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According to the 2017 National Air Pollutant Emissions Inventory (NEI), air pollutant emissions in the Republic of Korea comprised 817,420 metric tons (hereafter tons) of CO, 1,189,800 tons of NOx, 315,530 tons of SOx, 592,582 tons of TSP, 218,476 tons of PM10, 91,731 tons of PM2.5, 15,555 tons of black carbon (BC), 1,047,585 tons of VOCs, and 308,298 tons of NH3. Emissions of the 13 first-level emission source categories, which constitute the NEI, were estimated and, based on their characteristics, the emission source categories were grouped into five sectors (energy, industry, road, non-road, and everyday activities and others). In addition, the contributions of primary PM2.5 and its four precursors (NOx, SOx, VOCs, and NH3) to the 2017 NEI were assessed in this study. The emission contributions of NOx to the NEI were 36.5% for the road sector, which was the highest of those of all the air pollutants for this sector; NOx emissions for this sector were 4.2% lower than those in the previous year. The emission contributions of SOx and PM2.5 to the NEI were higher than those of the other air pollutants for the industry sector; SOx and PM2.5 emissions for this sector decreased by 9.8% and 19.7%, respectively, compared with those in the previous year. The emission contributions of VOCs and NH3 to the NEI were 65.3% and 83.9% for the everyday activities and others sector, respectively, higher than those of the other air pollutants for this sector; VOCs and NH3 emissions for this sector increased by 0.8% and 2.9%, respectively, compared with those in the previous year. A three-dimensional (3D) chemical transport modeling system was used to validate the emission estimates. These data suggest that simulated SOx emissions were overestimated in areas with dense large-scale industrial complexes, such as Jeollanam-do, Gyeongsangbuk- do, and Ulsan, and that simulated NOx emissions were overestimated in Seoul, Incheon, and Jeollanam-do.

Background: Lung epithelial cells serve as first line of defense against various inhaled pollutant particles. This study focused on assessing the impact of organic extracts of PM2.5 collected in Seoul, South Korea on primary human lung epithelial cells and identifying the relevant components and sources which induced lung epithelial cell injury.Results: We used primary lung epithelial cells isolated directly from healthy donors and evaluated the effects of organic compounds of twelve selected, seasonal PM2.5 on inflammation, cellular aging, and macroautophagy in primary lung epithelial cells. Organic extracts of PM2.5 specifically induced neutrophilic chemokine, interleukin-8, via extracellular signal regulated kinase activation. Moreover, PM2.5 significantly increased the expression of aging markers (p16, p21, and p27) and activated macroautophagy. Average mass concentrations, OC and EC, had no significant correlations with PM2.5 effects. However, regression analysis showed that polycyclic aromatic hydrocarbons and n-alkanes were the most relevant components of PM2.5 correlated with neutrophilic inflammation. Vegetative detritus and residential bituminous coal combustion sources were strongly correlated with neutrophilic inflammation, aging and macroautophagy activation.Conclusions: These data suggest that the chemical composition of PM2.5 is crucially important to determine the adverse health effects of PM2.5. Our study provides encouraging evidence to regulate the harmful components of PM2.5 in Seoul.

Inflammation, oxidative stress, and protease–antiprotease imbalance have been suggested to be a pathogenic triad in chronic obstructive pulmonary disease (COPD). However, it is not clear how proteases interact with components of inflammatory pathways. Therefore, this study aimed to evaluate the effect of neutrophil elastase (NE) on lipopolysaccharide (LPS)-induced interleukin 8 (IL-8) production and determine the molecular mechanism in human bronchial epithelial cells (HBECs). Immortalized bronchial epithelial cells and primary HBECs were used to investigate the impact of NE on LPS-induced IL-8 production. The molecular mechanism by which NE modulated LPS-induced IL-8 production was confirmed in elastase-treated C57BL/6 mice and primary HBECs obtained from COPD patients and healthy controls. The results showed that NE treatment synergistically augmented LPS-induced IL-8 production in both immortalized bronchial epithelial cells and primary HBECs. NE partially degraded peroxisome proliferator-activated receptor gamma (PPARγ), which is known to regulate IL-8 production in the nucleus. Treatment with a PPARγ agonist and overexpression of PPARγ reversed the NE-induced synergistic increase in LPS-induced IL-8 production. Moreover, PPARγ levels were lower in lung homogenates and lung epithelial cells from elastase-treated mice than in those from saline-treated mice. In accordance with the findings in mice, PPARγ levels were lower in primary HBECs from COPD patients than in those from healthy never-smokers or healthy smokers. In conclusion, a vicious cycle of mutual augmentation of protease activity and inflammation resulting from PPARγ degradation plays a role in the pathogenesis of COPD., Lung disease: getting to the root of inflammation Tracing how a protein-degrading enzyme called neutrophil elastase (NE) interacts with cytokines, molecules that trigger inflammation, has revealed a potential new treatment target for chronic obstructive pulmonary disease (COPD). COPD is a progressive disease in which chronic inflammation damages lung function. Although it was known that cytokines play key roles in COPD, the detailed molecular mechanism was not well understood. Chul-Gyu Yoo at Seoul National University College of Medicine in South Korea and co-workers investigated the role that NE plays in inflammation in COPD. They found that NE degraded peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor that keeps cytokine production in check. Patients with COPD showed low levels of PPARγ, and boosting PPARγ or suppressing NE in cultured cells showed potential for reducing inflammation. These results highlight PPARγ as a candidate for development of COPD treatments.

