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BACKGROUND: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. METHODS: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. FINDINGS: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). INTERPRETATION: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population. ispartof: THROMBOSIS RESEARCH vol:222 pages:31-39 ispartof: location:United States status: published

Pulmonary vein stump thrombosis (PVST) is uncommonly encountered postoperative in-situ thrombosis in the stump of pulmonary veins after lung resection. Data regarding the incidence and clinical behaviour of PVST are scarce. Thus, this study aims to investigate the incidence, clinical characteristics and outcome of PVST after lung resection in patients with lung cancer. Follow-up enhanced chest computed tomography (CT) scans acquired after the surgery were retrospectively reviewed to determine PVST presence for patients with lung cancer who underwent lung resection in two tertiary referral centres. Out of the 1885 patients with lung cancer who underwent lobectomy or more extensive lung resection, PVST was observed in 37 patients (2.0%) on their follow-up chest CT. Most stump thrombi were observed in the left superior pulmonary vein [35 (94.6%)] and in patients who underwent left upper lobectomy [34 (91.9%)]. At the last CT follow-up of each patient, 33 (89.2%) exhibited complete resolution, three partial resolution and one stabilization. Eleven (29.7%) patients received anticoagulant therapy after the diagnosis. The rate of complete PVST resolution did not differ significantly between the anticoagulation and nonanticoagulation groups. None of the PVST patients experienced systemic embolic events, regardless of anticoagulation. The PVST incidence diagnosed at routine chest CT follow-up following lung cancer surgery was 2%. PVST was characterized by a benign clinical course without progression and systemic embolization, regardless of anticoagulation. However, further studies are required to determine individualized therapeutic strategies, including anticoagulation.

Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression. We investigated whether variants in BET genes are associated with survival outcomes for lung cancer. To do this, the associations between 77 variants in BET family genes and survival outcomes were analyzed in 773 non‐small‐cell lung cancer (NSCLC) patients who underwent surgery (349 and 424 patients in the discovery and validation cohorts, respectively). We found that six variants were significantly associated with overall survival (OS) in the discovery cohort, and one variant (rs2506711C>T) was replicated in the validation cohort. BRD3 rs2506711C>T is located in the repressed area and has a strong linkage disequilibrium with rs2427964C>T in the promoter region. BRD3 rs2427964C>T was significantly associated with worse OS in the discovery cohort, validation cohort, and combined analysis. In a luciferase assay, promoter activity in the BRD3 rs2427964 T allele was significantly higher than that in the BRD3 rs2427964 C allele, which selectively bound with the transcriptional repressor SIN3A. Knockdown of BRD3 with BRD3‐specific siRNA decreased the proliferation and migration of lung cancer cells while also increasing the rate of apoptosis. These results suggest that BRD3 rs2427964C>T increases BRD3 expression through increased promoter activity, which is associated with poor prognosis for lung cancer., In this study, we investigated the association of BET gene variants with survival of patients with non‐small‐cell lung cancer (NSCLC). We observed that the rs2427964C>T SNP in the BRD3 promoter region was associated with poorer survival outcome. BRD3 promoter activity was higher in rs2427964_T than in rs2427964_C, which selectively bound with the transcriptional repressor SIN3A. Additionally, BRD3 silencing decreased the proliferation and migration of NSCLC cells. Our data suggest that elevated BRD3 expression regulated by rs2427964C>T leads to reduced overall survival in patients with NSCLC.

Background/Aims: Pleural fluid adenosine deaminase (ADA) levels are useful in discriminating tuberculous pleural effusions (TPEs) from malignant pleural effusions (MPEs). However, some patients with MPE exhibit high-ADA levels, which may mimic TPEs. There is limited data regarding the differential diagnosis between high-ADA MPE and high-ADA TPE. This study aimed to identify the predictors for distinguishing high-ADA MPEs from high-ADA TPEs.Methods: Patients with TPE and MPE with pleural f luid ADA levels ≥ 40 IU/L were included in this study. Clinical, laboratory, and radiological data were compared between the two groups. Independent predictors and their diagnostic performance for high-ADA MPEs were evaluated using multivariate logistic regression analysis and receiver operating characteristic curve.Results: A total of 200 patients (high-ADA MPE, n = 30, and high-ADA TPE, n = 170) were retrospectively included. In the multivariate analysis, pleural fluid ADA, pleural f luid carcinoembryonic antigen (CEA), and pleural nodularity were independent discriminators between high-ADA MPE and high-ADA TPE groups. Using pleural ADA level of 40 to 56 IU/L (3 points), pleural CEA level ≥ 6 ng/mL (6 points), and presence of pleural nodularity (3 points) for predicting high-ADA MPEs, a sum score ≥ 6 points yielded a sensitivity of 90%, specificity of 96%, positive predictive value of 82%, negative predictive value of 98%, and area under the receiver operating characteristic curve of 0.965.Conclusions: A scoring system using three parameters may be helpful in guiding the differential diagnosis between high-ADA MPEs and high-ADA TPEs.

