Search

Background: We aimed to verify the validity of the proportional recovery model for the lower extremity. Methods: We reviewed clinical data of patients enrolled in the Korean Stroke Cohort for Functioning and Rehabilitation between August 2012 and May 2015. Recovery proportion was calculated as the amount of motor recovery over initial motor impairment, measured as the Fugl-Meyer Assessment of Lower Extremity score. We used the logistic regression method to model the probability of achieving the full Fugl-Meyer Assessment of Lower Extremity score, whereby we considered the ceiling effect of the score. To show the difference in the prevalence of achieving the full Fugl-Meyer Assessment of Lower Extremity score between 3 and 6 months poststroke, we constructed a marginal model through the generalized estimating equation method. We also performed the propensity score matching analysis to show the dependency of recovery proportion on the initial motor deficit at 3 and 6 months poststroke. Results: We evaluated 1085 patients. The recovery proportions at 3 and 6 months poststroke were 0.67±0.42 and 0.75±0.39, respectively. A 1-unit decrease in the initial neurological impairment and the age at stroke onset increased the probability of achieving the full Fugl-Meyer Assessment of Lower Extremity score, which occurred at both 3 and 6 months poststroke. The prevalence of those who reach full lower limb motor recovery differs significantly between 3 and 6 months poststroke. We also found out that the recovery proportion at both 3 and 6 months poststroke is determined by the initial motor deficits of the lower limb. These results are not consistent with the proportional recovery model. Conclusions: Our results demonstrated that the proportional recovery model for the lower limb is invalid.

Interstitial lung abnormality (ILA) is closely related to lung cancer. This study aimed to assess whether the presence of ILA is associated with the clinicoradiological features of elderly patients (≥70 years) with early-stage non-small cell lung cancer (NSCLC).Elderly patients who underwent surgical resection for stage I or II NSCLC with preserved lung function between 2012 and 2019 were retrospectively identified. ILA was evaluated using a three-point scale. Univariate analyses were performed for clinicoradiological features based on the presence of ILA. Logistic and linear regression analyses were performed for cancer staging and tumor size, respectively.A total of 254 patients were evaluated. The presence of ILA (score = 2) was significantly associated with male sex, current or former smoker status, higher pack-years of smoking, low forced expiratory volume in one second/forced vital capacity ratios and diffusing capacity of the lung for carbon monoxide, and presence of emphysema (≥5%). Tumor characteristics, such as lower lobe and outer one-third location, squamous cell carcinoma, and higher cancer stage (stage II) were significantly associated with ILA. The presence of ILA independently predicted a higher cancer stage (adjusted odds ratio, 1.81; 95% confidence interval, 1.10-2.96; p = 0.02) and a larger tumor size in linear regression analysis (p = 0.04).Patients with ILA showed clinicoradiological features similar to those of idiopathic pulmonary fibrosis in elderly patients with early-stage NSCLC. Identifying the clinical implications of ILA in early-stage lung cancer will guide clinicians in providing appropriate management for these patients.

Pancreatic cancer is a lethal cancer with aggressive and invasive characteristics. By the time it is diagnosed, patients already have tumors extended to other organs and show extremely low survival rates. The gut microbiome is known to be associated with many diseases and its imbalance affects the pathogenesis of pancreatic cancer. In this study, we established an orthotopic, patient-derived xenograft model to identify how the gut microbiome is linked to pancreatic ductal adenocarcinoma (PDAC). Using the 16S rDNA metagenomic sequencing, we revealed that the levels of Alistipes onderdonkii and Roseburia hominis decreased in the gut microbiome of the PDAC model. To explore the crosstalk between the two bacteria and PDAC cells, we collected the supernatant of the bacteria or cancer cell culture medium and treated it in a cross manner. While the cancer cell medium did not affect bacterial growth, we observed that the A. onderdonkii medium suppressed the growth of the pancreatic primary cancer cells. Using the bromodeoxyuridine/7-amino-actinomycin D (BrdU/7-AAD) staining assay, we confirmed that the A. onderdonkii medium inhibited the proliferation of the pancreatic primary cancer cells. Furthermore, RNA-seq analysis revealed that the A. onderdonkii medium induced unique transcriptomic alterations in the PDAC cells, compared to the normal pancreatic cells. Altogether, our data suggest that the reduction in the A. onderdonkii in the gut microbiome provides a proliferation advantage to the pancreatic cancer cells. KEY POINTS: • Metagenome analysis of pancreatic cancer model reveals A. onderdonkii downregulation. • A. onderdonkii culture supernatant suppressed the proliferation of pancreatic cancer cells. • RNA seq data reveals typical gene expression changes induced by A. onderdonkii.

ImportanceBecause stroke causes diverse functional deficits, understanding the long-term recovery pattern of each functional domain may inform prognosis and therapeutic strategies.ObjectiveTo observe long-term changes in functional status and residual disability in survivors of first-time stroke.Design, Setting, and ParticipantsThis cohort study was an interim analysis of the Korean Stroke Cohort for Functioning and Rehabilitation. Between August 2012 and May 2015, 7858 of 10 636 screened patients with first-time strokes from 9 district hospitals in Korea provided informed consent to participate. Data were analyzed from September 2021 through February 2022.ExposureFirst-time stroke.Main Outcomes and MeasuresStudy data include multifaceted face-to-face functional assessments obtained at 8 to 9 points until 60 months after stroke onset. The Korean Mini-Mental State Examination (K-MMSE), Fugl-Meyer Assessment, Functional Ambulatory Category, American Speech-Language-Hearing Association National Outcome Measurement System Swallowing Scale, and Short Korean version of the Frenchay Aphasia Screening Test were performed from 7 days to 60 months after stroke. The Korean Modified Barthel Index was measured from 3 months to 60 months after stroke.ResultsA total of 4443 patients (2649 men [59.62%]; mean [SD] age 62.13 [12.43] years) who underwent repeated functional assessments for 60 months after stroke (3508 patients with ischemic and 935 patients with hemorrhagic stroke) were included. Overall, functions plateaued between 12 and 18 months after stroke and declined after 30 months; for example, mean (SD) K-MMSE improved from 7 days (22.89 [7.89]) to 12 months (26.03 [5.48]) (P P P for interaction P for interaction P for interaction P P = .004), and hemorrhagic stroke type (β vs ischemic stroke = 2.35; SE, 0.81; P = .004).Conclusions and RelevanceThis study found that long-term recovery patterns in multifaceted functional domains differed from one another and varied by patient age, stroke severity, and stroke type. Understanding the diversity of long-term functional recovery patterns and factors associated with these outcomes in survivors of stroke may help clinicians develop strategies for effective stroke care and rehabilitation.

The PACIFIC study demonstrated that durvalumab consolidation therapy significantly improved progression-free survival (PFS) and overall survival (OS) in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT). However, there was no clinical benefit in both PFS and OS in epidermal growth factor receptor (EGFR) mutation-positive patient groups in a post hoc exploratory analysis. Moreover, the clinical effects of immune checkpoint inhibitors (ICIs) in EGFR mutation-positive stage IV NSCLC were demonstrated to be poor. Personalized treatment according to the mutation status is also required in stage III NSCLC. Lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is newly developed and approved for use in Korea.This prospective, open, single-arm, multicenter, phase II clinical trial aims to evaluate the efficacy and safety of lazertinib as a consolidative therapy after CCRT treatment in unresectable, EGFR mutation-positive NSCLC stage III patients. The primary endpoint of this study is PFS, and the secondary endpoints are OS, objective response rate (ORR), duration of response (DoR), time to death or distant metastasis (TTDM), and safety profiles.Our study may extend the indications for third-generation EGFR-TKIs to treat patients with stage III NSCLC. Moreover, using this drug to treat stage III NSCLC would emphasize the value of mutation analysis and personalized medicine.

