text Network Analysis.

BACKGROUND: With the epidemiological transition, sociodemographic changes and differential lifetime experiences of women, women's health research improves knowledge of diverse health issues and the impact of policies. To explore the initiatives of women's health research in Korea, the present study examined the trends and topics of research on women's health funded by the government. METHODS: We searched all research projects on women's health funded by the government between 2012 and 2020 in Korea using the National Science & Technology Information Service database. We reviewed all the titles and abstract of the projects and examined the research trends by year. Content analysis was performed using both deductive and inductive approaches. Text network analysis and visualization by topic were conducted for keywords with a minimum of 10 occurrences in the title and abstract. RESULTS: Total number and funding amount of research projects on women's health in 2020 increased by 2.4 and 2.2 times over 2012 levels, respectively. The Ministry of Health and Welfare and the Ministry of Food and Drug Safety funded 20.9% of all projects. The majority of the topics (59.8%) addressed breast and gynecological cancers. Those on sexual and reproductive health accounted for 16.7%, with steep growth in the number (6.1 times) and funding (11.1 times) over 2012 levels. The topic analysis presented a more complex keyword network in 2020 than in 2012; however, the keywords frequently used in 2020 were similar to those of 2012. CONCLUSION: Women's health research projects have been growing in number and funding, with limited diversity in topics. Diversifying the topics and focusing on issues beyond the breast and pregnancy would be needed to reflect the complete life course of women. Institutionalization of diverse communication channels with various interest groups for women's health would be needed to better understand women's health needs from a public health perspective.

Operation of national coordinating service for interhospital transfer from emergency departments: experience and implications from Korea.

BACKGROUND: Since 2014, Korea has been operating the National Emergency Medical Situation Room (NEMSR) to provide regional emergency departments (EDs) with coordination services for the interhospital transfer of critically ill patients. The present study aimed to describe the NEMSR's experience and interhospital transfer pattern from EDs nationwide, and investigate the factors related to delayed transfers or transfers that could not be arranged by the NEMSR. METHODS: This study was a retrospective cross-sectional analysis of the NEMSR's coordination registry from 2017 to 2019. The demographic and hospital characteristics related to emergency transfers were analyzed with hierarchical logistic models. RESULTS: The NEMSR received a total of 14,003 requests for the arrangement of the interhospital transfers of critically ill patients from 2017 to 2019. Of 10,222 requests included in the analysis, 8297 (81.17%) successful transfers were coordinated by the NEMSR. Transfers were requested mainly due to a shortage of medical staff (59.79%) and ICU beds (30.80%). Delayed transfers were significantly associated with insufficient hospital resources. The larger the bed capacity of the sending hospital, the more difficult it was to coordinate the transfer (odds ratio [OR] for transfer not arranged = 2.04; 95% confidence interval [CI]: 1.48-2.82, ≥ 1000 beds vs. < 300 beds) and the longer the transfer was delayed (OR for delays of more than 44 minutes = 2.08; 95% CI: 1.57-2.76, ≥ 1000 beds vs. < 300 beds). CONCLUSIONS: The operation of the NEMSR has clinical importance in that it could efficiently coordinate interhospital transfers through a protocolized process and resource information system. The coordination role is significant as information technology in emergency care develops while regional gaps in the distribution of medical resources widen.

Patient and hospital characteristics predict prolonged emergency department length of stay and in-hospital mortality: a nationwide analysis in Korea.