Introduction Patients with aspiration pneumonia (AP) exhibit higher mortality than those with non-AP. However, data regarding predictors of short-term prognosis in patients with community-acquired AP are limited. Methods Patients hospitalized with community-acquired pneumonia (CAP) were retrospectively classified into aspiration pneumonia (AP) and non-AP groups. The AP patients were further divided into nonsurvivors and survivors by 30-day mortality, and various clinical variables were compared between the groups. Results Of 1249 CAP patients, 254 (20.3%) were classified into the AP group, of whom 76 patients (29.9%) died within 30 days. CURB-65, pneumonia severity index (PSI), and Infectious Diseases Society of America/American Thoracic Society criteria for severe CAP (SCAP) showed only modest prognostic performance for the prediction of 30-day mortality (c-statistics, 0.635, 0.647, and 0.681, respectively). Along with the PSI and SCAP, Eastern Cooperative Oncology Group performance status (ECOG-PS) and blood biomarkers, including, N-terminal of prohormone brain natriuretic peptide (NT-proBNP) and albumin, were independent predictors of 30-day mortality. In models based on clinical prediction rules, including CURB-65, PSI, and SCAP, the addition of ECOG-PS further improved their c-statistics compared to the clinical prediction rules alone. In the four combinations based on SCAP, ECOG-PS, and two blood biomarkers (NT-proBNP and albumin), the c-statistics further increased to reach approximately 0.8. Conclusions CURB-65, PSI, and SCAP exhibited only modest discriminatory power in predicting the 30-day mortality of patients with community-acquired AP. The addition of performance status and blood biomarkers, including NT-proBNP and albumin, further increased prognostic performance, showing good predictive accuracy in the SCAP-based model.

PDF file - 27K, The correlation between the CD3EAP gene copy number and mRNA expression. * Pearson correlation coefficient

PDF file - 29K, Luciferase activity according to rs967591G>A with E2 or 4-OHT treatment in H1299 cells.

Purpose: This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) in 19q13.3 and survival of patients with early-stage non–small cell lung cancer (NSCLC), and to define the causative functional SNP of the association.Experimental Design: A two-stage study design was used to evaluate five SNPs in relation to survival outcomes in 328 patients and then to validate the results in an independent patient population (n = 483). Luciferase assay and real-time PCR were conducted to examine functional relevance of a potentially functional SNP.Results: Of the five SNPs, three SNPs (rs105165C>T, rs967591G>A, and rs735482A>C) were significantly associated with survival outcomes in a stage I study. The rs967591A allele had significantly higher activity of the CD3EAP promoter compared with the rs967591G allele (P = 0.002), but the SNP did not have an effect on the activity of PPP1R13L promoter. The rs967591G>A was associated with the level of CD3EAP mRNA expression in lung tissues (P = 0.01). The rs967591G>A exhibited consistent associations in a stage II study. In combined analysis, the rs967591 AA genotype exhibited a worse overall survival (adjusted HR = 1.69; 95% confidence interval = 1.29–2.20; P = 0.0001).Conclusion: The rs967591G>A affects CD3EAP expression and thus influences survival in early-stage NSCLC. The analysis of the rs967591G>A polymorphism can help identify patients at high risk of a poor disease outcome. Clin Cancer Res; 19(15); 4185–95. ©2013 AACR.

PDF file - 70K, Primers used in this study.

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PDF file - 92K, Kaplan-Meier plot of overall survival according to the rs1005165C>T (A), rs967591G>A (B) rs735482A>C (C), rs3212986G>T (D) and rs11615G>A (E) genotypes in the stage I study, and the rs967591G>A (F) genotypes in the stage 2 validation study. P-values, Log-Rank test (*P-values in A, B, C and F: in recessive models for the variant allele).

Purpose To assess the safety and retrieval rate of a predischarge inferior vena cava (IVC) filter retrieval strategy based on contrast computed tomography (CT). Methods IVC filter insertion for trauma patients from 2010 to 2018 were reviewed. An active filter retrieval strategy was established in March 2017. The strategy sought early evaluation of venous thromboembolism (VTE) status and filter retrieval before a patient's discharge. The possibility of early IVC filter retrieval was evaluated by a multidisciplinary team based on pre-filter retrieval VTE-CT findings. Overall VTE-CT findings, retrieval rate, indwelling time, and recurrence of venous thromboembolic events were compared before and after the filter retrieval strategy setup. Results 177 IVC filters were inserted in trauma patients. All patients underwent pre-filter retrieval VTE-CT. VTE-CT findings were as follows: completely resolved VTE, n = 108 (61%); partially improved, n = 58 (33%); no change, n = 8 (5%); aggravated, n = 3 (2%). The overall retrieval rate was 84% with a mean indwelling time of 32 days. In subgroup analyses, 95 (53%) had filter retrieval with the before strategy (BS) setup and 82 (47%) with the after strategy (AS) setup. The retrieval rate was significantly higher in the AS group [81/82 (99%) vs. 68/95 (72%), (p Conclusions The active strategy of VTE-CT-based filter retrieval during the hospital stay markedly improved the filter retrieval rate from 72% to 99% without evidence of recurrence of VTE. Hazards of low retrieval rate versus CT-related radiation exposure should be studied in the future.