Pulmonary fibrosis is a progressive and lethal lung disease characterized by the proliferation and differentiation of lung fibroblasts and the accumulation of extracellular matrices. Since pulmonary fibrosis was reported to be associated with adenosine monophosphate-activated protein kinase (AMPK) activation, which is negatively regulated by cereblon (CRBN), we aimed to determine whether CRBN is involved in the development of pulmonary fibrosis. Therefore, we evaluated the role of CRBN in bleomycin (BLM)-induced pulmonary fibrosis in mice and in transforming growth factor-beta 1 (TGF-β1)-induced differentiation of human lung fibroblasts. BLM-induced fibrosis and the mRNA expression of collagen and fibronectin were increased in the lung tissues of wild-type (WT) mice; however, they were significantly suppressed in Crbn knockout (KO) mice. While the concentrations of TGF-β1/2 in bronchoalveolar lavage fluid were increased via BLM treatment, they were similar between BLM-treated WT and Crbn KO mice. Knockdown of CRBN suppressed TGF-β1-induced activation of small mothers against decapentaplegic 3 (SMAD3), and overexpression of CRBN increased it. TGF-β1-induced activation of SMAD3 increased α-smooth muscle actin (α-SMA) and collagen levels. CRBN was found to be colocalized with AMPKα1 in lung fibroblasts. CRBN overexpression inactivated AMPKα1. When cells were treated with metformin (an AMPK activator), the CRBN-induced activation of SMAD3 and upregulation of α-SMA and collagen expression were significantly suppressed, suggesting that increased TGF-β1-induced activation of SMAD3 via CRBN overexpression is associated with AMPKα1 inactivation. Taken together, these data suggest that CRBN is a profibrotic regulator and maybe a potential target for treating lung fibrosis., Lung disease: Putting the brakes on fibrosis Interventions that target a regulatory protein called cereblon could help reduce the damage inflicted on the lungs by idiopathic pulmonary fibrosis (IPF). This incurable and generally fatal condition is associated with the accumulation of scar tissue in the lungs, which leads to the gradual loss of respiratory function. Researchers led by Kyoung-Hee Lee at Seoul National University Hospital in South Korea have now identified cereblon as a potentially important contributor to this scarring process. They found that cereblon regulates a complex metabolic pathway that ultimately contributes to production of fibrosis-related proteins in a mouse model of IPF. Genetically modified animals that lacked the gene encoding cereblon showed reduced accumulation of these proteins in their lungs. These results suggest that cereblon-inhibiting agents could potentially control the progression of IPF and help preserve lung function.