Background Mutation analysis of circulating tumor DNA (ctDNA) is used for diagnosing lung cancer. This trial aimed to assess the efficacy of afatinib in treatment‐naïve patients with lung cancer harboring epidermal growth factor receptor mutations (EGFRm, exon 19 deletions or exon 21 point mutations) detected based on ctDNA. Methods The primary objective was the objective response rate (ORR) in the response evaluable (RE) population. EGFRm analysis of ctDNA was performed using PANA Mutype. Of the 331 patients screened, ctDNA was positive in 21% (68/331) in the detection of activating EGFRm. Among 81 subjects with tumor EGFRm, 48 showed matched EGFRm in their ctDNA (59% sensitivity). Results Therapy with afatinib 40 mg was initiated in 21 (female, 17; adenocarcinoma, 20) patients (intention‐to‐treat, ITT); dose modifications were made in 15 (71%). The ORR was 74% in the RE population (14/19); 11 patients showed EGFRm only in ctDNA (Group A), whereas 10 exhibited the same EGFRm in their ctDNA and tumor DNA (Group B). There was no significant difference in ORR between Groups A and B (80% and 67% RE, respectively). Median progression‐free survival (PFS) was 12.0 months, and no significant difference was observed according to the final afatinib dose, type of EGFRm, and Group A versus B. After progression, T790M mutation was found in 40% (6/15) of patients, and osimertinib was used as a second‐line treatment. Conclusions Afatinib showed similar ORR and PFS in patients with lung cancer harboring EGFRm in their ctDNA regardless of tumor EGFRm results. Key points Significant findings of the study Afatinib showed favorable ORR and PFS regardless of the tumor EGFR mutation status results, similar to the findings of previous trials assessing afatinib as first‐line treatment of EGFR‐mutated non‐small cell lung cancer based on tumor genotyping. What this study adds Our findings emphasize that the survival benefit of afatinib treatment can be achieved not only by appropriate dose reduction with frequent and detailed monitoring of toxicities, but also by using noninvasive (ctDNA) assays in a real‐world setting., Afatinib showed favorable ORR and PFS regardless of the tumor EGFR mutation status results, similar to the findings of previous trials assessing afatinib as first‐line treatment of EGFR‐mutated NSCLC based on tumor genotyping. The survival benefit of afatinib treatment can be achieved not only by appropriate dose reduction with frequent and detailed monitoring of toxicities, but also by using noninvasive (ctDNA) assays in a real‐world setting

Objective Pulmonary arteriovenous malformation (PAVM) is a rare pulmonary disease. Although most patients with PAVMs are asymptomatic, cerebral complications associated with PAVMs are often fatal. This study aimed to evaluate the risk factors for cerebral complications in patients with PAVMs. Methods We retrospectively reviewed the medical charts of patients with PAVMs between 2003 and 2021 at two tertiary referral hospitals and one secondary hospital. Results Fifty-five patients diagnosed with PAVMs were enrolled in this study. Most patients were female (89.1%), and the median age was 53 years. Thirty patients (54.5%) had incidentally detected PAVMs without symptoms. Twenty-four patients (43.7%) with PAVMs were treated with embolotherapy or surgery. Thirteen patients (23.6%) had cerebral complications. There was no significant difference in the development of cerebral complications according to treatment; however, older age (≥ 65 years) was associated with the development of new cerebral complications in untreated patients with PAVMs (odds ratio, 17.09; 95% confidence interval, 1.16–250.31; P = 0.038). Conclusion Older age (≥ 65 years) was a risk factor for the development of cerebral complications in patients with PAVMs; therefore, treatment should be considered in older patients with PAVMs.

Aim The efficacy and safety of pirfenidone have been previously demonstrated in patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF). However, the effect of pirfenidone in patients with advanced IPF remains unclear. Here, we investigated the effects of pirfenidone against advanced IPF in a real-world setting. Methods A prospective nationwide post-marketing study was conducted on 258 patients from 10 Korean institutions. Patients with a predicted forced vital capacity (FVC) less than 50% or a diffusing capacity of the lung for carbon monoxide (DLco) less than 35% at baseline were classified as the advanced IPF group. Results Of 219 patients included in the analysis, the majority were male (76.3%); the mean age was 67.3 years, and the advanced group accounted for 17.8% of the patients. The median treatment duration was 298 days. Among the subjects, 86.3% experienced adverse events (AEs), of which a decreased appetite (32.4%) and a photosensitivity reaction (13.7%) were the most frequent. The incidence of AEs was similar between the advanced and non-advanced groups (92.3% vs. 85.0%, respectively; p = 0.229). Although the overall discontinuation rate was higher in the advanced group than in the non-advanced group (74.4% vs. 50.0%, respectively; p = 0.006), the percentages of the patients who discontinued treatment as a result of AEs were similar in both groups (20.5% vs. 23.3%, respectively; p = 0.704). In all patients, the rates of decline in the predicted FVC and DLco over 48 weeks were − 4.3 ± 1.3% and − 4.4 ± 1.7%, respectively. There was no between-group difference in the rate of lung function decline. Conclusions Pirfenidone used for the treatment of patients with IPF in a real-world setting was well tolerated, with an acceptable safety profile and a consistent therapeutic effect, regardless of the disease severity. Trial Registration ClinicalTrials.gov NCT03761082; the trial was retrospectively registered on December 3, 2018. Electronic supplementary material The online version of this article (10.1007/s12325-020-01328-8) contains supplementary material, which is available to authorized users.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

Background The concurrence of sarcoidosis and primary lung cancer is very rare. We report a very rare case with a delayed diagnosis of primary lung cancer due to its misdiagnosis as worsening of pulmonary sarcoidosis. Case presentation A 68-year-old man presented to the outpatient department for evaluation of a mass in the right hilar area with lymphadenopathies in subcarinal and both interlobar areas on chest computed tomography (CT). Sufficient core samples were obtained from subcarinal and bilateral interlobar lymph nodes using endobronchial ultrasonography (EBUS) guided transbronchial needle aspiration (TBNA). EBUS could not reach the right hilar lymph node due to its high angle. The pathologic findings were consistent with sarcoidosis. After 5 months, chest CT revealed aggravation of the right upper paratracheal lymphadenopathy. Assuming worsening of sarcoidosis, he was prescribed an oral corticosteroid for 5 months. However, follow-up chest CT showed a newly developed right lower paratracheal lymphadenopathy and worsening right hilar lymphadenopathy. Bronchoscopy and EBUS were performed once again. Transbronchial lung biopsy from the right upper lobe and EBUS-TBNA from the right lower paratracheal lymph node revealed adenocarcinoma from the lung. Conclusions Although coexistence of sarcoidosis and lung cancer is very rare, the clinician should consider the possibility of accompanying lung cancer in sarcoidosis patients who are not responding to initial corticosteroid therapy.

Previous studies have investigated the predictors for home discharge without considering stroke severity. To develop a practical assessment tool that predicts home discharge for moderate stroke patients after subacute rehabilitation therapy in the tertiary hospitals. Stroke patients with National Institutes of Health Stroke Scale scores of 6 to 13 were included in this prospective cohort study. Various demographic, clinical, and functional factors were analyzed as potential predictive factors. A weighted scoring model was developed through the following three-step process: 1) selection of the factors by logistic regression analyses, 2) development of a weighted scoring model, and 3) validation of the generalizability of the model. The home discharge rate was 51% (n = 372), and the overall mean length of stay of hospitalization was 32.5 days. 1) The Cognitive Functional Independence Measure, 2) the Functional Ambulation Categories, 3) the modified Charlson Comorbidity Index, and 4) marital status were independent predictors of home discharge. The coefficient value for marital status was adjusted to 1 in the scoring system, and the values of the other parameters were proportionally converted to the nearest integer. Possible total scores ranged from 0 to 13 in the model, with a higher score indicating a higher probability of home discharge. With a cutoff point of 7, this model showed 87.0% sensitivity and 86.2% specificity (area under the curve = 0.90). This novel assessment tool can be useful in predicting home discharge after subacute rehabilitation of moderate stroke patients.

Alzheimer's disease (AD), one of the leading senile disorders in the world, causes severe memory loss and cognitive impairment. To date, there is no clear cure for AD. However, early diagnosis and monitoring can help mitigate the effects of this disease. In this study, we reported a platform for diagnosing early-stage AD using microRNAs (miRNAs) in the blood as biomarkers. First, we selected an appropriate target miRNA (miR-574-5p) using AD model mice (4-month-old 5XFAD mice) and developed a hydrogel-based sensor that enabled high-sensitivity detection of the target miRNA. This hydrogel contained catalytic hairpin assembly (CHA) reaction-based probes, leading to fluorescence signal amplification without enzymes and temperature changes, at room temperature. This sensor exhibited high sensitivity and selectivity, as evidenced by its picomolar-level detection limit (limit of detection: 1.29 pM). Additionally, this sensor was evaluated using the plasma of AD patients and non-AD control to validate its clinical applicability. Finally, to use this sensor as a point-of-care-testing (POCT) diagnostic system, a portable fluorometer was developed and verified for feasibility of application.