Differential leukocyte counts of pleural fluid are routinely recommended for the early diagnosis and management of exudative pleural effusions. Rapid automated cellular analysis agrees strongly with standard manual microscopic counts and has become a reality in many clinical laboratories. However, discordant results sometimes observed between automated and manual analyses raise concern about using automated analysis to aid prompt differential diagnosis. This study aimed to evaluate the real-world disagreement between automated and manual leukocyte analyses in exudative pleural effusions and to investigate whether the discordant results occur in specific cellular ranges or randomly. We conducted a retrospective study of patients who were diagnosed with parapneumonic pleural effusions (PPE), tuberculous pleural effusions (TPE), and malignant pleural effusions (MPE) between September 2018 and December 2020. Differential and predominant leukocyte counts were performed using an automated XN-350 analyzer with a two-part differential count consisting of polymorphonuclear (PMN) and mononuclear (MN) leukocytes and a manual method with Wright-stained cytospin slides. We compared the two methods on cases of 109 PPEs, 50 TPEs, and 116 MPEs. Although the overall correlation between the two methods for differential leukocyte counts was excellent, there were etiologic variations; MPEs showed a lower correlation compared to PPEs and TPEs. Automated-PMN predominance almost corresponded to manual cytospin-neutrophilic predominance. In contrast, ~10% of the automated-MN predominance did not correspond with the cytospin-lymphocytic predominance. These discrepancies occurred most in the automated-MN% range of 51% to 60%, followed by 61% to 70%. The PMN% range ≥50% and30% on the automated analysis reliably corresponds to the neutrophilic and lymphocytic predominance, respectively. However, the MN% range of 51% to 70% may not coincide with lymphocytic predominance on manual cytospin analysis. This range leaves the potential cause of exudative pleural effusions open.

Neurogenic differentiation factor 1 (NEUROD1) is frequently overexpressed in small-cell lung cancer (SCLC). NEUROD1 plays an important role in promoting malignant behavior and survival. In this study, we evaluated the association between putative functional polymorphisms in 45 NEUROD1 target genes and chemotherapy response and survival outcomes in 261 patients with SCLC. Among the 100 single nucleotide polymorphisms (SNPs) studied, two were significantly associated with both chemotherapy response and overall survival (OS) of patients with SCLC. The SNP rs3806915C>A in semaphorin 6A (SEMA6A) gene was significantly associated with better chemotherapy response and OS (P = 0.04 and P = 0.04, respectively). The SNPrs11265375C>T in nescient helix-loop helix 1 (NHLH1) gene was also associated with better chemotherapy response and OS (P = 0.04 and P = 0.02, respectively). Luciferase assay showed a significantly higher promoter activity of SEMA6A with the rs3806915 A allele than C allele in H446 lung cancer cells (P = 4 × 10-6). The promoter activity of NHLH1 showed a significantly higher with the rs11265375 T allele than C allele (P = 0.001). These results suggest that SEMA6A rs3806915C>A and NHLH1 rs11265375C>T polymorphisms affect the promoter activity and expression of the genes, which may affect the survival outcome of patients with SCLC.

Hemoptysis is a common cause of emergency department (ED) visits. There is little data about the role of systemic hypertension as a cause of hemoptysis. The aim of this study was to evaluate the association between systemic blood pressure and the unknown etiology of hemoptysis. This retrospective study included consecutive patients who visited the ED owing to hemoptysis and underwent a chest computed tomography between January 2011 and June 2021. Details of the initial blood pressure at the ED visit were compared between two groups with identified and unidentified causes of hemoptysis. In total, 1105 adult patients were included. The etiology of hemoptysis was identified in 1042 patients (94.3%) and remained unidentified in 63 patients (5.7%). The percentage of patients with severe hypertension was significantly higher in patients with unidentified causes of hemoptysis than in those with identified causes (35% vs. 11%, p < 0.001). In multivariate analysis, age, ever-smoker, and initial systolic blood pressure were significantly associated with hemoptysis of unidentified causes. Although further studies are needed, our findings suggest a possible association between high blood pressure and cryptogenic hemoptysis.

Objective: This study was conducted to investigate the association between genetic variants in histone modification regions and clinical outcomes of PEM chemotherapy in patients with lung adenocarcinoma. Methods: Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The associations of 279 SNPs with chemotherapy response and overall survival (OS) were analyzed in 314 lung adenocarcinoma patients who underwent PEM chemotherapy. Results: Among the SNPs investigated, 18 were significantly associated with response to chemotherapy, while 28 with OS. Of these SNPs, rs549794A>G in an enhancer which is expected to regulate the expression of ribosomal protein S3 (RPS3) gene was significantly associated with both worse response to chemotherapy and worse OS (adjusted odds ratio = 0.59, 95% CI = 0.36–0.97, p = 0.04; adjusted hazard ratio = 1.44, 95% CI = 1.09–1.91, p = 0.01, respectively). Previous studies suggested that RPS3, a multi-functional protein with various extraribosomal activities, may play a role in chemotherapy resistance. Therefore, it is postulated that rs549794-induced change in the expression level of RPS3 may affect the response to PEM chemotherapy and consequently the survival outcomes in lung adenocarcinoma patients. Conclusion: This study suggests that genetic variants in the histone modification regions may be useful for the prediction of clinical outcomes of PEM chemotherapy in advanced lung adenocarcinoma.