In 2016, air pollutant emissions in the Republic of Korea were 795,044 metric tons (hereafter tons) of CO, 1,248,309 tons of NOx, 358,951 tons of SOx , 611,539 tons of TSP, 233,085 tons of PM10, 100,247 tons of PM2.5, 16,401 tons of BC, 1,024,029 tons of VOCs, and 301,301 tons of NH3. Including energy production, thirteen emission sources, which comprise the national air pollutant emission inventory, were classified by their characteristics into five sectors (Energy, Industry, Road, Non-road, and Everyday Activities and Other Emission Sources) to analyze their relative contributions to the national emissions. Specifically, their contributions by pollutant were as follows: NOx (11.0%), SOx (21.9%), PM2.5 (3.2%), VOCs (0.8%), NH3 (0.5%) from the energy sector; NOx (20.2%), SOx (59.7%), PM2.5 (42.1%), VOCs (24.3%), and NH3 (14.4%) from the industry sector; NOx (36.3%), SOx (0.1%), PM2.5 (9.7%), VOCs (4.6%), and NH3 (1.7%) from the road sector; NOx (24.8%), SOx (11.5%), PM2.5 (14.3%), VOCs (4.0%), and NH3 (0.04%) from the non-road sector; and NOx (7.6%), SOx (6.7%), PM2.5 (30.6%), VOCs (66.3%), and NH3 (83.4%) from the everyday activities and other emission sources sector. The data we calculate are used as official national emissions data for the establishment, implementation, and assessment of national atmospheric environment policy to improve air quality. As critical and necessary materials, the data are also utilized on a wide range of studies on policies such as customized regional particulate matter reduction measures. Thus, it is crucial to estimate highly reliable national emissions by enhancing the emissions factors and inventory and to establish a scientific emissions testing system by using air quality modeling and satellite data.

To evaluate the association of sleep duration with health-related quality of life (HRQOL) and examine the influence of age, sex, and common comorbidities on this association. Using appropriate survey design, we analyzed 50,181 adults who participated in the 2007–2015 Korea National Health and Nutrition Examination Survey. Participants were categorized into five groups according to self-reported sleep duration ≤ 5 (short sleeper), 6, 7, 8, and ≥ 9 h (long sleeper). HRQOL was measured with the European Quality of Life-5 Dimensions (EQ-5D) index and visual analogue scale (VAS). In multiple linear regression, short sleep duration was associated with lower EQ-5D index (β = − 0.024; 95% confidence interval [CI], − 0.027 to − 0.021) and lower EQ-VAS (β = − 3.0; 95% CI, − 3.7 to − 2.3), and long sleep duration was associated with lower EQ-5D index (β = − 0.016; 95% CI, − 0.021 to − 0.011) and lower EQ-VAS (β = − 2.2; 95% CI, − 3.1 to − 1.3) compared with 7-h sleepers. Old-age (≥ 65 years old) short and long sleepers had significantly lower EQ-5D index than those of

Although inflammation, oxidative stress, and protease-antiprotease imbalance have been referred to as a pathogenic triad in chronic obstructive pulmonary disease (COPD), little is known about how they interact. The objectives of this study were to elucidate the effect of cigarette smoke extract (CSE) on the neutrophil elastase (NE)-induced inflammatory response and its molecular mechanism in bronchial epithelial cells. We observed that NE activated extracellular signal-regulated kinase (ERK) and induced IL-8 production. Blocking ERK activation using a MEK inhibitor (U0126) suppressed NE-induced IL-8 secretion and knockdown of proteinase-activated receptor 2 (PAR2) using siRNAs inhibited both NE-induced ERK activation and subsequent IL-8 release, suggesting that NE-induced IL-8 production is dependent on PAR2-mediated ERK activation. Interestingly, pre-exposure to CSE markedly enhanced NE-induced IL-8 production. As PAR2 acts as a receptor for NE, we next investigated the effect of CSE on PAR2 expression as a molecular mechanism for the increased IL-8 production induced by NE in CSE exposed cells. CSE, but not NE, increased the expression of PAR2 mRNA and surface membrane protein. Inhibition of p38 MAPK reduced PAR2 expression induced by CSE while inhibition of the ERK and Akt pathway had no effect. Consequently, p38 inhibition significantly abrogated CSE-induced enhancement of IL-8 production in NE-treated cells. Of note, we observed increased PAR2 levels in lung homogenates and lung epithelial cells from CSE-treated mice and from both smokers and patients with COPD. Taken together, these results suggest that CSE upregulates PAR2 in normal human bronchial epithelial cells, thereby enhancing the inflammatory response to NE., Lung disease: How cigarette smoking enhances lung inflammation A study of the effect of cigarette smoke extract (CSE) on lung lining cells clarifies the interaction between CSE and an enzyme implicated in causing chronic obstructive pulmonary disease (COPD). The enzyme elastase is released by neutrophils and is known to induce inflammation, which causes lung irritation in COPD. Chul-Gyu Yoo and colleagues at Seoul National University in South Korea exposed cultured human lung cells to CSE. This exposure activated specific molecular signaling processes by which the elastase enzyme-induced inflammation was enhanced. Of particular note was an increase in the levels of a cell surface receptor protein in CSE-treated cells. This protein was increased in lungs of smokers and COPD patients. The research helps to understand the role of cigarette smoking in the pathogenesis of COPD.

