Nationwide prevalence and trends in cigarette smoking among adult men with and without disabilities in South Korea between 2009 and 2017.

OBJECTIVES: Current smoking rates for people with and without disabilities vary among countries. This study analyzed smoking behavior over 9 years in adult South Korean men with disabilities, according to disability severity and type, and in those without disabilities. STUDY DESIGN: This was a cross-sectional study. METHODS: This analysis was conducted using national disability registration data and national general health checkup data for 2009-2017. Age-standardized smoking behaviors were analyzed for each year according to the presence, severity, and type of disability. The odds of current smoking were determined by multivariate logistic regression after adjusting for sociodemographic and clinical variables. RESULTS: The age-standardized smoking rate and average number of cigarettes for men with mild disabilities in the younger age group were 1.16 (43.0 vs 36.8%) and 1.05 (16.1 vs 15.3 cigarettes) times higher than in non-disabled men as of 2017. The highest smoking rate was observed in men with physical disabilities in the younger age. In the older age group, the highest smoking rate was that of men with intellectual or psychological disabilities. CONCLUSION: Smoking behaviors remained poorest in men with disabilities, especially those with mild, physical, and intellectual/psychological disabilities. Public health policies should focus on people with disabilities to promote health, prevent secondary conditions, and reduce health disparities by implementing antismoking health policies.

Preoperative Chemoradiotherapy With Capecitabine With or Without Temozolomide in Patients With Locally Advanced Rectal Cancer: A Prospective, Randomised Phase II Study Stratified by O6-Methylguanine DNA Methyltransferase Status: KCSG-CO17-02.

AIMS: To evaluate the clinical efficacy of adding temozolomide (TMZ) to preoperative capecitabine (CAP)-based chemoradiotherapy in patients with locally advanced rectal cancer (LARC) and validate O6-methylguanine DNA methyltransferase (MGMT) methylation status as a predictive marker for TMZ combined regimens. MATERIALS AND METHODS: LARC patients with clinical stage II (cT3-4N0) or III (cTanyN+) disease were enrolled. They were stratified into unmethylated MGMT (uMGMT) and methylated MGMT (mMGMT) groups by methylation-specific polymerase chain reaction before randomisation and were then randomly assigned (1:1) to one of four treatment arms: uMGMT/CAP (arm A), uMGMT/TMZ + CAP (arm B), mMGMT/CAP (arm C) and mMGMT/TMZ + CAP (arm D). The primary end point was the pathological complete response (pCR) rate. RESULTS: Between November 2017 and July 2020, 64 patients were randomised. Slow accrual caused early study termination. After excluding four ineligible patients, 60 were included in the full analysis set. The pCR rate was 15.0% (9/60), 0%, 14.3%, 18.8% and 26.7% for the entire cohort, arms A, B, C and D, respectively (P = 0.0498 between arms A and D). The pCR rate was 9.7% in the CAP group (arms A + C), 20.7% in the TMZ + CAP group (arms B + D), 6.9% in the uMGMT group (arms A + B) and 22.6% in the mMGMT group (arms C + D). Grade 1-2 nausea or vomiting was significantly more frequent in the TMZ + CAP treatment groups (arms B + D) than in the CAP treatment groups (arms A + C, P < 0.001) with no difference in grade 3 adverse events. There were no grade 4 or 5 adverse events. CONCLUSION: The addition of TMZ to CAP-based chemoradiotherapy tended to improve pCR rates, particularly in those with mMGMT LARC. MGMT status may warrant further investigation as a predictive biomarker for chemotherapeutic agents and radiotherapy.

In vitro mitochondrial apoptosis of melanoma cells via immature Poncirus trifoliata fruit extract.