The clinical relevance of concomitant deep vein thrombosis (DVT) in patients with pulmonary embolism remains controversial. The aim of the present study was to assess clinical characteristics of patients with isolated pulmonary embolism, thereby investigating isolated pulmonary embolism related clinical factors. Patients hospitalized for pulmonary embolism who underwent DVT workup within 3 days of pulmonary embolism diagnosis were retrospectively classified into two groups: patients with isolated pulmonary embolism and patients with DVT-associated pulmonary embolism (DVT-PE). The clinical, laboratorial and radiological parameters were compared between the two groups. Of 1012 patients, 322 (31.8%) presented with isolated pulmonary embolism, and 690 (68.2%) presented with DVT-PE. In a multivariate analysis, female sex was an independent factor for predicting isolated pulmonary embolism [odds ratio (OR) 1.69, 95% confidence interval (CI) 1.26-2.26, P < 0.001], whereas cancer (OR 0.64, 95% CI 0.43-0.96, P = 0.031), leg pain or swelling (OR 0.08, 95% CI 0.04-0.18, P < 0.001), and central pulmonary embolism (OR 0.44, 95% CI 0.32-0.59, P < 0.001) were negatively associated with isolated pulmonary embolism. There were no significant differences between the two groups with regard to risk stratification and short-term prognosis of pulmonary embolism, including adverse outcomes and pulmonary embolism related in-hospital mortality. Of pulmonary embolism patients who underwent imaging tests for DVT, approximately 32% presented with isolated pulmonary embolism. Isolated pulmonary embolism was positively associated with female sex, whereas it was negatively associated with cancer, leg pain or swelling, and central pulmonary embolism. The presence or absence of concomitant DVT did not influence the severity and short-term prognosis of pulmonary embolism.

BACKGROUND AND PURPOSE: Isocitrate dehydrogenase (IDH) wild-type lower-grade gliomas (histologic grades II and III) with epidermal growth factor receptor (EGFR) amplification or telomerase reverse transcriptase (TERT) promoter mutation are reported to behave similar to glioblastoma. We aimed to evaluate whether MR imaging features could identify a subset of IDH wild-type lower-grade gliomas that carry molecular features of glioblastoma. MATERIALS AND METHODS: In this multi-institutional retrospective study, pathologically confirmed IDH wild-type lower-grade gliomas from 2 tertiary institutions and The Cancer Genome Atlas constituted the training set (institution 1 and The Cancer Genome Atlas, 64 patients) and the independent test set (institution 2, 57 patients). Preoperative MRIs were analyzed using the Visually AcceSAble Rembrandt Images and radiomics. The molecular glioblastoma status was determined on the basis of the presence of EGFR amplification and TERT promoter mutation. Molecular glioblastoma was present in 73.4% and 56.1% in the training and test sets, respectively. Models using clinical, Visually AcceSAble Rembrandt Images, and radiomic features were built to predict the molecular glioblastoma status in the training set; then they were validated in the test set. RESULTS: In the test set, a model using both Visually AcceSAble Rembrandt Images and radiomic features showed superior predictive performance (area under the curve = 0.854) than that with only clinical features or Visually AcceSAble Rembrandt Images (areas under the curve = 0.514 and 0.648, respectively; P CONCLUSIONS: MR imaging features integrated with machine learning classifiers may predict a subset of IDH wild-type lower-grade gliomas that carry molecular features of glioblastoma.

Background: Activating transcription factor 3 (ATF3) plays a significant role in cancer development and progression. We investigated the association between variants in expression quantitative trait loci (eQTLs) within ATF3 binding regions and the prognosis of non-small cell lung cancer (NSCLC) after surgery. Methods: A total of 772 patients with NSCLC who underwent curative surgery were enrolled. Using a public database (http://galaxyproject.org), we selected 104 single nucleotide polymorphisms (SNPs) in eQTLs in the ATF3 binding regions. The association of those SNPs with disease-free survival (DFS) was evaluated. Results: Among those SNPs, HAX1 rs11265425T>G was associated with significantly worse DFS (aHR = 1.30, 95% CI = 1.00–1.69, p = 0.05), and ME3 rs10400291C>A was associated with significantly better DFS (aHR = 0.66, 95% CI = 0.46–0.95, p = 0.03). Regarding HAX1 rs11265425T>G, the significant association remained only in adenocarcinoma, and the association was significant only in squamous cell carcinoma regarding ME3 rs10400291C>A. ChIP-qPCR assays showed that the two variants reside in active enhancers where H3K27Ac and ATF3 binding occurs. Promoter assays showed that rs11265425 G allele had significantly higher HAX1 promoter activity than T allele. HAX1 RNA expression was significantly higher in tumor than in normal lung, and higher in rs11265425 TG+GG genotypes than in TT genotype. Conversely, ME3 expression was significantly lower in tumor than in normal lung, and higher in rs10400291 AA genotype than in CC+CA genotypes. Conclusions: In conclusion, this study shows that the functional polymorphisms in ATF3 binding sites, HAX1 rs11265425T>G and ME3 rs10400291C>A are associated with the clinical outcomes of patients in surgically resected NSCLC.