Background We correlated the tumor proportion score (TPS) of programmed cell death ligand 1 (PD‐L1, SP263 or 22C3) expression with the disease control rate (DCR, partial remission and stable disease), and progression free survival (PFS) after nivolumab or pembrolizumab treatment. Methods A total of 70 case records (55 males, 15 females) of patients with non‐small cell lung cancer (NSCLC, 46 adenocarcinoma, 22 squamous cell carcinoma, and two others) were reviewed. The PD‐L1 expressions were divided into High (SP263 ≥ 30%, 22C3 ≥ 80%) and Low groups (SP263

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients.

BackgroundCD8+ tumor-infiltrating lymphocytes (TILs) comprise phenotypically and functionally heterogeneous subpopulations. Of these, effector memory CD45RA re-expressing CD8+ T cells (Temra) have been discovered and characterized as the most terminally differentiated subset. However, their exact ontogeny and physiological importance in association with tumor progression remain poorly understood.MethodsWe analyzed primary tumors and peripheral blood samples from 26 patients with non-small cell lung cancer and analyzed their phenotypes and functional characteristics using flow cytometry, RNA-sequencing, and bioinformatics.ResultsWe found that tumor-infiltrating Temra (tilTemra) cells largely differ from peripheral blood Temra (pTemra), with distinct transcriptomes and functional properties. Notably, although majority of the pTemra was CD27−CD28− double-negative (DN), a large fraction of tilTemra population was CD27+CD28+ double-positive (DP), a characteristic of early-stage, less differentiated effector cells. Trajectory analysis revealed that CD8+ TILs undergo a divergent sequence of events for differentiation into either DP or DN tilTemra. Such a differentiation toward DP tilTemra relied on persistent expression of CD27 and CD28 and was associated with weak T cell receptor engagement. Thus, a higher proportion of DP Temra was correlated with lower immunogenicity of tumor antigens and consequently lower accumulation of CD8+ TILs.ConclusionsThese data suggest a complex interplay between CD8+ T cells and tumors and define DP Temra as a unique subset of tumor-specific CD8+ TILs that are produced in patients with relatively low immunogenic cancer types, predicting immunogenicity of tumor antigens and CD8+ TIL counts, a reliable biomarker for successful cancer immunotherapy.

This study investigated the long-term functional changes in patients with moderate-to-severe ischemic stroke. In addition, we investigated whether there was a difference between the modified Barthel Index (MBI) and Functional Independence Measure (FIM) according to severity. To evaluate the changes in the long-term functional independence of the subjects, six evaluations were conducted over 2 years, and the evaluation was performed using MBI and FIM. A total of 798 participants participated in this study, of which 673 were classified as moderate and 125 as severe. During the first 3 months, the moderate group showed greater recovery than the severe group. The period of significant change in the National Institutes of Health Stroke Scale (NIHSS) score was up to 6 months after onset in the moderate group, and up to 3 months after onset in the severe group. In the severe group, MBI evaluation showed significant changes up to 6 months after onset, whereas FIM showed significant changes up to 18–24 months. Our results showed that functional recovery of patients with ischemic stroke in the 3 months after onset was greater in the moderate group than in the severe group. FIM is more appropriate than MBI for evaluating the functional status of patients with severe stroke.

One essential step in radiotherapy treatment planning is the organ at risk of segmentation in Computed Tomography (CT). Many recent studies have focused on several organs such as the lung, heart, esophagus, trachea, liver, aorta, kidney, and prostate. However, among the above organs, the esophagus is one of the most difficult organs to segment because of its small size, ambiguous boundary, and very low contrast in CT images. To address these challenges, we propose a fully automated framework for the esophagus segmentation from CT images. The proposed method is based on the processing of slice images from the original three-dimensional (3D) image so that our method does not require large computational resources. We employ the spatial attention mechanism with the atrous spatial pyramid pooling module to locate the esophagus effectively, which enhances the segmentation performance. To optimize our model, we use group normalization because the computation is independent of batch sizes, and its performance is stable. We also used the simultaneous truth and performance level estimation (STAPLE) algorithm to reach robust results for segmentation. Firstly, our model was trained by k-fold cross-validation. And then, the candidate labels generated by each fold were combined by using the STAPLE algorithm. And as a result, Dice and Hausdorff Distance scores have an improvement when applying this algorithm to our segmentation results. Our method was evaluated on SegTHOR and StructSeg 2019 datasets, and the experiment shows that our method outperforms the state-of-the-art methods in esophagus segmentation. Our approach shows a promising result in esophagus segmentation, which is still challenging in medical analyses.

PurposeIdentifying pretreatment interstitial lung abnormalities (ILAs) is important because of their predictive value for complications after lung cancer treatment. This study aimed to assess the predictive value of ILAs for postoperative pulmonary complications (PPCs) in elderly patients undergoing curative resection for early-stage non-small cell lung cancer (NSCLC).Materials and MethodsElderly patients (age ≥ 70 years) who underwent curative resection for pathologic stage I or II NSCLC with normal preoperative spirometry results (pre-bronchodilator forced expiratory volume in 1 s to forced vital capacity [FVC] ratio > 0.70 and FVC ≥ 80% of the predicted value) between January 2012 and December 2019 were retrospectively identified. Univariable and multivariable regression analyses were performed to assess risk factors for PPCs. The Kaplan–Meier method and log-rank test were used to analyze the relationship between ILAs and postoperative mortality. One-way analysis of variance was performed to assess the correlation between ILAs and hospital stay duration.ResultsA total of 262 patients (median age, 73 [interquartile range, 71–76] years; 132 male) were evaluated. A multivariable logistic regression model revealed that, among several relevant risk factors, fibrotic ILAs independently predicted both overall PPCs (adjusted odds ratio [OR], 4.84; 95% confidence interval [CI], 1.35–17.38; p=0.016) and major PPCs (adjusted OR, 8.72; 95% CI, 1.71–44.38; p=0.009). Fibrotic ILAs were significantly associated with higher postoperative mortality and longer hospital stay (F=5.21, p=0.006).ConclusionPretreatment fibrotic ILAs are associated with PPCs, higher postoperative mortality, and longer hospital stay.

Background and Purpose: The aim of this study was to verify the validity of the proportional recovery model in view of the ceiling effect of the Fugl-Meyer Assessment. Methods: We reviewed the medical records of patients enrolled in the Korean Stroke Cohort for Functioning and Rehabilitation between August 2012 and May 2015. Recovery proportion was defined as the actual change in Fugl-Meyer Assessment score of the upper extremity between 7 days and 6 months poststroke, relative to the initial neurological impairment. We then used logistic regression to identify clinical factors attributable to a ceiling effect of the Fugl-Meyer Assessment score of the upper extremity and propensity score matching to verify the validity of the proportional recovery rule. Results: We screened 10 636 patients and analyzed 849 patients (mean age, 65.4±11.9 years; female, 320 [37.7%]) with first-ever ischemic stroke. We found, through logistic regression analysis, that a one-unit increase in the initial neurological impairment and the age at stroke onset affected the odds ratio (1.0386 and 0.9736, respectively) of achieving the full Fugl-Meyer Assessment score of the upper limb at 6 months poststroke. We also demonstrated, through propensity score matching, that the difference in initial neurological impairment of the upper extremity resulted in discrepancy of the recovery proportion (0.92±0.20 [0–1] versus 0.81±0.31 [0–1], P Conclusions: We demonstrated that the ceiling effect of the Fugl-Meyer Assessment score of the upper extremity is pronounced in patients with mild initial motor deficits of the upper extremity and that the recovery proportion varies according to the initial motor deficit of the upper limb using logistic regression analysis and propensity score matching, respectively. These results suggest that the proportional recovery model is not valid.