OBJECTIVE: Poncirus trifoliata (P. trifoliata) fruits exert phytotherapeutic effects, depending on their maturity level. However, the mechanism by which these phytotherapeutic effects are exerted remains undefined - especially in cancers. Therefore, in this study, we investigated the effects of the immature fruit extract of P. trifoliata on a B16 melanoma cell line. MATERIALS AND METHODS: The effect of immature P. trifoliata extract on B16 cells was evaluated by MTT assay, cell proliferation, FACScan analysis of cell cycles, confocal imaging analysis, nuclear (Hoechst) staining, apoptosis assay (Annexin V-fluorescein isothiocyanate/propidium iodide staining), and Western blot assay. The capacity of immature P. trifoliata extract to inhibit the invasion and migration of B16 cells was assessed using the scratch-wound assay and Matrigel migration assay. The effect of immature P. trifoliata extract on mitochondrial function was determined via the mitochondrial membrane potential assay, activity, and fraction and cytosol proteins. RESULTS: Treating B16 cells with a methanol extract of immature P. trifoliata (MEPT) significantly inhibited cell viability, migration, and invasiveness in a dose- (p<0.01) and time (p<0.01)- dependent manner. MEPT arrested the cells in the G1 phase of the cell cycle and led to the activation of the PI3K/AKT/p21 pathway. Furthermore, MEPT dose-dependently induced apoptosis in B16 cells by increasing the expression of the pro-apoptotic proteins Bax and Apaf-1, while decreasing the expression of the anti-apoptotic protein, Bcl-2. MEPT treatment also decreased mitochondrial membrane potential. CONCLUSIONS: Immature P. trifoliata extract inhibited the growth of melanoma cells by inducing cell apoptosis through mitochondrial pathways. Therefore, further research into immature P. trifoliata extract as a potential therapeutic compound for melanoma treatment is warranted.

Facemask ventilation and vocal cord angle following neuromuscular blockade: a prospective observational study.

Numerous studies support the idea that neuromuscular blockade facilitates facemask ventilation after induction of anaesthesia. Although improved airway patency or pulmonary compliance and a resolution of laryngospasm have been suggested as possible causes, the exact mechanism remains unclear. We aimed to assess whether neuromuscular blockade improves facemask ventilation and to clarify whether this phenomenon is associated with the vocal cord angle. This prospective observational study included patients aged between 20 and 65 years scheduled for elective surgery under general anaesthesia. After induction of anaesthesia, patients' lungs were ventilated with pressure-controlled ventilation using a facemask. During facemask ventilation, a flexible bronchoscope was inserted through a self-sealing diaphragm at the elbow connector attached to the facemask and breathing circuit and positioned to allow a continuous view of the vocal cords. The mean tidal volume and vocal cord angle were measured before and after administration of neuromuscular blocking drugs. Of 108 patients, 100 completed the study. Mean (SD) tidal volume ((11.0 (3.9) ml.kg-1 vs. 13.6 (2.6) ml.kg-1 ; p < 0.001) and mean (SD) vocal cord angle (17° (10°) vs. 26° (5°); p < 0.001) increased significantly after neuromuscular blockade. The proportional increase in mean tidal volume after neuromuscular blockade was positively correlated with vocal cord angle (Spearman's ρ = 0.803; p < 0.001). In conclusion, neuromuscular blockade facilitated facemask ventilation, and the improvement was correlated with further opening of the vocal cords.

Diagnostic accuracy of the jetting sign and a dilatation ratio of left renal vein in CT urography for detecting anterior nutcracker syndrome.

AIM: To investigate the diagnostic value of computed tomography (CT) urography findings of anterior nutcracker syndrome (NCS). MATERIALS AND METHODS: The study included patients with left renal vein (LRV) compression at the aortomesenteric portion at CT urography who underwent renal venography or cystoscopy. Patients with a renocaval pressure gradient of ≥3 mmHg on renal venography or bloody urine jetting from the left ureteral orifice on cystoscopy were defined as the NCS group; the remaining patients comprised the non-NCS group. CT findings were analysed using the jetting of contrast medium flow from the LRV to the inferior vena cava (jetting sign), aortomesenteric distance, presence of collateral veins, and a dilatation ratio of LRV diameter at the aortomesenteric portion (arterial phase/delayed phases). Clinical findings, including age, gender, and body-mass-index, were also analysed. CT features and clinical findings were compared between the NCS and non-NCS groups. Diagnostic performance of CT parameters was assessed using receiver operating characteristic curve analysis. RESULTS: A total of 70 patients (21 men, mean age 44.4 ± 17.2 years) with NCS (n=13) and non-NCS (n=57) were included. Younger age (<40 years), presence of the jetting sign, and a lower dilatation ratio of LRV diameter between the arterial and delayed phases (<1.7) were found to be significant independent factors for predicting the NCS group (OR 24.5, 18.9, 19.4, respectively, p<0.05 for all). The combination of the presence of the jetting sign and a dilatation ratio of LRV diameter of <1.7 obtained the highest AUC of 0.88. CONCLUSION: The jetting sign and the dilatation ratio of LRV diameter between the arterial and delayed phases can both be very useful in the diagnosis of anterior nutcracker syndrome during CT urography.