Background We investigated the clinical features and surgical outcomes of lung adenocarcinoma with minimal solid or micropapillary (S/MP) components, with a focus on stage IA. Methods We enrolled 506 patients with lung adenocarcinoma who underwent curative resection in this study. Clinical features and surgical outcomes were compared between the groups with and without the S/MP subtype (S/MP+ and S/MP−, respectively), and between the group with an S/MP proportion of ≤5% (S/MP5) and the S/MP−. Results The S/MP subtype was present in 247 patients (48.8%); 129 (25.5%) were grouped as the S/MP5 group. The S/MP+ and S/MP5 groups had larger tumors, higher frequency of lymph node metastasis, and more advanced stages of disease than the S/MP− group (P, We demonstrated that only minimal presence of solid or micropapillary component was profoundly associated with aggressive clinicopathological features and poor prognosis after complete resection even in stage IA lung adenocarcinoma. Our results suggest that minimal presence of these subtypes is a strong prognostic factor which should be taken into account in the risk assessment for adjuvant chemotherapy in lung adenocarcinoma.

Background/aims Genome wide and candidate gene association studies have identified polymorphisms associated with the risk of lung cancer in never-smokers. This study was conducted to evaluate the association between 11 polymorphisms identified in female never smokers and the lung cancer risk in male smokers. Methods This study included 714 lung cancer patients and 626 healthy controls. The polymorphisms were genotyped using SEQUENOM MassARRAY iPLEX assay or Taq-Man assay. Results Two polymorphisms were associated with the risk of lung cancer in male smokers, as in female never smokers. Male smokers carrying the rs4975616 variant allele had a significantly decreased risk of lung cancer (in a codominant model: odds ratio, 0.77; 95% confidence interval, 0.61 to 0.96; p = 0.02). The rs9387478 polymorphism also reduced lung cancer risk in male smokers (in a codominant model: odds ratio, 0.85; 95% confidence interval, 0.73 to 0.997; p = 0.046). In a stratified analysis, the association between these polymorphisms and the risk of lung cancer was predominant in lighter smokers and for cases of adenocarcinoma. Conclusion These results suggest that a subset of polymorphisms known to be associated with the risk of lung cancer in female never smokers is also associated with the risk of lung cancer in male smokers.

BACKGROUND Achaete-scute homolog 1 (ASCL1) is a basic helix-loop-helix transcription factor and is essential in the differentiation of neuroendocrine cells and neural tissues. ASCL1 is frequently overexpressed in small cell lung cancer (SCLC) and plays a crucial role in the pathogenesis of SCLC. METHODS This study was conducted to identify the association between single nucleotide polymorphisms (SNPs) in ASCL1 target genes and clinical outcomes of patients with SCLC after chemotherapy. A total of 261 patients diagnosed with SCLC were enrolled in this study. The association between 103 SNPs in 58 ASCL1 target genes and the response to chemotherapy and survival of patients with SCLC were analyzed. RESULTS Among the 103 SNPs, 10 SNPs were significantly associated with the response to chemotherapy, and 19 SNPs were associated with OS in multivariate analyses. Among these, Dopa Decarboxylase (DDC) rs12666409A>T was significantly associated with both a worse response to chemotherapy and worse OS (adjusted odds ratio [aOR] = 0.40, 95% CI = 0.18-0.90, P = 0.03; adjusted hazard ratio [aHR] = 1.52, 95% CI = 1.10-2.10, P = 0.01, respectively, under a dominant model). In a stage-stratified analysis, the association was significant only in the extensive disease subgroup (aOR = 0.19, 95% CI = 0.06-0.60, P = 0.01; aHR = 1.73, 95% CI = 1.16-2.56, P = 0.01, respectively, under a dominant model), but not in the limited disease subgroup. CONCLUSION The results of our study suggest that DDC rs12666409A>T may be useful markers for predicting the clinical outcomes of patients with SCLC undergoing chemotherapy.