Background We aimed to evaluate whether serum activin-A levels are elevated and have any value in predicting severity and prognosis in acute respiratory distress syndrome (ARDS). Methods Retrospective cohort study was performed with patients who were admitted to MICU with diagnosis of ARDS and have serum samples stored within 48 h of Intensive care unit (ICU) admission between March 2013 and December 2016 at a single tertiary referral hospital. Serum activin-A levels were measured with ELISA kit, and were compared with those of normal healthy control and non-ARDS sepsis patients. Results Total 97 ARDS patients were included for the study. Levels of Activin-A were elevated in ARDS patients compared to those of healthy controls (Log-transformed activin-A levels 2.89 ± 0.36 vs. 2.34 ± 0.11, p

Erdosteine is widely used as a mucolytic agent and also has free radical scavenging and antioxidant activities. However, little is known about the mechanisms of the anti-inflammatory effect of erdosteine. We investigated the effect of erdosteine on the activation of the nuclear factor (NF)-kB/inhibitor of NFkB (IkB), and the mitogen-activated protein kinase (MAPK) and Akt pathways in the mouse macrophage cell line RAW 264.7. Cultured RAW 264.7 cells were pretreated with erdosteine and stimulated with lipopolysaccharide (LPS). In Western blotting, pretreatment with erdosteine inhibited the IkBα degradation induced in RAW 264.7 cells by LPS. LPS-induced IkB kinase (IKK) activity and NF-kB transcription were inhibited by pretreatment with erdosteine. Production of IL-6 and IL-1β was also inhibited by erdosteine pretreatment. However, erdosteine did not inhibit LPS-induced phosphorylation of Akt and MAPKs. These results suggest that the anti-inflammatory effect of erdosteine in mouse macrophages is mediated through inhibition of LPS-induced NF-kB activation.

Background An adequate threshold for the Clinical Chronic Obstructive Pulmonary Disease (COPD) Questionnaire (CCQ) defining more symptomatic COPD patients has not been determined. We aimed to determine the efficacy of the CCQ and the appropriate CCQ threshold for more symptomatic COPD patients. Methods COPD patients aged > 40 years who smoked/had smoked ≥10 packs/year were prospectively enrolled over 1 year from three South Korean hospitals (n = 126). Correlations between the CCQ and St. George’s Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), the modified Medical Round Council (mMRC) scale, lung function, and exercise capacity were evaluated. “More symptomatic patients” were those with an SGRQ score ≥ 25. Area under the receiver operating curve and classification and regression tree analyses were performed to determine the CCQ threshold equivalent to an SGRQ score ≥ 25. Results The CCQ significantly correlated with the SGRQ, CAT, and mMRC scale (r = 0.76, 0.69, and 0.53, respectively). A CCQ cutoff of 1.4 predicted an SGRQ score of 25 better than others. A CCQ score of 1.4 was a significant determinant of an SGRQ score ≥ 25 even after adjusting for potential confounders. Conclusions The CCQ was correlated with other symptom indicators, lung function, and exercise capacity. A CCQ cutoff of 1.4 agreed better than CCQ cutoff of 1.0, suggested by guideline, and this cutoff value may identify more symptomatic COPD patients well. Trial registration ClinicalTrials.gov Identifier: NCT02527486. Date of registration: December 19, 2014, retrospectively registered.

Blood lactate levels and central venous oxygen saturation (ScvO(2)) are known to be useful indicators of global tissue hypoxia. However, it is unclear whether ScvO(2) correlates with lactate levels when measured simultaneously and whether changes in ScvO(2) or lactate levels in serial measurements have prognostic value. We investigated the correlation between ScvO(2) and lactate levels measured simultaneously and their association with clinical outcomes.We performed a prospective observational study of patients with severe systemic inflammatory response syndrome (SIRS) and severe sepsis who were admitted to the medical intensive care unit. ScvO(2) and lactate levels were measured simultaneously at the time of study enrollment, every 6 h for 24 h, and then every 24 h until the goal was reached.Twenty-five patients were enrolled in the study; 13 have died and 12 have survived. There was no correlation between lactate levels and ScvO(2). Neither lactate levels nor ScvO(2) at the time of admission differed between nonsurvivors and survivors. Normalization of lactate levels within 48 h was significantly associated with survival.In patients with severe SIRS and severe sepsis, simultaneously measured ScvO(2) and lactate levels showed no correlation, and normalization of lactate levels within 48 h was a predictive factor for survival.