Altered distributions in circulating follicular helper and follicular regulatory T cells accountable for imbalanced cytokine production in multiple sclerosis.

Follicular T helper (Tfh) and regulatory (Tfr) cells are distinct subsets of CD4+ T lymphocytes, regulating humoral immune responses in the germinal center. It is widely accepted that dysregulated Tfh and Tfr cells are associated with autoimmunity. In this study, we evaluated the frequencies of circulating chemokine receptor (CXCR)5+ programmed cell death 1 (PD-1+ ) Tfh (cTfh) and CXCR5+ PD-1+ forkhead box protein 3 (FoxP3+ ) CD25+ Tfr (cTfr) cells, and their corresponding cytokines from the peripheral blood mononuclear cells of 28 patients with relapsing-remitting multiple sclerosis (MS) and 16 age- and sex-matched healthy controls (HC). Subsets of cTfh cells by Th1- and Th17-related surface markers (CXCR3 and CCR6) were also evaluated. We found that the frequency of cTfh cells was significantly higher in MS patients compared to that of HC. Conversely, the frequency of cTfr cells was lower in MS patients than that of HC. Interleukin (IL)-21-producing cTfh cells were significantly increased in MS patients, while IL-10-secreting cTfr cells were lower in MS patients compared to levels in HC. Among cTfh cells, cTfh17.1 cells were the major subtypes that were significantly increased in MS patients compared to HC, with the frequency of IL-21-secreting cells being the highest. These results suggest that an imbalanced distribution of cTfh and cTfr exist in MS patients, which contributes to the reciprocally altered IL-21 and IL-10 production.

Association between benign paroxysmal positional vertigo and osteoporosis: two nested case-control studies.

Benign paroxysmal positional vertigo (BPPV) was related to a 1.28 times higher risk of osteoporosis. In addition, osteoporosis was associated with a 1.34 times higher risk of BPPV. This bidirectional relation was maintained after adjusting past medical histories and lifestyle factors, including obesity, smoking, and alcohol consumption. To our knowledge, this is the first study to explore the reciprocal association between BPPV and osteoporosis. In subgroup analyses, only women showed a reciprocal association between BPPV and osteoporosis. INTRODUCTION: A previous population cohort study suggested an association between osteoporosis and benign paroxysmal positional vertigo (BPPV). This study aimed to investigate the bidirectional association between BPPV and osteoporosis. METHODS: The Korean National Health Insurance Service-Health Screening Cohort data from 2002 to 2013 were used. In study I, the 50,897 osteoporosis patients were 1:1 matched with control I participants for age, sex, income, and region of residence. The previous histories of BPPV were analyzed in both groups using conditional logistic regression analysis. In study II, 9621 BPPV patients were 1:4 matched with control II participants. The previous histories of osteoporosis were analyzed in both groups using conditional logistic regression analysis. According to age and sex, subgroup analyses were achieved in both studies I and II. RESULTS: A total of 1.6% (822/50,897) of osteoporosis patients and 1.3% (644/50,897) of control I participants had BPPV. The osteoporosis patients demonstrated a 1.28 times higher chance of developing BPPV (95% confidence intervals [95% CI] = 1.16-1.42, P < 0.001). In study II, 21.2% (2040/9621) of BPPV patients and 17.6% (6790/38,484) of control II participants had osteoporosis. The BPPV patients showed 1.34 times higher chance of having osteoporosis (95% CI = 1.26-1.43, P < 0.001). In the analysis of the women subgroup, these relations were reliable. CONCLUSION: Osteoporosis patients had increased odds of having BPPV. On the other hand, BPPV patients had increased odds of having osteoporosis. This bidirectional relation was consistent only in the women subgroup.