Purpose Fluorescence in situ hybridization (FISH) using tumor tissue is the gold standard for detection of anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC). However, this method often is not repeatable due to difficulties in the acquisition of tumor tissues. Blood-based liquid biopsy using reverse transcription polymerase chain reaction (RT-PCR) is expected to be useful to overcome this limitation. Here, we investigated the feasibility of liquid biopsy using plasma and platelets for detection of ALK rearrangement and prediction of ALK inhibitor treatment outcomes. Methods ALK-FISH assays were performed in 1128 tumor specimens of NSCLC between January 2015 and June 2018. We retrospectively analyzed formalin-fixed paraffin-embedded (FFPE) tissues from previously confirmed FISH-positive (n = 199) and -negative (n = 920) cases. We recruited patients who had available tissue specimens and agreed to venous sampling. RNA was extracted from FFPE blocks, plasma, and platelets. Fusion RNA of echinoderm microtubule-associated protein-like 4 (EML4)-ALK was detected by quantitative PCR. Results Thirty-three FISH-positive and 28 FISH-negative patients were enrolled. In validation, data compared with FISH, RT-PCR using FFPE tissues showed 54.5% sensitivity, 78.6% specificity, and 75.5% accuracy. Liquid biopsy had higher sensitivity (78.8%), specificity (89.3%) and accuracy (83.6%). Higher positivity for liquid biopsy was shown in subgroups with delayed (≥ 6 months from diagnosis) blood sampling (plasma, 85.7%; platelets, 87.0%). In 26 patients treated with crizotinib, the platelet-positive subgroup showed longer median duration of treatment (7.2 versus 1.5 months), longer median progression-free survival (5.7 months versus 1.7 months), a higher overall response rate (70.6% versus 11.1%), and a higher disease control rate (88.2% versus 44.4%) than the platelet-negative subgroup. Conclusion Liquid biopsy could have applications in the diagnosis of ALK-positive NSCLC, even when using RT-PCR, and platelets can be useful for predicting treatment outcomes of ALK inhibitors.

Background We determined the clinical characteristics and predictive factors of long-term response to pemetrexed maintenance therapy as first-line treatment for non-small cell lung cancer (NSCLC). Methods A total of 950 advanced NSCLC patients received pemetrexed (500 mg/m2 ) plus cisplatin (60 mg/m2 ) (Pem-Cis) induction chemotherapy every three weeks as first-line treatment between January 2010 and August 2018. Patients who did not show progression after four cycles of Pem-Cis and received at least one cycle of pemetrexed maintenance were recruited (n = 199). Results Patients were divided into subgroups according to total cycles of pemetrexed: ≤ 10 (F10, n = 134) and > 10 (M10, n = 65). The M10 group had a higher proportion of patients with stage M1a (intrathoracic metastasis alone) and exhibited lower levels of thymidylate synthase (TS) than the F10 group (median H-score 10.0% vs. 60.0%; P = 0.031). Further subgrouping identified extreme responders: ≤ 7 (F7, n = 101) and ≥ 20 (M20, n = 26) cycles. The M20 group showed lower mean serum CEA levels before (17.5 vs. 147.0; P = 0.099) and after (6.9 vs. 53.2; P = 0.001) Pem-Cis treatment, and a higher incidence of normalization after Pem-Cis (abnormal 41.7% vs. 68.5%; P = 0.015). M1a stage, normalization of CEA levels after Pem-Cis, and lower TS H-score were predictors of progression-free survival in patients administered pemetrexed maintenance. Conclusion M1a stage and lower TS expression were predictors of long-term response to pemetrexed maintenance. CEA normalization after Pem-Cis could be an additional surrogate marker of positive response to long-term treatment.

One of the primary goals of epidemiology is to quantify various aspects of a population’s health, illness, and death status and the determinants (or risk factors) thereof by calculating health indicators that measure the magnitudes of various conditions. There has been some confusion regarding health indicators, with discrepancies in usage among organizations such as the World Health Organization the, Centers for Disease Control and Prevention (CDC), and the CDC of other countries, and the usage of the relevant terminology may vary across papers. Therefore, in this review, we would like to propose appropriate terminological definitions for health indicators based on the most commonly used meanings and/or the terms used by official agencies, in order to bring clarity to this area of confusion. We have used appropriate examples to make each health indicator easy for the reader to understand. We have included practical exercises for some health indicators to help readers understand the underlying concepts.

Since it is a widely known fact that smoking cessation is beneficial physically and cognitively, efforts should be made to enable smokers to quit smoking through policy. Intensive care smoking cessation camps generally show a high smoking cessation success rate, but research is needed to determine which smokers should be admitted due to costeffectiveness. Although many studies have been conducted to find factors related to smoking cessation success, there is still controversy about the will and success rate of smoking cessation of elderly smokers. We performed this study to determine behavior characteristics and smoking cessation success rates in nonelderly and elderly smokers who participated in an intensive care smoking cessation camp. Heavy smokers participating in an intensive care smoking cessation camp at Chonnam National University Hospital between the August 2015 and December 2017 were classified into elderly (age ≥65 years old) or nonelderly (age65 years old) groups after excluding missing data. Smokers were followed up at 4 weeks, 6 weeks, 12 weeks, and 6 months from the start of abstinence by self-report, measurement of carbon monoxide expiration levels or cotinine testing. A total of 351 smokers were enrolled in the study. At the 6-month follow-up, 56 of 107 (52.3%) elderly smokers and 109 of 244 (44.7%) nonelderly smokers continued to abstain from smoking. Elderly smokers showed a higher smoking cessation rate than that of nonelderly smokers, but it was not statistically significant (OR = 1.36, 95%CI: 0.862, 2.145). The most common causes of cessation failure in both groups were stress and temptation, followed by withdrawal symptoms. Smoking cessation rates in the elderly are comparable to that in the nonelderly after an intensive care smoking cessation camp. Intensive care smoking cessation camps can help both elderly and nonelderly smokers who intend to quit smoking by providing motivation, education and medication. Smoking cessation should be strongly recommended regardless of age.

Background We report a subgroup analysis of afatinib with respect to its efficacy, safety, and the long‐term survival of patients in a Named Patient Use program at a single institution. Methods We analyzed 60 patients with stage IV non‐small cell lung cancer (NSCLC) who had been treated with ≥1 line of platinum‐based chemotherapy and had activating epidermal growth factor receptor (EGFR) mutations or disease control for ≥6 months with prior EGFR inhibitors. Afatinib was started on a daily dose of 50 mg, which was decreased according to the adverse events and tolerability. Results A total of 13 patients achieved partial remission, whereas 33, 12, and two showed stable disease, had progression, and were not evaluable, respectively, resulting in an objective response rate and disease control rate of 21.7% and 76.7%, respectively. The median progression‐free survival (PFS) was 5.4 (95% confidence interval [CI]: 4.0–7.7) months and median overall survival (OS) was 10.1 (8.5–13.6) months. Toxicities leading to drug discontinuation were experienced by four patients (6.7%). Grade 3 diarrhea occurred in 10 patients (16.7%), and afatinib dose reductions were required in 35 patients. The PFS and OS were significantly longer for patients whose dose was reduced to 40 or 30 mg than for those without dose reduction (7.0 vs 3.1 months and 13.5 vs 8.1 months, respectively, p, In non‐small cell carcinoma, a 40 mg or lower daily dose of afatinib prolonged progression‐free survival and overall survival more than the 50‐mg daily dose.

Objective Pneumocystis jirovecii pneumonia (PCP) is a fatal respiratory infection, mostly associated with immunocompromised conditions. Several reports have described PCP development in patients who were not immunocompromised, but the clinical course and prognosis of PCP are not well understood. We compared the clinical characteristics and prognoses between patients with and without immunocompromised conditions who developed PCP. Methods We retrospectively analyzed patients who had been treated for PCP from three hospitals. We defined immunocompromised (IC) status as following: human immunodeficiency virus (HIV) infection; hematological malignancy; solid organ tumor under chemotherapy; rheumatic disease; medication with immunosuppressive agents. Patients without immunocompromised status were defined as being non-immunocompromised (non-IC). Results The IC and non-IC groups comprised 173 and 14 patients. The median ages were 62.0 and 74.0 years in the IC and the non-IC group, respectively. The median interval between admission and anti-PCP treatment was significantly longer for patients in the non-IC group than that for patients in the IC group (7 vs. 2 days). The in-hospital mortality rates were significantly higher for patients in the non-IC group than that for patients in the IC group (71.4% vs. 43.9%; P = 0.047). A longer interval between admission and anti-PCP therapy was associated with increased 90-day mortality rate in patients with PCP (hazard ratio, 1.082; 95% confidence interval, 1.015–1.153; P = 0.016). Conclusions Patients with PCP with no predisposing illnesses were older and had higher mortality rates than IC patients with PCP. Delayed anti-PCP treatment was associated with increased 90-day mortality.