Korea has experienced dramatic development and has become highly industrialized and urbanized during the past 40 years, which has resulted in rapid economic growth. Due to the industrialization and urbanization, however, air pollutant emission sources have increased substantially. Rapid increases in emission sources have caused Korea to suffer from serious air pollution. An air pollutant emissions inventory is one set of essential data to help policymakers understand the current status of air pollution levels, to establish air pollution control policies and to analyze the impacts of implementation of policies, as well as for air quality studies. To accurately and realistically estimate administrative district level air pollutant emissions of Korea, we developed a Korean Emissions Inventory System named the Clean Air Policy Support System (CAPSS). In CAPSS, emissions sources are classified into four levels. Emission factors for each classification category are collected from various domestic and international research reports, and the CAPSS utilizes various national, regional and local level statistical data, compiled by approximately 150 Korean organizations. In this paper, we introduced for the first time, a Korean national emissions inventory system and release Korea’s official 2007 air pollutant emissions for five regulated air pollutants.

TRAIL is a cytokine with a unique ability to induce apoptosis selectively in many transformed cell lines. The instability of TRAIL and the resistance of some cancer cells to TRAIL present the main obstacles for clinical experimentation. We generated an adenovirus expressing full-length TRAIL and tested its efficacy in several cancer cell lines. Ad-TRAIL-infected cancer cells localized full-length TRAIL protein to the cytoplasm and released same-sized TRAIL in the media. Ad-TRAIL was found to induce apoptotic cell death in several cancer cell lines resistant to soluble TRAIL (A549, SKOV3, HT-29 and LNCap) and in TRAIL-sensitive cell lines. Ad-TRAIL, but not soluble TRAIL, induced apoptotic cell death in TRAIL-resistant cell lines, manifested by an increased sub-G1 proportion, caspase-3 activation and PARP cleavage. Ad-TRAIL also induced a media-transferable bystander effect, but only in soluble TRAIL-sensitive cell lines. In conclusion, two novel characteristics of ad-TRAIL were found during this study. First, that ad-TRAIL can induce apoptotic cell death in several cancer cell lines resistant to sTRAIL. Second, that ad-TRAIL induces a media-transferable bystander effect, which is expected to increase its therapeutic value by allowing TRAIL to overcome the locally acting nature and low transduction rate commonly encountered in clinical situation.

Uteroglobin is a secretory protein synthesized by most epithelia, including the respiratory tract. It has strong anti-inflammatory properties that appear to be related to the inhibition of phospholipase A2. Recent experimental evidence indicates that uteroglobin has an inhibitory effect on the proliferation and invasion of cancer cells. We investigated the effects of the adenovirus-uteroglobin (ad-UG) transduction on the growth of lung cancer cell lines, which did not express the uteroglobin gene. Upon transduction of ad-UG, the rate of cell growth and the ability to produce colonies in soft agar were evaluated. Cell cycle analysis, Western blot for cell cycle-related proteins and annexin V staining for apoptosis were carried out to see if they were associated with the changes in cell growth. All the tested lung cancer cell lines did not express the uteroglobin gene. The growth rates, and colony-forming ability of transformed cells, were significantly inhibited by the induction of uteroglobin gene expression. The DNA histogram showed that the cell fraction of the G2/M phase was increased, and this G2/M phase arrest was related to a decrease of cdk1 and cyclin A. However, a fraction of apoptotic cells were same as the control. From these results, uteroglobin is thought to have an inhibitory effect on the growth of lung cancer cells. This suggests a potential role for uteroglobin in gene therapy for lung cancer.