Dynamic predictive model for postoperative nausea and vomiting for intravenous fentanyl patient-controlled analgesia.

Postoperative nausea and vomiting is the most common side-effect of opioid-based intravenous patient-controlled analgesia. Apfel's simplified risk score is popular but it has some limitations. We developed and validated a dynamic predictive model for nausea or vomiting up to 48 postoperative hours, available as an online web application. Fentanyl was used by 22,144 adult patients for analgesia after non-cardiac surgery under general anaesthesia: we randomly divided them into development (80%) and validation (20%) cohorts, repeated 100 times. We used linear discriminant analysis to select variables for multivariate logistic regression. The incidences of postoperative nausea or vomiting were: 0-48 h, 5691/22,144 (26%); 0-6 h, 2749/22,144 (12%); 6-12 h, 2687/22,144 (12%); 12-18 h, 2624/22,144 (12%); 18-24 h, 1884/22,144 (9%); and 24-48 h, 1082/22,144 (5%). The median (95%CI) area under the receiver operating characteristic curve was 0.72 (0.71-0.73) up to 48 postoperative hours compared with 0.65 (0.64-0.66) for the Apfel model, p < 0.001. The equivalent areas for 0-6 h, 6-12 h, 12-18 h, 18-24 h and 24-48 h were: 0.70 (0.69-0.72); 0.71 (0.69-0.73); 0.69 (0.68-0.71); 0.70 (0.67-0.72); and 0.69 (0.66-0.71), respectively. Our web application allows clinicians to calculate incidences of nausea and vomiting in patients receiving intravenous fentanyl for patient-controlled analgesia.

Dermatologist-level classification of malignant lip diseases using a deep convolutional neural network.

BACKGROUND: Deep convolutional neural networks (DCNNs) can classify skin diseases at a level equivalent to a dermatologist, but their performance in specific areas requires further research. OBJECTIVE: To evaluate the performance of a trained DCNN-based algorithm in classifying benign and malignant lip diseases. METHODS: A training set of 1629 images (743 malignant, 886 benign) was used with Inception-Resnet-V2. Performance was evaluated using another set of 344 images and 281 images from other hospitals. Classifications by 44 participants (six board-certified dermatologists, 12 dermatology residents, nine medical doctors not specialized in dermatology and 17 medical students) were used for comparison. RESULTS: The outcomes based on the area under curve, sensitivity and specificity were 0·827 [95% confidence interval (CI) 0·782-0·873], 0·755 (95% CI 0·673-0·827) and 0·803 (95% CI 0·752-0·855), respectively, for the set of 344 images; and 0·774 (95% CI 0·699-0·849), 0·702 (95% CI 0·579-0·808) and 0·759 (95% CI 0·701-0·813), respectively, for the set of 281 images. The DCNN was equivalent to the dermatologists and superior to the nondermatologists in classifying malignancy. After referencing the DCNN result, the mean ± SD Youden index increased significantly for nondermatologists, from 0·201 ± 0·156 to 0·322 ± 0·141 (P < 0·001). CONCLUSIONS: DCNNs can classify lip diseases at a level similar to dermatologists. This will help unskilled physicians discriminate between benign and malignant lip diseases. What's already known about this topic? Deep convolutional neural networks (DCNNs) can classify malignant and benign skin diseases at a level equivalent to dermatologists. The lips are a unique feature in terms of histology and morphology. Previous studies of DCNNs have not investigated tumours on specific locations. What does this study add? This study shows that DCNNs can distinguish rare malignant and benign lip disorders at the same rate as dermatologists. DCNNs can help nondermatologists to distinguish malignant lip diseases. What are the clinical implications of this work? DCNNs can distinguish malignant and benign skin diseases even at specific locations such as the lips, as well as board-certified dermatologists. Malignant lip diseases are rare and difficult for less trained doctors to differentiate them from benign lesions. This study shows that in dermatology, DCNN can help improve decision-making processes for rare skin diseases in specific areas of the body.

Three-dimensional changes of proximal segments in facial asymmetry patients after bilateral vertical ramus osteotomy.