Although immune-checkpoint inhibitors have become a new therapeutic option for recurrent/metastatic non-small cell lung cancers (R/M-NSCLC), its clinical benefit in the real-world is still unclear. We investigated 1181 Korean patients with programmed death-1 ligand 1 (PD-L1)-positive [tumor proportion score (TPS) ≥ 10% by the SP263 assay or ≥ 50% by the 22C3 assay] R/M-NSCLC treated with pembrolizumab or nivolumab after failure of platinum-based chemotherapy. The median age was 67 years, 13% of patients had ECOG-PS ≥ 2, and 27% were never-smokers. Adenocarcinoma was predominant (61%) and 18.1% harbored an EGFR activating mutation or ALK rearrangement. Pembrolizumab and nivolumab were administered to 51.3% and 48.7, respectively, and 42% received them beyond the third-line chemotherapy. Objective response rate (ORR) was 28.6%. Pembrolizumab group showed numerically higher ORR (30.7%) than the nivolumab group (26.4%), but it was comparable with that of the nivolumab group having PD-L1 TPS ≥ 50% (32.4%). Median progression-free survival (PFS) and overall survival (OS) were 2.9 (95% CI 0–27.9) and 10.7 months (95% CI 0–28.2), respectively. In multivariable analysis, concordance of TPS ≥ 50% in both PD-L1 assays and the development of immune-related adverse events (irAEs) were two significant predictors of better ORR, PFS, and OS. EGFR mutation could also predict significantly worse OS outcomes. The real-world benefit of later-line anti-PD1 antibodies was comparable to clinical trials in patients with R/M-NSCLC, although patients generally were more heavily pretreated and had poorer ECOG-PS. Concordantly high PD-L1 TPS ≥ 50% and development of irAE could independently predict better treatment outcomes, while EGFR mutation negatively affected OS.

Purpose Osimertinib is a potent, irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for both EGFR-activating and T790M resistant mutation. The treatment efficacy of osimertinib was assessed in previously untreated patients with metastatic non–small cell lung carcinoma (NSCLC) harboring activating EGFR mutations in circulating tumor DNA (ctDNA) as well as tumor DNA.Materials and Methods Patients with activating EGFR mutations in their tumor DNA underwent screening with ctDNA analysis using Mutyper and Cobas v2 assays. Enrolled subjects received osimertinib 80 mg, once daily. Primary endpoint was objective response rate (ORR) and secondary endpoints were ctDNA test sensitivity, progression-free survival (PFS), duration of response (DoR), and safety.Results Among 39 screened patients, 29 were ctDNA positive for activating EGFR mutations and 19 were enrolled (ex19del, n=11; L858R/L861Q, n=7; G719A, n=1). Median age was 70 and most patients had brain metastases (15/19, 79%). ctDNA test sensitivity for activating EGFR mutations was 74% using both methods and 62% (Mutyper) or 64% (Cobas v2) for individual methods. ORR was 68% (13/19), median PFS was 11.1 months (95% confidence interval [CI], 0.0 to 26.7), and median DoR was 17.6 months (95% CI, 3.5 to 31.7). ORR and median PFS were significantly superior with ex19del (91%; 21.9 months; 95% CI, 5.5 to 38.3) than with L858R/L861Q (43%; 5.1 months; 95% CI, 2.3 to 7.9). One patient discontinued the drug because of drug-related interstitial pneumonitis.Conclusion Osimertinib had favorable efficacy in the first-line treatment of metastatic NSCLC harboring activating EGFR mutations in ctDNA as well as tumor DNA.

This study aims to evaluate the experience and awareness of a hearing conservation program to explore its activation plan. Three focus group discussions were conducted with five health managers, five labor supervisors, and five workers. A single in-depth interview was conducted with a health manager. Since hearing loss has a significant influence on the quality of life of workers, all participants recognized the importance of management. Although the need for hearing conservation programs was acknowledged, the participants had negative views about their effectiveness. Most health managers have not been able to demonstrate tangible results from their efforts to solve hearing problems, and they have been unable to demand that their employers actively invest resources and personnel in solving or preventing hearing problems. The participants in this study did not entirely understand the hearing conservation program, negative comments suggested that it is impossible to eliminate noise sources from the workplace, and measures for noise reduction would reduce work efficiency. This study can be supplied not only as a basis for reidentifying the real problems of the hearing conservation program but also for the tailored implementation method of future hearing conservation programs at each worksite.

Introduction HER2 mutations are found in 2% to 4% of non–small-cell lung cancer cases and are usually mutually exclusive with other genetic alterations. We screened a large cohort of patients from multiple institutions in Korea, described the characteristics of HER2-mutant cases, and reported on several patients who were treated with pan-HER inhibitors. Patients and Methods The study population consisted of 360 patients diagnosed with adenocarcinoma from 4 institutions in Korea from June 2015 to September 2016. Tissue specimens from all participants were screened by direct sequencing, and next-generation sequencing was conducted only on specimens that were positive in direct sequencing. HER2-targeted therapy, either poziotinib or afatinib, was orally administrated. Results Next-generation sequencing was conducted in 129 patients, and finally 29 (8.1%) patients with HER2 mutation were identified. Most patients were female (58.6%), had never smoked (70.0%), and had stage IV non–small-cell lung cancer (55.2%). For all patients, the histologic type was adenocarcinoma, with no coexisting EGFR or ALK alterations. The most common type of HER2 mutation (48.3%) was c.2326_2327insTGT in exon 20. A partial response was observed in 2 patients who received poziotinib and 1 patient who received afatinib. The main toxicities of the pan-HER inhibitors were nausea, diarrhea, and mucositis. Conclusion HER2 mutation was estimated at a frequency of approximately 8.1% in Korean patients with adenocarcinoma in the absence of known driver mutations. Because some of the HER2-mutant cases responded to poziotinib or afatinib, further studies are warranted.

The aim of the study was to investigate the correlation between spasticity severity and functional outcomes during the first year after stroke.The Korean Stroke Cohort for Functioning and Rehabilitation is a large, multicenter, prospective cohort study of all patients with acute first-ever stroke admitted to participating hospitals in nine Korean areas. To investigate the correlation between spasticity severity and functional status measured by using the Institutes of Health Stroke Scale (NIHSS), Modified Barthel Index (MBI), Functional Independence Measurement (FIM), Fugl-Meyer Assessment (FMA), Functional Ambulatory Category (FAC), modified Rankin scale (mRS), and American Speech-Language Hearing Association National Outcome Measurement System Swallowing Scale (ASHA-NOMS), data were analyzed at 3, 6, and 12 mos after the occurrence of stroke.A total of 7359 stroke patients, 3056 were finally included. Prevalence rates of spasticity in patients after stroke were 6.8% at 3 mos, 6.9% at 6 mos, and 7.6% at 12 mos. The scores of mRS and NIHSS were higher and those of K-MBI, FIM, FMA, and ASHA-NOMS were lower in more severe spastic patients, indicating poorer functional outcomes (P0.05).This study demonstrated the coexistence of spasticity and poor functional outcome during the first year after first-ever stroke patients.

Introduction Afatinib, an irreversible ErbB family blocker, approved for first-line treatment of epidermal growth factor receptor (EGFR) mutated advanced non-small cell lung cancer (NSCLC). This study investigated experience of afatinib within a compassionate use program (CUP). Methods The afatinib CUP was an open-label, multicenter, single-arm program in Korea. We enrolled patients with stage IV NSCLC and who had received at least one line of previous cytotoxic chemotherapy and previous EGFR TKI treatment with either an EGFR mutation or documented clinical benefit. The starting dose of afatinib was 50 mg once daily. Results From August 2011 to September 2014, 332 patients received at least one dose of afatinib. Most patients were registered in the CUP for fourth- or fifth-line treatment with afatinib. Adverse events (AEs) occurred in 98.1% of patients, including 29.8% with serious AEs. The most common AEs (all grades) were diarrhea (90.1%) and skin rash (62.0%). Dose reductions occurred in 60.5% of patients and discontinuations due to AEs were reported in 11.1% of patients. The response rate and median time to treatment failure (TTF) were 27.4% and 3.3 months (CI 95%, 2.8–3.8 months), respectively, in this highly pretreated population. In subgroup analysis, ECOG PS 0 or 1 and immediate pretreatment with pemetrexed monotherapy or a platinum doublet were associated with a longer TTF for afatinib. Conclusions No additional or unexpected safety concerns were observed, and afatinib demonstrated moderate antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib in a real-world setting.