The continuous growth of tumors depends on the altered regulation of the cell cycle, which is in turn modulated by signals from growth factors and their receptors. Blockade of insulin-like growth factor (IGF)-I and IGF-IR by antisense or dominant negative plasmid transfection can suppress tumorigenicity and induce regression of established tumors. We have constructed two recombinant adenoviruses: an adenovirus expressing truncated IGF-IR (ad-IGF-IR/950) with an engineered stop codon at amino acid residue 950, and an adenovirus expressing the soluble extracellular domain of IGF-IR (ad-IGF-IR/482) with an engineered stop codon at amino acid residue 482. Ad-IGF-IR/950 produces a defective receptor with an intact alpha subunit and a defective beta subunit lacking the tyrosine kinase domain. Dominant negative inhibition results from competition of the defective receptor with normal IGF-IR subunits, or the competition with normal IGF-IR for ligand by the soluble receptor. We were able to show here that ad-IGF-IR/950 induced the increased expression of IGF-IR on the cell surface and ad-IGF-IR/482 induced the secretion of the soluble fragment of IGF-IR. The transduction of both ad-IGF-IR/950 and ad-IGF-IR/482 could blunt the growth-stimulatory effect of IGF-I on human lung cancer cell lines. Both ad-IGF-IR/950 and ad-IGF-IR/482 effectively blocked IGF-I-induced Akt kinase activation. Intratumoral injection of ad-IGF-IR/482 virus showed significant growth suppression in established lung cancer xenografts. These findings suggest that these ad-IGF-IR/dn (950, 482) have the potential to be effective and practical cancer gene therapy strategies.

Background There have been few studies of pulmonary actinomycosis, which is an uncommon anaerobic infection. Consequently, the optimal therapeutic regimen, appropriate duration of treatment, long-term prognosis, and factors predicting prognosis are not well established. Methods We retrospectively reviewed the medical records of histopathologically confirmed cases of pulmonary actinomycosis seen between November 2003 and December 2012. Results The study included 68 patients with a mean age of 58.4 ± 11.6 years. Of the 68, initial surgery was performed in 15 patients (22.1%), while the remaining 53 (77.9%) received antibiotic therapy initially. In the initial antibiotic group, 45/53 (84.9%) were cured without relapse (median antibiotic duration 5.3 months). 5/53 (9.4%) patients were refractory medically (median antibiotic duration 9.7 months), and 3/53 (5.7%) experienced a recurrence (median time to relapse 35.3 months). In the initial surgery group, 14/15 (93.3%) were cured and treatment failure occurred in one (6.7%). In the multivariate analysis, the absence of an antibiotic response at 1 month was the only independent factor associated with a poor treatment outcome, with an adjusted odds ratio of 49.2 (95% CI, 3.34–724.30). There was no significant difference in treatment outcome based on the size of the parenchymal lesion, comorbidities, whether intravenous antibiotics were used, antibiotic therapy duration, or whether the initial treatment was surgical. Conclusions Antibiotic treatment with or without surgery was effective for treatment of pulmonary actinomycosis. Nevertheless, treatment failure or recurrence occurred in a considerable proportion of patients, especially those resistant to the initial antibiotic treatment.

Background Carcinoma of unknown primary tumors (CUP) is present in 0.5%-9% of all patients with malignant neoplasms; only 20%-27% of primary sites are identified before the patients die. Currently, 18F-fluorodeoxy-glucose positron-emission tomography (18F-FDG PET) or PET combined with computed tomography (PET/CT) is widely used for the diagnosis of CUP. However, the diagnostic yield of the primary site varies. The aim of this study was to determine whether PET or PET/CT has additional advantages over the conventional diagnostic workup in detecting the primary origin of CUP. Findings Twenty patients with unknown primary tumors that underwent PET or PET/CT were included in this study. For all patients, the conventional diagnostic workup was unsuccessful in detecting the primary sites. Among 20 patients, 11 had PET scans. The remaining nine patients had PET/CT. In all 20 patients, neither the PET nor PET/CT identified the primary site of the tumor, including six cases with cervical lymph node metastases. The PET and PET/CT revealed sites of FDG uptake other than those associated with known metastases in seven patients, but these findings did not influence patient management or therapy. Two patients had unnecessary invasive diagnostic procedures due to false positive results on the PET or PET/CT. Conclusions Although it is inconclusive because of small sample size of the study, the additional value of PET or PET/CT for the detection of primary sites in patients with CUP might be less than expected; especially in patients that have already had extensive conventional diagnostic workups. Further study is needed to confirm this finding.