The intraoral vertical ramus osteotomy (IVRO) is a useful technique for mandibular setback surgery. However, there is a tendency for lateral flaring of the proximal segments on the non-deviation side after the correction of mandibular asymmetry with this technique. The purpose of this retrospective study was to evaluate the positional changes of the proximal segments after IVRO setback in skeletal class III patients with asymmetry, using preoperative and postoperative computed tomography scan data, and to apply the results in clinical practice. A total of 28 skeletal class III patients with asymmetry who underwent bimaxillary orthognathic surgery were included. A three-dimensional cone beam computed tomography scan was obtained preoperative, at 1month postoperative, and at 1year postoperative. At 1month after the surgery, the proximal segments showed an outward rotation, lateral flaring, and anterior rotation of the condylar head. All postsurgical directional changes had returned to the preoperative state at 1year postoperative, and there was no statistically significant difference in postoperative angulation changes between the two sides. The results showed no statistical differences in the positional changes of the proximal segments between the deviation and non-deviation sides. This study reaffirms the benefits of the IVRO for a minimal bony interference between the proximal and distal segments in three dimensions, including mandibular asymmetry cases.

Relationship between smoking and spontaneously healed pulmonary TB on chest radiography in a South Korean population.

SETTING: The Korea National Health and Nutrition Examination Survey is a national, population-based, cross-sectional surveillance programme.OBJECTIVE: 1) To investigate the prevalence of spontaneously healed pulmonary tuberculosis (SHPTB) on chest radiographs (CXRs) in South Korea, as well as its demographic and clinical associations, and 2) to determine the relationship between SHPTB and smoking.DESIGN: People with normal findings on CXRs (n = 24 190) and those with SHPTB (n = 1863) were compared in univariate, bivariate and multivariate analyses with respect to smoking and demographic and clinical factors.RESULTS: The prevalence of SHPTB was 7.2%. The proportion of patients with SHPTB tended to be higher in males, people of older age, ever smokers, as well as people with low body mass index and low education level. In bivariate analysis, after adjustments for age and sex, SHPTB was found more often among ex-smokers (P = 0.005) and current smokers (P = 0.024) than in non-smokers. Multivariate analyses revealed increased relative odds for SHPTB with increased age (P < 0.001), male sex (P < 0.001) and ex-smoker status (P = 0.016). Passive smoking was also significantly associated with SHPTB (P = 0.022).CONCLUSION: In addition to increasing the risk of active TB and negatively affecting the outcome of TB treatment, smoking is also associated with SHPTB, as detected on CXRs.

Detection of Local Recurrence in Patients with Head and Neck Squamous Cell Carcinoma Using Voxel-Based Color Maps of Initial and Final Area under the Curve Values Derived from DCE-MRI.

BACKGROUND AND PURPOSE: Early detection of local recurrence is important to increase the chance of cure because local recurrence is the main cause of treatment failure in head and neck squamous cell carcinoma. We evaluated the added value of voxel-based color maps of dynamic contrast-enhanced MR imaging compared with conventional MR imaging alone for detecting local recurrence of head and neck squamous cell carcinoma. MATERIALS AND METHODS: We retrospectively enrolled 63 consecutive patients with head and neck squamous cell carcinoma after definitive treatment and posttreatment surveillance MR imaging studies that demonstrated focal enhancement at the primary site. Three independent readers assessed conventional MR imaging and a pair of color maps of initial and final 90-second time-signal intensity areas under the curve from dynamic contrast-enhanced MR imaging. The sensitivities, specificities, and accuracies of both conventional MR imaging alone and combined interpretation of conventional and dynamic contrast-enhanced MR imaging were assessed using the clinicopathologic diagnosis as the criterion standard. κ statistics were used to evaluate interreader agreement. RESULTS: There were 28 patients with subsequently documented local recurrence and 35 with posttreatment change. Adding dynamic contrast-enhanced MR imaging to conventional MR imaging significantly increased the diagnostic accuracies for detecting local recurrence (48%-54% versus 87%-91%; P < .05), with excellent interreader agreement (κ = 0.8; 95% CI, 0.67-0.92 to κ = 0.81; 95% CI, 0.69-0.93). By all 3 readers, the specificities were also significantly improved by adding dynamic contrast-enhanced MR imaging to conventional MR imaging (22%-43% versus 87%-91%; P < .001) without sacrificing the sensitivities (68%-82% versus 86%-89%; P > .05). CONCLUSIONS: Adding voxel-based color maps of initial and final 90-second time-signal intensity areas under the curve from dynamic contrast-enhanced MR imaging to conventional MR imaging increases the diagnostic accuracy to detect local recurrence in head and neck squamous cell carcinoma by improving the specificity without sacrificing the sensitivity.