Ji Eun Park,1,&ast; Mi Jeong Hong,2,3,&ast; Shin Yup Lee,1,4 Jang Hyuck Lee,2,4 Jin Eun Choi,2,3 Hyo-Gyoung Kang,2,3 Sook Kyung Do,2,3 Ji Yun Jeong,5 Kyung Min Shin,6 Won Kee Lee,7 Sun Ha Choi,1 Yong Hoon Lee,1 Hye won Seo,1 Seung Soo Yoo,1 Jaehee Lee,1 Seung Ick Cha,1 Chang Ho Kim,1 Jae Yong Park1,2 1Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 2Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 3Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 4BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea; 5Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 6Department of Radiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 7Department of Medical Informatics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Shin Yup Lee; Jae Yong ParkDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of KoreaTel +82-53-200-2632Fax +82-53-200-2027Email shinyup@knu.ac.kr; jaeyong@knu.ac.krIntroduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have represented the prototype of targeted therapy in NSCLC. Patients with EGFR-mutant lung adenocarcinoma extract an extraordinary clinical benefit from EGFR-TKIs. However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual’s response to TKIs. We investigated whether genetic variants in miRNA binding sites are associated with the clinical outcome of EGFR-TKIs in lung adenocarcinoma patients.Methods: One hundred SNPs at miRNA binding sites in cancer-related genes were selected for the analysis using the crosslinking, ligation and sequencing of hybrids (CLASH) and CancerGenes database. qRT-PCR and luciferase assays were conducted to evaluate the functional relevance of the SNPs.Results: NUP62 rs9523A>G were significantly associated with worse response to EGFR-TKIs, overall survival (OS), and progression-free survival (PFS). The other three SNPs (DVL2 rs2074216G>A, ARF1 rs11541557G>T, and UHRF1 rs2261988C>A) were significantly associated with worse OS and PFS. The rs9523A>G was significantly associated with decreased NUP62 expression in tumor tissues. In addition, a significantly decreased luciferase activity was noted in NUP62 rs9523 G allele compared to A allele.Conclusion: Genetic variants in miRNA binding sites, especially NUP62 rs9523A>G, may be useful in predicting the clinical outcomes of EGFR-mutant lung adenocarcinoma patients treated with EGFR-TKIs.Keywords: lung adenocarcinoma, EGFR-TKI, clinical outcome, miRNA binding site, polymorphism

Background To investigate the difference in the measured diameter of subsolid lung adenocarcinomas of thin‐section computed tomography (TSCT) and pathology according to presence of emphysema. Methods A total of 268 surgically resected pathologic T1 or T2 adenocarcinomas visualized as subsolid nodules (SSNs) on TSCT were analyzed in 252 patients. Two observers measured the greatest diameters of the whole tumor (WTsize) and solid tumor (STsize) on TSCT in lung windows, classified nodules as part‐solid or nonsolid, and recorded the presence of regional emphysema. Interobserver variability was determined with intraclass correlation coefficients (ICC). CT measurements were compared to pathologic size (Psize) and invasive size (PIsize) using the Wilcoxon signed‐rank test. Results The interobserver agreement between the diameters measured by the two observers was strong for WTsize (ICC = 0.968 [95% confidence interval, 0.960–0.975]) and STsize (ICC = 0.966 [95% CI, 0.950–0.969]). Radiologic WTsize was significantly greater than Psize (P

Purpose To assess the efficacy and safety of the AMPLATZER Vascular Plug type IV for pulmonary arteriovenous malformation (PAVM) treatment. Materials and Methods Between June 2013 and January 2018, 13 patients with 26 PAVMs were treated with the type IV AVP. Patients without follow-up computed tomography (CT) were excluded. Technical success was defined as flow occlusion on angiography. Plug-to-sac distance was measured on angiographic images. Feeding artery and venous sac diameter changes were measured on preprocedural and follow-up CT. Successful embolization was defined as > 70% sac size regression. Procedure time, device migration, and complications were evaluated. Results Nine female patients (mean age, 49 y; range, 40–71 y) with 19 PAVMs were enrolled. Four patients with 7 PAVMs were lost to follow-up. Nineteen PAVMs were treated in 11 sessions, and the mean procedure time was 29 min. The technical success rate was 100%. Mean feeding artery diameter was 3.1 mm ± 0.7 (range, 2.1–4.9 mm). Mean plug-to-sac distance was 5.4 mm ± 4.9 (range, 0–13.3 mm). The mean CT follow-up period was 14 months ± 7 (range, 6–30 mo). Sixteen of 19 PAVMs (84%) were successfully embolized. Minor complications (tachycardia and chest discomfort) arose in 2 of 11 sessions. No device migrations or major complications occurred. Conclusions The type IV AVP showed an 84% treatment success rate based on 70% sac size regression criteria in small PAVMs. There were no device migrations or major complications.

This study was conducted to explore whether polymorphisms of glucose transporter 3 (GLUT3) gene affect the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Four single nucleotide polymorphisms (SNPs) in GLUT3 were investigated in a total of 782 patients with NSCLC who underwent curative surgery. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. Among the four SNPs investigated, GLUT3 rs7309332C>T was significantly associated with OS and DFS in multivariate analyses. The SNP was associated with significantly worse OS (adjusted hazard ratio [aHR] = 1.62, 95% confidence interval [CI] = 1.04–2.53, P = 0.03, under recessive model), and worse DFS (aHR = 1.64, 95% CI = 1.18–2.29, P = 0.003, under recessive model). When stratified by tumor histology, the association between the GLUT3 rs7309332C>T and OS/DFS was not limited to either squamous cell carcinoma (SCC) or adenocarcinoma (AC), although the significant association remained only in AC for OS (P = 0.40 for SCC and P = 0.04 for OS) and only in SCC for DFS (P = 0.03 for SCC and P = 0.08 for OS). When AC patients were stratified according to EGFR mutation status, the SNP was significantly associated with DFS in patients with EGFR mutant tumors (aHR = 2.47, 95% CI = 1.15–5.30, P = 0.02, under recessive model), but not in those with EGFR wild-type tumors. This study suggests that genetic variation in GLUT3 may be useful in predicting survival of patients with early stage NSCLC.