Purpose To perform a systematic review comparing the clinical scores, union rate, complications, reoperations, hospital stay, and operation time between open ankle arthrodesis (OAA) and arthroscopic ankle arthrodesis (AAA). Methods We conducted a comprehensive search in the MEDLINE, Embase, and Cochrane Library databases. Only comparative studies were included in this meta-analysis. The literature search, data extraction, and quality assessment were conducted by 2 independent reviewers. The outcomes analyzed included clinical scores, union rate, complications, reoperations, hospital stay, operation time, and intraoperative blood loss. Results A total of 7 retrospective comparative studies were included in this systematic review. Clinical scores were noted in 3 studies. The American Orthopaedic Foot & Ankle Society ankle-hindfoot score and the Ankle Osteoarthritis Scale score were better in the AAA group than in the OAA group. The union rate was similar between the OAA (70%-100%) and AAA (76.2%-100%) groups. The complication rate was higher in the OAA group (6.7%-47.1%) than in the AAA group (0%-23.8%) in 6 studies. The reoperation rate was similar between the OAA (0%-26.5%) and AAA (0%-27.6%) groups. The hospital stay was shorter in the AAA group in 6 studies. Among the 5 studies that reported operation time, 4 reported no significant difference. Two studies showed that intraoperative blood loss was significantly less in the AAA group. Conclusions AAA was shown to offer the advantages of better clinical scores, fewer complications, a shorter hospital stay, and less blood loss compared with OAA. However, the union rate, reoperation rate, and operation time were similar overall between the 2 groups. Level of Evidence Level III, systematic review of Level III studies.

Objective Estimating carcinogen exposure prevalence is important for preventing occupational cancers. To develop the Korean version of CARcinogen EXposure (CAREX), a carcinogen surveillance system used in many countries, we estimated lead exposure prevalence in the Korean working population. Methods We used three Korean nationwide data sources to obtain objective database-derived prevalences of lead exposure across industries: airborne lead measurement data from the work environment measurement database (WEMD), blood lead measurement data from the special health examination database (SHED), and lead exposure prevalence computed using data from the work environment condition survey (WECS), which is a nationwide occupational exposure survey. We also asked a panel of 52 experts with ≥20 years of experience in industrial hygiene practice for their judgment about lead exposure prevalence across industries after they reviewed the database-derived prevalences computed from the three exposure databases. We developed and compared various estimation methods for combining the experts' judgments. The 2010 census was used as the reference population to estimate the number of lead-exposed workers in 228 industries by multiplying the exposure prevalence by the number of workers in each industry. Results The database-derived prevalences of lead exposure in the 228 industries were calculated using data collected between 2009 and 2011 from the WEMD and SHED and from the 2009 WECS. From the various estimation methods assessed, the median values of experts' responses were selected as our estimates of lead exposure prevalence in each industry. As a result, it was estimated that 129,250 Korean workers were exposed to lead in 2010. Conclusions Based on objective databases, we developed a method for estimating exposure prevalence for the CAREX system by combining experts' judgments. This work may offer an unbiased approach to the development process that accounts for the uncertainty in exposure.

Objective To identify contributing factors that can be used to predict which patients with first-ever stroke will return to driving during 1 year after stroke. Design Multicentre cohort study. Subjects A total of 620 first-ever stroke patients who drove before stroke. Methods The Stroke Cohort for Functioning and Rehabilitation is a large, multicentre, prospective cohort study of all patients with acute first-ever stroke admitted to participating hospitals in 9 areas of Korea. This study analysed the data from 1,354 patients who completed a face-to-face survey about return to driving at 1 year after stroke. A multiple binary logistic regression analysis model was used to analyse factors that potentially influenced return to driving during 12 months after stroke. Results Of 620 subjects, 410 (66.1%) returned to driving after stroke. They resumed driving at a mean of 2.15 months after stroke (standard deviation 2.32 years). Regression models showed that sex, age, modified Rankin scale (mRS), education about return to driving, and Fugl-Meyer Assessment (FMA) were significantly related to return to driving. Stroke type, ambulatory function, and language function at 7 days were not correlated with return to driving. Conclusion Male patients, education about return to driving, lower mRS, and higher FMA at 7 days after stroke are predictors of return to driving. This model could be used by clinicians to help counsel patients and their families.

Objective To identify the incidence of dysphagia after ischemic stroke and determine factors affecting the presence of dysphagia. Design Retrospective case-control study. This was an interim analysis of a prospective multicenter Korean stroke cohort. Setting Acute care university hospitals. Participants Patients (N=6000) with first-ever acute ischemic stroke. Patients were divided into 2 groups according to the presence or absence of dysphagia confirmed at 7 days after onset using the American Speech-Language-Hearing Association National Outcomes Measurement System (ASHA-NOMS) scale, which was determined after conducting screening or standardized tests. Interventions Not applicable. Main Outcome Measures Age at stroke onset, body mass index (BMI), premorbid modified Rankin Scale (mRS), brainstem lesions, National Institutes of Health Stroke Scale (NIHSS), poststroke mRS, and ASHA-NOMS swallowing level at poststroke day 7 were evaluated. Results Among patients with ischemic stroke, 32.3% (n=1940) had dysphagia at 7 days after stroke onset. At discharge, 80.5% (n=1561) still had dysphagia. The prediction model for the presence of dysphagia identified age at onset, underweight (BMI Conclusions The incidence of dysphagia after ischemic stroke was 32.3%. The prediction model for the presence of dysphagia identified age, low BMI, premorbid disabilities, brainstem lesions, and NIHSS as predictive factors.

Photodynamic therapy (PDT) is a treatment option for skin cancer and premalignant skin diseases and exhibits rejuvenation effects, including reducing fine wrinkles and whitening, on aged skin. In this study, we investigated the mechanism underlying the whitening effects of PDT on melanocytes (MCs) in vitro and in vivo. Exposure of MCs to PDT in vitro reduced their melanin content and tyrosinase activity without, however, affecting cell survival. Interestingly, melanogenesis was also inhibited by exposing MCs to conditioned media of PDT-treated keratinocytes or dermal fibroblasts. This paracrine effect was likely due to a decreased release of melanocyte-stimulating cytokines such as Kit ligand and hepatocyte growth factor from these cells. Furthermore, we observed that PDT reduced mottled hyperpigmentation of photoaged patient skin in vivo, highlighting the clinical importance of skin whitening by PDT.

Introduction To date, no prospective phase III trials have directly compared the efficacy of pemetrexed plus cisplatin (Pem-Cis) with docetaxel plus cisplatin (Doc-Cis) in patients with nonsquamous non–small-cell lung cancer. Materials and Methods A total of 148 chemotherapy-naive patients lacking driver mutations were randomized into 21-day regimens of cisplatin 70 mg/m 2 with either docetaxel 60 mg/m 2 (n = 71) or pemetrexed 500 mg/m 2 (n = 77) for ≤ 4 cycles. The primary objective was to assess the noninferiority of progression-free survival (PFS) for patients receiving the Doc-Cis regimen. The secondary endpoints were the response rates, overall survival, and toxicity profiles. Results Partial remission was observed in 24 (31.2%) and 24 (33.8%) patients in the Pem-Cis and Doc-Cis groups, respectively. The median PFS was 4.7 months (95% confidence interval [CI], 4.4-5.0) in the Pem-Cis arm and 4.4 months (95% CI, 3.7-5.1) in the Doc-Cis arm ( P > .05). The median overall survival was longer in the Doc-Cis arm (13.3 months; 95% CI, 8.1-18.5) than in the Pem-Cis arm (11.7 months; 95% CI, 8.6-14.8; P > .05). Between the 2 arms, no significant difference was found in the subsequent treatments after failure of first-line treatment. The rate of grade 3 or 4 neutropenia and febrile neutropenia was greater in the Doc-Cis arm than in the Pem-Cis arm. Conclusion In nonsquamous non–small-cell lung cancer patients lacking driver mutations, the PFS and response rates were similar between the 2 arms, and toxicity was tolerable, although adverse events and more severe toxicities were observed more frequently in the Doc-Cis arm.