Clinical features and prognosis of patients with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease.

Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) share common risk factors. They could therefore be expressed in a single patient. However, the prevalence, clinical characteristics and prognosis of individuals with comorbid IPF and COPD are not known. From 2003 to 2007, the Korean Interstitial Lung Disease Study Group created a register for idiopathic interstitial pneumonia using 2002 ATS/ERS (American Thoracic Society/European Respiratory Society) criteria. Of the 1546 IPF patients assessed, 143 had decreased lung function consistent with COPD (IPF-COPD). COPD was diagnosed based on age (≥40 years) and pulmonary function (forced expiratory volume in 1 sec [FEV1]/forced vital capacity [FVC] ratio < 0.7). The median age of the IPF-COPD group was 71.0 years (interquartile range 66.0-76.0); most patients were male (88.1%). FVC (%) was significantly higher in the IPF-COPD group; however, FEV1 (%) was significantly lower in the IPF-COPD group (P < 0.001). Diffusing capacity of the lung for carbon monoxide (DLCO) was not significantly different between the two groups. In survival analysis, age and FVC (%), but not COPD, were significantly associated with prognosis (respectively P = 0.003, 0.001 and 0.401). COPD severity was also not related to prognosis (P = 0.935). The prevalence of IPF-COPD was estimated to be ∼9.2% among all IPF patients; prognosis of patients with IPF-COPD was not worse than those with IPF alone. .

Correlation of human papilloma virus status with quantitative perfusion/diffusion/metabolic imaging parameters in the oral cavity and oropharyngeal squamous cell carcinoma: comparison of primary tumour sites and metastatic lymph nodes.

AIM: To investigate the differences in perfusion/diffusion/metabolic imaging parameters according to human papilloma virus (HPV) status in the oral cavity and oropharyngeal squamous cell carcinoma (OC-OPSCC), separately in primary tumour sites and metastatic lymph nodes. MATERIALS AND METHODS: This retrospective study comprised 41 patients with primary OC-OPSCCs and 29 patients with metastatic lymph nodes. The perfusion/diffusion/metabolic imaging parameters were measured at the primary tumour and the largest ipsilateral metastatic lymph node. The quantitative parameters were compared between the HPV-positive and -negative groups. RESULTS: The HPV-positivity was 39% (16 patients) for the primary tumours and 51.7% (15 patients) for the metastatic lymph nodes. Patients with HPV-positive tumours had a lower T stage (p=0.034). The metastatic lymph nodes for the HPV-positive patients were bulkier (p=0.016) and more frequently had cystic morphology (p=0.005). The perfusion parameters were not different, regardless of HPV status. The diffusion parameter (ADCmin, p=0.011) of the metastatic lymph nodes in the HPV-positive groups was lower and metabolic parameter (metabolic tumour volume p=0.035 and total lesion glycolysis p=0.037) were higher than those in HPV-negative groups. CONCLUSION: The diffusion and metabolic parameters of metastatic lymph nodes from OC-OPSCC were different according to HPV status. The perfusion parameters did not clearly represent HPV status.

Association between ambient air pollution and pregnancy rate in women who underwent IVF.