BACKGROUND: Prolonged emergency department length of stay (EDLOS) in critically ill patients leads to increased mortality. This nationwide study investigated patient and hospital characteristics associated with prolonged EDLOS and in-hospital mortality in adult patients admitted from the emergency department (ED) to the intensive care unit (ICU). METHODS: We conducted a retrospective cohort study using data from the National Emergency Department Information System. Prolonged EDLOS was defined as an EDLOS of ≥ 6 h. We constructed multivariate logistic regression models of patient and hospital variables as predictors of prolonged EDLOS and in-hospital mortality. RESULTS: Between 2016 and 2019, 657,622 adult patients were admitted to the ICU from the ED, representing 2.4% of all ED presentations. The median EDLOS of the overall study population was 3.3 h (interquartile range, 1.9-6.1 h) and 25.3% of patients had a prolonged EDLOS. Patient characteristics associated with prolonged EDLOS included night-time ED presentation and Charlson comorbidity index (CCI) score of 1 or higher. Hospital characteristics associated with prolonged EDLOS included a greater number of staffed beds and a higher ED level. Prolonged EDLOS was associated with in-hospital mortality after adjustment for selected confounders (adjusted odds ratio: 1.18, 95% confidence interval: 1.16-1.20). Patient characteristics associated with in-hospital mortality included age ≥ 65 years, transferred-in, artificially ventilated in the ED, assignment of initial triage to more urgency, and CCI score of 1 or higher. Hospital characteristics associated with in-hospital mortality included a lesser number of staffed beds and a lower ED level. CONCLUSIONS: In this nationwide study, 25.3% of adult patients admitted to the ICU from the ED had a prolonged EDLOS, which in turn was significantly associated with an increased in-hospital mortality risk. Hospital characteristics, including the number of staffed beds and the ED level, were associated with prolonged EDLOS and in-hospital mortality.

Acute invasive fungal rhinosinusitis: MR imaging features and their impact on prognosis.

PURPOSE: Acute invasive fungal rhinosinusitis (AIFRS) is a life-threatening disease that is difficult to diagnose. Its overall imaging features have not been evaluated and the prognostic impact is unclear. The purpose of our study was to present MR imaging features and their impact on prognosis of AIFRS. METHODS: MR images and clinical records of 23 patients with AIFRS were retrospectively evaluated to identify the imaging features and to determine the factors affecting patients' survival. A multivariable Cox proportional hazard model was used to estimate the hazard ratio of the prognostic factors, and Kaplan-Meier survival curves were compared by using a log-rank test. RESULTS: All cases showed extra-sinonasal involvement and the orbit was the most common (65.2%, 15/23) location. The lesion enhancement pattern was classified into lack of contrast enhancement (LoCE) (47.8%, 11/23) and homogeneous (34.8%, 8/23) and heterogeneous (17.4%, 4/23) enhancement. Although LoCE showed variable signal intensity (SI), homogeneously or heterogeneously enhancing lesions showed exclusively low SI (100%, 12/12) on T2WI. Among various clinical and imaging factors, LoCE was correlated with coagulation necrosis, probably provoked by numerous fungal hyphae, and was found to be a sole independent prognostic factor for disease-specific mortality (hazard ratio = 16.819; 95% CI, 1.646-171.841, p = 0.017). In addition, patients with LoCE showed worse survival than patients without LoCE (p = 0.008). CONCLUSION: AIFRS showed frequent extra-sinonasal involvement and variable MR enhancement patterns. An enhancement pattern of LoCE was seen in about half of the cases and was a unique prognostic factor among the various clinico-radiologic factors.

Income Difference in Attitudes towards Cancer in General Population: Findings from a National Survey.

BACKGROUND: To better understand cancer-related health behaviors, it is critical to know how general populations with different socioeconomic and demographic backgrounds perceive cancer. The current paper explored differences in general attitudes and beliefs towards cancer among Koreans. METHODS: A cross-sectional national survey was conducted for 1,000 Korean participants who were not cancer patients and did not have immediate family members with cancer via proportional quota random sampling. General attitudes and beliefs about cancer were measured by face-to-face interview using the awareness and beliefs about cancer (ABC) measure. RESULTS: Most respondents (84.8%-88.5%) had optimistic attitudes towards cancer. However, 35.6% to 87.7% agreed with negative cancer beliefs across all age groups simultaneously. Socioeconomic disparity of positive cancer beliefs was not evident. Unexpectedly, the highest income group agreed more strongly with the negatively framed statements that cancer treatment is worse than the cancer itself (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.31-5.53), that they would not want to know if they have cancer (OR, 1.61; 95% CI, 0.94-2.75), and that a cancer diagnosis is a death sentence (OR, 2.32; 95% CI, 1.34-4.01), than the lowest income group. CONCLUSION: The present results imply a complicated context of cancer beliefs in Korea, unlike those shown in the studies of western populations. While the contradictory attitudes toward cancer can be attributable to the dual nature of information processing, social environment might have played a role. The association between socioeconomic status and negative attitudes toward cancer may vary depending on the diversity of the contexts.