This study examined the association between long working hours and psychosocial stress responses. In total, 1,122 white-collar workers from a company in Korea completed self-administered questionnaires following a lecture about the study aim, procedures, and confidentiality. Psychosocial stress responses were evaluated using the Psychosocial Well-being Index - Short Form (PWI-SF), and psychosocial working conditions were evaluated with the Korean Occupational Stress Scale - Short Form (KOSS-SF). Multivariate logistic regression analysis was performed after adjusting for demographic variables and psychosocial working conditions to examine associations between long working hours and psychosocial stress responses. In comparison with the reference group, which worked 40–44 hours per week, the crude odds ratio (OR) of the respondents who worked 60 or more hours was 4.56 (95% confidence interval (CI), 2.55–8.15) in terms of psychosocial stress responses. After adjusting for demographic variables, the adjusted OR of those working ≥60 hours was 5.61 (95% CI, 3.01–10.47). After adjusting for both demographic variables and psychosocial working conditions, the adjusted OR of those working ≥60 hours was 3.25 (95% CI, 1.56–6.79). This study found that long working hours are significantly related to psychosocial stress responses among white-collar workers in one Korean company.

Background The resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Mitogen-inducible gene 6 (Mig-6) is known to inhibit the kinase activity of epidermal growth factor receptor (EGFR). Similarly, numerous studies of mouse models suggested tumor suppressive function of Mig-6 in lung cancer. On the contrary, the results of clinical investigations revealed that lung cancer patients with elevated expression of Mig-6 are associated with a poor prognosis. More recent work showed that unlike wild type (WT) EGFR, mutant EGFR phosphorylates Mig-6 and phosphorylated Mig-6 negatively regulates the degradation of EGFR mutants in lung adenocarcinoma. Here, we tried to untangle the controversies surrounding Mig-6 function as a protagonist or an antagonist of EGFR-TKI resistant lung cancer. Methods We compared the expression and phosphorylation status of Mig-6 in the EGFR-TKI resistant lung adenocarcinoma (PC9/GR cells) to EGFR-TKI sensitive lung adenocarcinoma (PC9 cells). We investigated the function of Mig-6 by either depletion or overexpression of Mig-6 in those cells and evaluated the efficacy of combining of Mig-6 knock-down and EGFR-TKI treatment in PC9/GR. The correlation between Mig-6 expressions and the prognoses of lung adenocarcinoma was examined by The Cancer Genome Atlas (TCGA) data and clinical samples. Results Our results indicated that the expression of Mig-6 was significantly increased in PC9/GR cells compared to that of PC9 cells. The significant portion of Mig-6 existed as a phosphorylated form in PC9 and PC9/GR cells. Moreover, overexpression of Mig-6 significantly increased the cell proliferation, invasion and epithelial mesenchymal transition (EMT) in PC9 cells. Combination of Mig-6 knock-down and EGFR-TKI treatment significantly overcame the EGFR-TKI resistance of PC9/GR cells. In addition, our analyses of clinical samples confirmed that high Mig-6 expressions positively correlate with a poor prognosis and EGFR-TKI resistance in lung adenocarcinoma. Conclusion Our findings reinforce scientific notion of Mig-6 as an oncoprotein in the context of EGFR-TKI resistant lung adenocarcinoma. We propose that targeting Mig-6 may be a promising strategy to overcome the EGFR-TKI resistance in lung cancer.

Blood glucose sensing is very important for diabetic management. It is shifting towards a continuous glucose monitoring because such a system can alleviate patient suffering and provide a large number of glucose measurements. Here, we proposed a novel approach for the development of durable and accurate enzymatic continuous glucose monitoring system (CGMS). For the long-term durable and selective immobilization of glucose oxidase on a microneedle electrode, a biocompatible engineered mussel adhesive protein was employed through efficient electrochemical oxidation strategy. For the accurate performance in in vivo environments, we also suggested dual real-time compensated algorithms to cover both temperature and time-lag differences. After pre-clinical and pilot-clinical evaluations, we confirmed that our proposed CGMS has an outstanding performance compared with various commercially available continuous systems and achieves comparable performance to disposable glucose sensors.

Rationale: Current guidelines for advanced non-small cell lung cancer (NSCLC) recommend the use of targeted agents for specific driver genes after confirming genetic alterations. Although epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement are usually mutually exclusive, EGFR and ALK co-alterations have been reported increasingly in cases of NSCLC. However, the optimal treatment for these cases has not been established. Patient concerns: This case series describes three patients diagnosed with advanced non-squamous NSCLC who harbored EGFR and ALK co-alterations. The complaints for each case are as follows: 57-year-old woman with coughing and dyspnea in case 1, 32-year-old man with diplopia in case 2 and 77-year-old woman with chest discomfort in case 3. Diagnoses: Three never-smokers were diagnosed pathologically with stage IV adenocarcinoma of the lung. Subsequent molecular studies revealed the EGFR L858R mutation gene and ALK rearrangement, which were proven by real-time polymerase chain reaction and fluorescence in situ hybridization, respectively. Interventions: All 3 patients received first-line therapy with EGFR-tyrosine kinase inhibitors (TKIs). Cases 1 and 2 were treated with ALK-TKIs as second-line therapy and received additional EGFR-TKIs as third- and fourth-line regimens. Outcomes: The patients achieved partial responses to EGFR-TKIs according to radiologic findings. However, second-line ALK-TKI therapy was ineffective in cases 1 and 2. Lessons: Cases of NSCLC with concomitant EGFR mutation and ALK rearrangement are rare, and the selection of an optimal targeted therapy is challenging. Here, EGFR-TKI appeared to yield better outcomes than ALK-TKI in patients with NSCLC who harbored EGFR/ALK co-alterations.

We evaluated the association between genetic variants in the Notch pathway and survival outcomes of patients with surgically resected NSCLC. Sixty-four single nucleotide polymorphisms (SNPs) in the Notch pathway genes were evaluated in the discovery study (n = 354) and two sequential validation studies (n = 772 and n = 746, respectively). The association of genotype with overall survival (OS) and disease-free survival (DFS) was evaluated. Of the 64 SNPs analyzed in the discovery study, 9 were significantly associated with OS or DFS. Among them, the association remained significant only for Deltex-1 (DTX1) rs1732786A>G in the first validation study. The second validation study confirmed again the association between DTX1 rs1732786A>G and survival outcomes. In the combined analysis, rs1732786A>G was significantly associated with better OS and DFS (adjusted HR ·aHR· for OS, 0.75; 95% CI 0.64–0.87; P = 0.0002; aHR for DFS, 0.79; 95% CI 0.71–0.89; P = 0.0001). In vitro luciferase assay showed that the rs1732786G allele was associated with higher promoter activity compared to rs1732786A allele. Consistently, relative mRNA expression level of DTX1 showed significant positive correlation with rs1732786 A-to-G change (Ptrend = 0.02) in tumor tissues. These results suggest that DTX1 rs1732786 is a potential prognostic factor that may have clinical utility in the management of early stage NSCLC.