STUDY QUESTION: Are the concentrations of five criteria air pollutants associated with probabilities of biochemical pregnancy loss and intrauterine pregnancy in women? SUMMARY ANSWER: Increased concentrations of ambient particulate matter (PM10), nitrogen dioxide (NO2), carbon monoxide (CO) during controlled ovarian stimulation (COS) and after embryo transfer were associated with a decreased probability of intrauterine pregnancy. WHAT IS KNOWN ALREADY: Exposure to high ambient air pollution was suggested to be associated with low fertility and high early pregnancy loss in women. STUDY DESIGN, SIZE, DURATION: Using a retrospective cohort study design, we analysed 6621 cycles of 4581 patients who underwent one or more fresh IVF cycles at a fertility centre from January 2006 to December 2014, and lived in Seoul at the time of IVF treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: To estimate patients' individual exposure to air pollution, we computed averages of hourly concentrations of five air pollutants including PM10, NO2, CO, sulphur dioxide (SO2) and ozone (O3) measured at 40 regulatory monitoring sites in Seoul for each of the four exposure periods: period 1 (start of COS to oocyte retrieval), period 2 (oocyte retrieval to embryo transfer), period 3 (embryo transfer to hCG test), and period 4 (start of COS to hCG test). Hazard ratios (HRs) from the time-varying Cox-proportional hazards model were used to estimate probabilities of biochemical pregnancy loss and intrauterine pregnancy for an interquartile range (IQR) increase in each air pollutant concentration during each period, after adjusting for individual characteristics. We tested the robustness of the result using generalised linear mixed model, accounting for within-woman correlation. MAIN RESULTS AND THE ROLE OF CHANCE: Mean age of the women was 35 years. Average BMI was 20.9 kg/m2 and the study population underwent 1.4 IVF cycles on average. Cumulative pregnancy rate in multiple IVF cycles was 51.3% per person. Survival analysis showed that air pollution during periods 1 and 3 was generally associated with IVF outcomes. Increased NO2 (adjusted HR = 0.93, 95% CI: 0.87, 0.99) and CO (0.94, 95% CI: 0.89, 1.00) during period 1 were associated with decreased probability of intrauterine pregnancy. PM10 (0.92, 95% CI: 0.85, 0.99), NO2 (0.93, 95% CI = 0.86, 1.00) and CO (0.93, 95% CI: 0.87, 1.00) levels during period 3 were also inversely associated with intrauterine pregnancy. Both PM10 (1.17, 95% CI: 1.04 1.33) and NO2 (1.18, 95% CI: 1.03, 1.34) during period 3 showed positive associations with biochemical pregnancy loss. LIMITATIONS, REASONS FOR CAUTION: The district-specific ambient air pollution treated as an individual exposure may not represent the actual level of each woman's exposure to air pollution. Smoking, working status, parity or gravidity of women, and semen analysis data were not included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: This study provided evidence of an association between increased ambient concentrations of PM10, NO2 and CO and reduced probabilities for achieving intrauterine pregnancy using multiple IVF cycle data. Specifically, our results indicated that lower intrauterine pregnancy rates in IVF cycles may be linked to ambient air pollution during COS and the post-transfer period. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013 R1A6A3A04059017, 2016 R1D1A1B03933410 and 2018 R1A2B6004608) and the National Cancer Center of Korea (NCC-1810220-01). The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Human Papillomavirus 16 E6 Induces FoxM1B in Oral Keratinocytes through GRHL2.

High-risk human papillomavirus (HPV) is a major risk factor for oral and pharyngeal cancers (OPCs), yet the detailed mechanisms by which HPV promotes OPCs are not understood. Forkhead box M1B (FoxM1B) is an oncogene essential for cell cycle progression and tumorigenesis, and it is aberrantly overexpressed in many tumors. We previously showed that FoxM1B was the putative target of an epithelial-specific transcription factor, Grainyhead-like 2 (GRHL2). In the current study, we demonstrate that HPV type 16 (HPV-16) E6 induces FoxM1B in human oral keratinocytes (HOKs) and tonsillar epithelial cells (TECs) in part through GRHL2. FoxM1B was barely detectable in cultured normal human oral keratinocytes (NHOKs) and progressively increased in immortalized HOKs harboring HPV-16 genome (HOK-16B) and tumorigenic HOK-16B/BaP-T cells. Retroviral expression of HPV-16 E6 and/or E7 in NHOKs, TECs, and hypopharyngeal carcinoma cells (FaDu) revealed induction of FoxM1B and GRHL2 by the E6 protein but not E7. Both GRHL2 and FoxM1B were strongly induced in the epidermis of HPV-16 E6 transgenic mice and HPV+ oral squamous cell carcinomas. Ectopic expression of FoxM1B led to acquisition of transformed phenotype in HOK-16B cells. Loss of FoxM1B by lentiviral short hairpin RNA vector or chemical inhibitor led to elimination of tumorigenic characteristics of HOK-16B/BaP-T cells. Luciferase reporter assay revealed that GRHL2 directly bound and regulated the FoxM1B gene promoter activity. Using epithelial-specific Grhl2 conditional knockout mice, we exposed wild-type (WT) and Grhl2 KO mice to 4-nitroquinolin 1-oxide (4-NQO), which led to induction of FoxM1B in the tongue tissues and rampant oral tumor development in the WT mice. However, 4-NQO exposure failed to induce tongue tumors or induction of FoxM1B expression in Grhl2 KO mice. Collectively, these results indicate that HPV-16 induces FoxM1B in part through GRHL2 transcriptional activity and that elevated FoxM1B level is required for oropharyngeal cancer development.

Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients.

Background: To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and methods: We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples. Results: Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications. Conclusions: The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.

Underestimated caregiver burden by cancer patients and its association with quality of life, depression and anxiety among caregivers.

This study examined how patients with cancer estimate caregiver burden (CB) and the association between their underestimation of CB and their caregivers' self-ratings of their quality of life (CQOLC-K; Korean version of the Caregiver Quality of Life Index-Cancer), depression and anxiety (Korean version of the Hospital Anxiety and Depression Scale). Participants consisted of 990 patient-caregiver dyads recruited from a nationwide cross-sectional survey conducted in South Korea. Medical baseline data were retrieved from the hospital information systems of the participating centres. The patients with cancer who underestimated CB ranged from 18.62% (for physical CB) to 23.33% (for social CB). They had less advanced cancer, a lower income, were the caregiver's spouse, reported higher levels of family avoidance of communication about cancer, and had female caregivers. The patients' underestimation of CB was significantly related to lower CQoL and higher levels of caregiver depression and anxiety. The current study provides empirical evidence for the link between the underestimation of CB by patients with cancer and compromised caregiving experiences of cancer caregivers. Open family communication about cancer was discussed as one of several practical strategies for decreasing patients' underestimation of CB.

C-reactive protein binds to integrin α2 and Fcγ receptor I, leading to breast cell adhesion and breast cancer progression.

C-reactive protein (CRP) is an acute phase protein synthesized upon the inflammatory responses, associated with breast cancer. The process of tumor cell invasion and metastasis involves the adherence of cells to the extracellular matrix via integrin as a receptor for matrix molecules. The present study investigated the role of CRP in the adhesive phenotype of breast cells and the underlying mechanisms. Here, we first showed that CRP induces adhesion of MCF10A human breast epithelial cells through the activation of integrin α2 signaling. Expression of integrin α2 was induced by CRP in which transcription factors c-fos and SP1 may be involved. Binding of CRP with integrin α2 leads to the activation of focal adhesion kinase (FAK), paxillin and ERKs. CRP also binds to an Fcγ receptor Fcγ receptor I (FcγRI), and induces activation of paxillin, FAK and ERKs. Integrin α2 and FAK have crucial roles in the adhesive and invasive phenotypes as well as MMP-9 upregulation induced by CRP in MCF10A cells. Treatment with an inflammatory lipid sphingosine-1-phosphate induced CRP, which may be secreted and exert an autocrine effect by binding to FcγRI and integrin α2. Involvement of CRP in adhesion, invasion, anchorage-independent growth and upregulation of integrin α2, paxillin and FAK was observed in MDA-MB-231 triple-negative human breast cancer (TNBC) cells. Using an in vivo invasion model and an orthotopic mouse tumor model with MDA-MB-231 cells, we showed that CRP has an important role in intravasation and tumor growth in vivo, demonstrating the in vivo relevance of our in vitro results. The present study elucidates a critical molecular basis between CRP, integrin α2 and FcγRI pathways in MCF10A breast cells and MDA-MB-231 TNBC cells, thereby providing useful information on CRP-induced aggressiveness of breast cells in the inflammatory microenvironment.