APX-115, a first-in-class pan-NADPH oxidase (Nox) inhibitor, protects db/db mice from renal injury.

Recent studies have suggested that renal Nox is important in the progression of diabetic nephropathy. Therefore, we investigated the effect of a novel pan-NOX-inhibitor, APX-115, on diabetic nephropathy in type 2 diabetic mice. Eight- week-old db/m and db/db mice were treated with APX-115 for 12 weeks. APX-115 was administered by oral gavage at a dose of 60 mg/kg per day. To compare the effects of APX-115 with a dual Nox1/Nox4 inhibitor, db/db mice were treated with GKT137831 according to the same protocol. APX-115 significantly improved insulin resistance in diabetic mice, similar to GKT137831. Oxidative stress as measured by plasma 8-isoprostane level was decreased in the APX-115 group compared with diabetic controls. All lipid profiles, both in plasma and tissues improved with Nox inhibition. APX-115 treatment decreased Nox1, Nox2, and Nox4 protein expression in the kidney. APX-115 decreased urinary albumin excretion and preserved creatinine level. In diabetic kidneys, APX-115 significantly improved mesangial expansion, but GKT137831 did not. In addition, F4/80 infiltration in the adipose tissue and kidney decreased with APX-115 treatment. We also found that TGF-ß stimulated ROS generation in primary mouse mesangial cells (pMMCs) from wild-type, Nox1 KO, and Duox1 KO mice, but did not induce Nox activity in pMMCs from Nox2 knockout (KO), Nox4 KO, or Duox2 KO mice. These results indicate that activating Nox2, Nox4, or Duox2 in pMMCs is essential for TGF-ß-mediated ROS generation. Our findings suggest that APX-115 may be as effective or may provide better protection than the dual Nox1/Nox4 inhibitor, and pan-Nox inhibition with APX-115 might be a promising therapy for diabetic nephropathy.

Radiofrequency ablation of low-risk small papillary thyroidcarcinoma: preliminary results for patients ineligible for surgery.

PURPOSE: The purpose of this study is to retrospectively evaluate the outcomes of radiofrequency ablation (RFA) of low-risk small papillary thyroid carcinomas (PTCs) in patients who were ineligible for surgery. MATERIALS AND METHODS: Between 2005 and 2009, six PTCs (mean diameter, 0.92 cm; range, 0.6-1.3 cm) in six patients were treated with RFA by three radiologists in two hospitals. The inclusion criteria for this study were (1) pathologically confirmed PTC without cytological aggressiveness, (2) single PTC without extrathyroidal extension, (3) no metastatic tumours and (4) ineligibility for surgery. RFA was performed using a radiofrequency generator and an 18-gauge internally cooled electrode. The medical records were reviewed and analysed, focussing on the procedural profiles of RFA, symptoms and complications during and after RFA, and changes in tumours on follow-up ultrasonography. RESULTS: Before and after RFA, the results of thyroid function tests were normal in all patients. During 48.5 ± 12.3 months (range, 36-65 months) of follow-up, along with a significant reduction in the mean volume (98.5 ± 3.3%), four ablation zones (4/6, 66.7%) completely disappeared. Two ablation zones exhibited only small calcified residues with nearly complete disappearance of the corresponding non-calcified solid portions, and in one of them, malignant cells were absent as assessed by fine-needle aspiration and core-needle biopsy. Transient hypertension with mild headache (n = 1) and mild neck pain (n = 1) developed during the procedure and subsided without any treatment. CONCLUSION: Besides surgery and active surveillance, which are conflicting currently used management plans, RFA might represent an effective and a safe alternative for managing low-risk small PTCs, especially in patients ineligible for surgery.

Decreased Risk of Preeclampsia After the Introduction of Universal Voucher Scheme for Antenatal Care and Birth Services in the Republic of Korea.