Objectives Clinical manifestations of lipoid pneumonia (LP) vary depending on the causative agents or underlying causes. The aim of the present study was to investigate the clinical and radiological features of LP, classified according to etiologic agents. Methods The clinico-radiological characteristics of LP patients were retrospectively compared among groups: exogenous versus idiopathic and squalene versus omega-3-acid ethyl esters (O-3-AEE) versus idiopathic. Idiopathic group was defined as LP with no proven or reported etiological evidence. Results Twenty-two patients met the diagnostic criteria for LP: squalene (9 [41%]), O-3-AEE (6 [27%]), olive oil (1 [5%]), and idiopathic (7 [32%]). Compared with the exogenous group, the idiopathic group showed a higher recurrence rate; higher frequencies of bronchial anthracofibrosis (BAF) and bronchoalveolar lavage (BAL) lymphocytosis; and a higher rate of crazy-paving pattern and lower rate of consolidation on computed tomography scan. In three-group tests, compared with the O-3-AEE group, the squalene group exhibited a significantly higher percentage of neutrophils and a higher rate of right middle lobe (RML) involvement. Conclusions In comparison with the exogenous group, the idiopathic group demonstrated BAL lymphocytosis, higher rates of recurrence and BAF, and a higher rate of crazy-paving pattern. Compared with the O-3-AEE group, the squlaene group showed a higher percentage of BAL neutrophils and predominant RML involvement.

Background: Data regarding community-acquired pneumonia (CAP) identified on chest computed tomography (CT) but not on chest radiography (CR) are limited. Objectives: The present study aimed to investigate the clinical and radiological features of these patients. Methods: We retrospectively compared the clinical characteristics, etiological agents, treatment outcomes, and CT findings between CAP patients with negative CR and positive CT findings (negative CR group) and those with positive CR as well as CT findings (control group). Results: Of 1,925 patients, 94 patients (4.9%) were included in the negative CR group. Negative CR findings could be attributed to the location of the lesions (e.g., those located in the dependent lung) and CT pattern with a low attenuation, such as ground-glass opacity (GGO). The negative CR group was characterized by a higher frequency of aspiration pneumonia, lower incidences of complicated parapneumonic effusion or empyema and pleural drainage, and lower blood levels of inflammatory markers than the control group. On CT, the negative CR group exhibited higher rates of GGO- and bronchiolitis-predominant patterns and a lower rate of consolidation pattern. Despite shorter length of hospital stay in the negative CR group, 30-day and in-hospital mortalities were similar between the two groups. Conclusions: CAP patients with negative CR findings are characterized by lower blood levels of inflammatory markers, a higher incidence of aspiration pneumonia, and a lower incidence of complicated para­pneumonic effusion or empyema than those with positive CR findings. Chest CT scan should be considered in suspected CAP patients with a negative CR, especially in bedridden patients.

We investigated the association between genetic variants in the histone modification regions and the prognosis of lung adenocarcinoma after curative surgery. Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The SNPs were analyzed in a discovery set (n=166) and a validation set (n=238). The associations of the SNPs with overall survival (OS) and disease-free survival (DFS) were analyzed. A total of 279 SNPs were selected for genotyping. Among these, CAPN1 rs17583C>T was significantly associated with better OS and DFS (P = 0.001 and P = 0.007, respectively), and LINC00959 rs4751162A>G was significantly associated with worse DFS (P = 0.008). Luciferase assays showed a significantly lower promoter activity of CAPN1 in the rs17583 T allele than C allele (P = 0.008), and consistently the CT+TT genotypes had significantly lower CAPN1 expression than CC genotype (P = 0.01) in clinical samples. The rs4751162 G allele had higher promoter activity of GLRX3 than A allele (P = 0.05). The motif analyses and ChIP-qPCR confirmed that the variants are located in the active promoter/enhancer regions where transcription factor binding occurs. This study showed that genetic variants in the histone modification regions could predict the prognosis of lung adenocarcinoma after surgery.