Smoking is the leading cause of preventable death and a risk factor for cancer, but smoking cessation is difficult even in patients who need hospitalization. This study aimed to investigate the usefulness of an inpatient smoking cessation consultation program and to analyze the clinical factors associated with abstinence. In this observational study, patients received regular counseling for 6 months, and abstinence was objectively assessed via urine and exhaled carbon monoxide testing. Cessation rates were assessed at 4 weeks and 6 months, and clinical characteristics associated with cessation success were investigated. Of the 571 patients referred to participate in the program, 170 (29.8%) were enrolled, and only 2 (1.2%) used smoking cessation drugs in addition to counseling. The smoking cessation rate was 77.6% after 4 weeks and 59.1% after 6 months. The cessation rates were significantly higher in patients with cancer than in those without cancer at both timepoints (63.8% vs 21.9%, P

Objective This study aimed to evaluate hypersensitivity reactions to anti-tuberculosis (TB) drugs. Methods We retrospectively compared the clinical manifestations and treatment outcomes of single and multiple drug hypersensitivity reactions (DHRs). Results Twenty-eight patients were diagnosed with anti-TB DHRs using oral drug provocation tests. Of these 28 patients, 17 patients (60.7%) had DHRs to a single drug and 11 (39.3%) had multiple DHRs. The median age of patients was 57.5 years (interquartile range [IQR], 39.2–73.2). Of the total patients, 18 patients (64.3%) were men. The median number of anti-TB drugs causing multiple DHRs was 2.0 (IQR 2.0–3.0). Rifampin was the most common drug that caused DHRs in both the single and multiple DHR groups (n = 8 [47.1%] and n = 9 [52.9%], respectively). The treatment success rate was lower in the multiple DHR group than in the single DHR group; however, the difference was not statistically significant (81.8% vs. 94.1%; P = 0.543). Conclusions Multiple anti-TB DHRs were common in all patients who experienced DHRs, and rifampin was the most common causative drug. The treatment outcomes appeared to be poorer in patients with multiple DHRs than in those with single DHRs.

We identified traditional risk factors and investigated poorly understood risk factors for suicide attempts according to gender in a large Korean population. We analyzed the data from 6,768 males and 12,475 females with suicidal ideation obtained from the nationwide 2013 Korean Community Health Survey. The dependent variable was suicide attempts within the past year. There was a significant trend towards an increase in suicide attempts with decreasing age in both genders. Compared with those who were married, suicide attempts were significantly higher among those who were widowed, divorced, or separated for males (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.34–3.20), but lower for females (OR, 0.66; 95% CI, 0.45–0.98). Current smoking and depression were significant risk factor for suicide attempts in males and females. However, monthly household income, myocardial infarction, and osteoporosis were significantly associated with suicide attempts only in males, whereas education level, recipient of National Basic Livelihood Security, family contact, leisure activity, and drinking frequency were significantly associated only in females. These findings indicate that gender difference should be considered in the assessment, prevention, and management of future suicide attempts by community policy-makers and clinicians., Graphical Abstract

Background There are a few reports on the impact of central facial palsy and dysarthria on quality of life (QOL) in stroke patients. Objective To investigate the impact of central facial palsy on QOL compared with dysarthria during the chronic phase in patients with first-ever strokes. Methods This study represents an interim analysis of the Korean Stroke Cohort for Functioning and Rehabilitation study. We selected data from patients with functional independence of 0 or 1 by the modified Rankin Scale at 6 months after stroke onset, who showed an impairment only in National Institute of Health Stroke Scale items 4 (facial palsy) or 10 (dysarthria). Assessments included the European Quality of Life-5 Dimensions (EQ-5D) and the Geriatric depression scale-short form (GDS-SF). Results Data from 149 patients were selected for this analysis from 3,929 patients who were followed up at 6 months. Thirty-nine and 110 patients were classified into the facial palsy and dysarthria groups, respectively. The groups did not differ significantly in baseline characteristics or functional assessments. EQ-5D was significantly lower in the facial palsy group than in the dysarthria group at 6 months after stroke (p = 0.036). GDS-SF was significantly higher in the facial palsy group than in the dysarthria group (p = 0.005). Conclusions The results of this study revealed that central facial palsy clearly has a more negative impact on QOL than dysarthria in chronic stroke patients with functional independence.

Glutathione peroxidase 3 (GPx3), an antioxidant enzyme, acts as a modulator of redox signaling, has immunomodulatory function, and catalyzes the detoxification of reactive oxygen species (ROS). GPx3 has been identified as a tumor suppressor in many cancers. Although hyper-methylation of the GPx3 promoter has been shown to down-regulate its expression, other mechanisms by which GPx3 expression is regulated have not been reported. The aim of this study was to further elucidate the mechanisms of GPx3 regulation. GPx3 gene analysis predicted the presence of ten glucocorticoid response elements (GREs) on the GPx3 gene. This result prompted us to investigate whether GPx3 expression is regulated by the glucocorticoid receptor (GR), which is implicated in tumor response to chemotherapy. The corticosteroid dexamethasone (Dex) was used to examine the possible relationship between GR and GPx3 expression. Dex significantly induced GPx3 expression in H1299, H1650, and H1975 cell lines, which exhibit low levels of GPx3 expression under normal conditions. The results of EMSA and ChIP-PCR suggest that GR binds directly to GRE 6 and 7, both of which are located near the GPx3 promoter. Assessment of GPx3 transcription efficiency using a luciferase reporter system showed that blocking formation of the GR-GRE complexes reduced luciferase activity by 7-8-fold. Suppression of GR expression by siRNA transfection also induced down-regulation of GPx3. These data indicate that GPx3 expression can be regulated independently via epigenetic or GR-mediated mechanisms in lung cancer cells, and suggest that GPx3 could potentiate glucocorticoid (GC)-mediated anti-inflammatory signaling in lung cancer cells.

Predicting functional outcome and quality of life (QOL) is critical to the treatment of patients with stroke. The purpose of this study was to analyze the factors influencing functional status and QOL of stroke patients 6 months after a first-ever stroke. This study was an interim analysis of the Korean Stroke Cohort for Functioning and Rehabilitation Study, designed to include 10 years of follow-up for first-ever stroke patients. This study analyzed data from 2857 patients who completed face-to-face assessments with the functional independence measurement (FIM) and Euro Quality of Life-5D (EQ-5D) at 6 months after stroke onset. A multivariate regression analysis was used to analyze factors that potentially influenced FIM and EQ-5D results at 6 months after stroke. Of the patients in this study, 80.1 % suffered from ischemic stroke and 19.9 % experienced hemorrhagic stroke. The independent predictors of functional independency measured by FIM at 6 months after stroke were age, initial stroke severity, duration of hospitalization, and functional level at discharge in terms of motor, ambulation, and language. For QOL measured by EQ-5D at 6 months after stroke, age, duration of hospitalization, and motor function at discharge were significant predictors. In conclusion, proper treatment to achieve maximal functional gain at discharge may be an important factor in improving functional independency and QOL in chronic stage stroke survivors. These results provide useful information for establishing comprehensive and systematic care for stroke patients.

Objectives We examined the associations between HbA1c levels and various atherosclerotic vascular parameters among adults without diabetes from the general population. Methods A total of 6500 community-dwelling adults, who were free of type 2 diabetes and ≥50 years of age, were included. High-resolution B-mode ultrasound was used to evaluate carotid artery structure, including intima-media thickness (IMT), plaque, and luminal diameter. Brachial-ankle pulse wave velocity (baPWV), which is a useful indicator of systemic arterial stiffness, was determined using an automatic waveform analysis device. Results No significant associations were observed between HbA1c, carotid IMT, plaque, or luminal diameter in a fully adjusted model. However, the odds ratio (95% confidence interval) for high baPWV (defined as the highest quartile) increased by 1.43 (1.19–1.71) per 1% HbA1c increase after adjusting for conventional risk factors in a multivariate logistic regression analysis. In addition, HbA1c was independently associated with baPWV in a multivariate linear regression analysis. Conclusions High-normal HbA1c level was independently associated with arterial stiffness, but not with carotid atherosclerotic parameters, in the general population without diabetes. Our results suggest that the functional atherosclerotic process may already be accelerated according to HbA1c level, even at a level below the diagnostic threshold for diabetes.

Objective To investigate the return to work status of patients with first-ever stroke with functional independence 6 months post-stroke. Design Prospective cohort study. Participants Nine hundred and thirty-three patients with functional independence at 6 months after stroke onset. Methods A complete post-enumeration survey was performed through a review of the medical records for first admission. In addition, structured self-administered questionnaires and a face-to-face interview were performed assessing occupational status, quality of life, and emotional status at 6 months after stroke. Results Of the patients in this study, 60.0% returned to work at 6 months after stroke. Sex, age, educational level, and comorbidity level were independent factors related to return to work. The rate of return to work in female patients under 65 years of age was similar to that of male patients 65 years of age or older. Stroke patients who returned to work showed better emotional statuses than those who did not return to work. Conclusion Many stroke patients did not return to work despite functional independence at 6 months after stroke. Based on the results of this study, we suggest providing appropriate vocational rehabilitation for stroke patients and proper education for employers to increase the rate of early return to work in stroke patients.