Objectives A number of interventions to reduce disparities in maternal health have been introduced and implemented without concrete evidence to support them. In Korea, a universal voucher scheme for antenatal care and birth services was initiated in December 2008 to improve Korea's fertility rate. This study explores the risk of preeclampsia after the introduction of a universal voucher scheme. Methods Population-based cohort data from the National Health Insurance Service-National Sample Cohort (NHIS-NSC) covering 2002-2013 were analysed. A generalized linear mixed model (GLMM) was used to estimate the relationship between the risk of preeclampsia and voucher scheme introduction. Results The annual age-adjusted incidence of preeclampsia showed no significant unidirectional change during the study period. In the GLMM analysis, the introduction of a voucher scheme was associated with a reduced risk of preeclampsia, controlling for potential confounding factors. The interaction between household income level and voucher scheme was not significant. Conclusions for Practice This finding suggests that the introduction of a voucher scheme for mothers is related to a reduced risk of preeclampsia even under universal health coverage.

Recognition of the Concept of Publicness in Healthcare: a Content Analysis of Korean Newspapers.

The traditional boundaries between public and private sectors has been blurred, and questions raised regarding how publicness could be conceptualized. The empirical study on the concept of publicness can reveal greatly diversified views on publicness, and help to reduce confusion over publicness. For the content analysis, 750 news articles of 8 national Korean newspapers were retrieved from the Korea Integrated News Database System. The articles were coded by the inductive category for the topic of the paragraph, the concept related to publicness, and the overall tone toward publicness. Publicness was addressed in a number of different issues, and diverse and specific statuses or actions were associated with the realization of publicness. The most frequent concept was "government," which represented the main agent of healthcare provision and the owner of institutions for "the vulnerable." Issues of industrialization of healthcare/healthcare industry and reform of the national healthcare system mentioned publicness in a normative sense, which laid stress on "not-for-profit" service and the right of "universal access" to service for publicness. Articles of health/disease information or global health regarded "the population/public" as the main targets or beneficiaries of healthcare services. Occasionally, publicness was not related to specific concepts, being used unclearly or as a routine. The fulfillment of the specific actions or status may lead to the enhancement of publicness. However, publicness itself could not be reduced to the specific concepts suggested. The use of publicness in healthcare delivered only its normative sense without substantive meaning.

DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury.

Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.

Renoprotective Effects of a Highly Selective A3 Adenosine Receptor Antagonist in a Mouse Model of Adriamycin-induced Nephropathy.

The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-ß1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1ß, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria.

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status.

Immunotherapies targeting the programmed cell death-1/programmed cell death-ligand 1 pathway have emerged as promising therapeutic strategies for lung cancer. However, the expression pattern and prognostic implications of programmed cell death-ligand 1 and 2 and programmed cell death-1 in comparison with the histology and genetic alterations in pulmonary adenocarcinomas remains unclear and thus were addressed here. Programmed cell death-ligand 1 and 2 expression in tumor cells and the quantities of programmed cell death-1(+) and CD8(+) tumor-infiltrating lymphocytes were immunohistochemically evaluated in 497 resected pulmonary adenocarcinomas and analyzed according to clinicopathological and genetic statuses. Programmed cell death-ligand 1 and 2 expression were observed in 59% and 64% of pulmonary adenocarcinomas, respectively, and showed a strong positive correlation with each other (P < 0.001). Programmed cell death-ligand 1 expression was higher in nodal metastasis cases (P = 0.006), smokers (P = 0.056), poorly differentiated tumors and histologic subtypes of solid and micropapillary patterns (P < 0.001). There was no significant difference in programmed cell death-ligand 1 and 2 expression according to EGFR mutation status. However, programmed cell death-ligand 1 expression was correlated with ALK translocation (P =0.054) and expression of EGFR and MET (P < 0.001). Meanwhile, programmed cell death-ligand 2 expression was correlated with ALK translocation (P = 0.052), and expression of MET (P < 0.001) and ERBB2 (P = 0.013). The numbers of CD8(+) and programmed cell death-1(+) lymphocytes were higher in smokers (P = 0.012 and 0.016) and MET-expressing adenocarcinomas (P < 0.001). Patients expressing programmed cell death-ligand 1 and/or high ratios of programmed cell death-1(+)/CD8(+) lymphocytes showed shorter disease-free survival (P = 0.001). Our study demonstrated that programmed cell death-ligand 1 and 2 expression varied with histology, EGFR, ALK, MET, and ERBB2 statuses, and activation of the programmed cell death-1/programmed cell death-ligand 1 pathway may be a poor prognostic factor in pulmonary adenocarcinomas.

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction.