Background To assess pulmonary arteriovenous malformation (PAVM) recanalization after embolization based on PAVM diameter changes on computed tomography (CT), with pulmonary angiography used as a gold standard. Methods A retrospective review was done of patients from 2008 to 2019 with a PAVM treated with endovascular embolization. The treatment outcome was determined by conventional angiography. Follow-up pulmonary angiography was performed when recanalization was suspected on CT, or embolization of all lesions in multiple PAVM patients could not be completed in a single session. Patients who had no preprocedural or follow-up CT were excluded. Draining vein, feeding artery, and venous sac diameter were measured on CT, and diameter reduction rates were compared with the widely-used, binary 70 % criteria. Results Forty-one patients with 114 PAVMs were treated during the study period. Eight patients with 50 PAVMs met the inclusion criteria. Mean vein, artery, and venous sac diameter reduction rates were as follows: 59.2 ± 9.3 %, 47.5 ± 10.6 %, and 62.6 ± 13.2 %, respectively, in the occluded group and 5.4 ± 19.5 %, 11.3 ± 17.7 %, and 26.8 ± 14.2 %, respectively, in the recanalized group. The area under the receiver operating characteristic curves for PAVM recanalization for the draining vein was 1.00, showing a better result than the artery (0.97) and sac (0.99). Patients showed > 42 % draining vein diameter reduction in the occluded group and Conclusions The widely-used 70 % binary criteria showed limited performance in predicting outcomes in this angiographically-confirmed case series. Further investigations are warranted to establish a strategy for detecting recanalization after PAVM embolization.

The cause of epithelioid granulomatous inflammation varies widely depending on the affected organ, geographic region, and whether the granulomas morphologically contain necrosis. Compared with other organs, the etiological distribution and morphological patterns of pleural epithelioid granulomas have rarely been investigated. We evaluated the final etiologies and morphological patterns of pleural epithelioid granulomatous inflammation in a tuberculosis (TB)-prevalent country. Of 83 patients with pleural granulomas, 50 (60.2%) had confirmed TB pleurisy (TB-P) and 29 (34.9%) had probable TB-P. Four patients (4.8%) with non-TB-P were diagnosed. With the exception of microbiological results, there was no significant difference in clinical characteristics and granuloma patterns between the confirmed TB-P and non-TB-P groups, or between patients with confirmed and probable TB-Ps. These findings suggest that most pleural granulomatous inflammation (95.2%) was attributable to TB-P in TB-endemic areas and that the granuloma patterns contributed little to the prediction of final diagnosis compared with other organs., Graphical Abstract

Objectives The Cat Eye Syndrome Critical Region, Candidate 1 (CECR1) gene encoding adenosine deaminase 2 (ADA2) is mainly expressed by macrophages. Given the immunomodulatory functions of butyrate, we examined the effect of butyrate on CECR1 expression of macrophages and the relationship between ADA2 and M1/M2 macrophages-associated chemokines in pleural fluid of patients with tuberculous pleural effusion (TPE). Methods Expression of CECR1 was evaluated in lipopolysaccharide (LPS)-stimulated and/or butyrate treated THP-1 cells. The role of CECR1 on butyrate-induced immune response was evaluated using siRNA transfected THP-1 cells. M1/M2 chemokines and ADA2 were measured in pleural fluid of patients with TPE. Results Butyrate promoted the expression of CECR1 and M2-macrophage markers in THP-1 cells. CECR1 was found to be involved in regulating M2 polarization in THP-1 cells treated with LPS and butyrate. Among chemokines measured in pleural fluid of patients with TPE, there was a significant negative correlation between CCL21 and ADA2 levels and between CCL25 and ADA2 levels, and a significant positive correlation between TGF-β and ADA2 levels and between IL-22 and ADA2 levels. Conclusions CECR1 played an important role in the butyrate-modulated inflammatory responses in LPS-stimulated THP-1 cells. ADA2 may exert anti-inflammatory effects during the process of pleural inflammation in patients with TPE.

Background Data regarding predictors of the outcome for patients with community-acquired complicated parapneumonic effusion (CPPE) or empyema are insufficient. Method Patients with community-acquired pneumonia (CAP) were classified into CPPE or empyema and control groups based on pleural fluid analysis and microbiological data. The patients with CPPE or empyema were further divided into longer and shorter length of stay (LOS) groups, and clinical characteristics, pleural fluid data, and computed tomographic (CT) findings were compared between the two groups. Result Of outcome variables, LOS was significantly longer in CPPE or empyema group than in the control group (13 days [interquartile range, 10-17 days] versus 8 days [6-12 days], p < 0.001), whereas 30-day mortality and in-hospital mortality were not significantly different between the two groups. Patients with CPPE or empyema were divided into the shorter (≤ 13 days) and longer LOS (≥ 14 days) groups. Multivariate analysis demonstrated that pneumonia severity index (PSI) class IV-V (odds ratio [OR] 2.79, 95% CI 1.35-5.76, p=0.006), increased attenuation of extrapleural fat (OR 2.26, 95% CI 1.06-4.80, p=0.034), and air bubbles in pleural space (OR 3.93, 95% CI 1.03-14.98, p=0.045) were independent predictors of prolonged LOS in CAP patients with CPPE or empyema. Conclusion Increased attenuation of extrapleural fat and air bubbles in pleural space assessed with CT and PSI class IV-V independently predicted prolonged LOS in CAP patients with CPPE or empyema. These findings may be helpful to identify patients who need more intensive evaluation and intervention.