Dipeptidyl peptidase IV (DPPIV) is an exopeptidase that modulates the function of several substrates, among which insulin-releasing incretin hormones are the most well known. DPPIV also modulate substrates involved in inflammation, cell migration, and cell differentiation. Although DPPIV is highly expressed in proximal renal tubular cells, the role of DPPIV inhibition in renal disease is not fully understood. For this reason, we investigated the effects of LC15-0444, a DPPIV inhibitor, on renal function in a mouse model of renal fibrosis. Eight-week-old C57/BL6 mice were subjected to unilateral ureteral obstruction (UUO) and were treated with LC15-0444 (a DPPIV inhibitor) at a dose of 150 mg/kg per day in food or vehicle for 14 days. DPPIV activity was significantly increased in obstructed kidneys, and reduced after treatment with LC15-0444. Administration of LC15-0444 resulted in a significant decrease in albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis. DPPIV inhibition also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, as well as the infiltration of macrophages. UUO significantly increased, and LC15-0444 markedly suppressed, levels of phosphorylated Smad2/3, TGFß1, toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-κB. These results suggest that activation of DPPIV in the kidney has a role in the progression of renal disease and that targeted therapy inhibiting DPPIV may prove to be a useful new approach in the management of progressive renal disease, independent of mechanisms mediated by glucagon-like peptide-1.

Role of pigment epithelium-derived factor in the involution of hemangioma: autocrine growth inhibition of hemangioma-derived endothelial cells.

Hemangioma is a benign tumor derived from abnormal blood vessel growth. Unlike other vascular tumor counterparts, a hemangioma is known to proliferate during its early stage but it is followed by a stage of involution where regression of the tumor occurs. The critical onset leading to the involution of hemangioma is currently not well understood. This study focused on the molecular identities of the involution of hemangioma. We demonstrated that a soluble factor released from the involuting phase of hemangioma-derived endothelial cells (HemECs) and identified pigment epithelium-derived factor (PEDF) as an anti-angiogenic factor that was associated with the growth inhibition of the involuting HemECs. The growth inhibition of the involuting HemECs was reversed by suppression of PEDF in the involuting HemECs. Furthermore, we found that PEDF was more up-regulated in the involuting phase of hemangioma tissues than in the proliferating or the involuted. Taken together, we propose that PEDF accelerates the involution of hemangioma by growth inhibition of HemECs in an autocrine manner. The regulatory mechanism of PEDF expression could be a potential therapeutic target to treat hemangiomas.

BRAF mutation in follicular variant of papillary thyroid carcinoma is associated with unfavourable clinicopathological characteristics and malignant features on ultrasonography.

OBJECTIVE: Follicular variant of papillary thyroid carcinoma (FVPTC) is a common variant of papillary thyroid carcinoma (PTC), but the association between BRAF mutation and the clinicopathological and ultrasonographical characteristics of FVPTC has not been well studied. The aim of this study was to determine the significance of BRAF mutation in FVPTC. PATIENTS: The medical records of the 137 patients with >5 mm FVPTCs and known BRAF mutation status in the interested nodule were reviewed. BRAF mutation analysis was performed routinely and prospectively by Sanger sequencing. Clinicopathological and ultrasonographical characteristics were compared between BRAF mutation-positive and BRAF mutation-negative groups. RESULTS: BRAF mutation was detected in 35 (25·5%) patients. The BRAF mutation-positive group was associated with smaller tumour size (P = 0·022), extrathyroidal extension (P = 0·001), multifocality (P = 0·046) and higher (III/IV) TNM stages (P = 0·005). In multivariable analysis, higher (III/IV) TNM stage was an independent predictive factor for BRAF mutation-positive status (adjusted OR 2·966, 95% CI 1·321-6·663). In diagnosis of FVPTC, the presence of BRAF mutation was associated with malignant features on ultrasonography (P < 0·001) and higher incidence of suspicious for malignancy or malignant diagnosis on the fine needle aspiration cytology (P = 0·023). Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of US for detecting BRAF mutation were 82·9%, 57·8%, 40·3%, 90·8% and 64·2%, respectively. Conclusions BRAF mutation in FVPTC is associated with unfavourable clinicopathological characteristics and malignant features on ultrasonography and may be a potential prognostic factor as it is in classical PTC.