Showing papers by "New Generation University College published in 2019"

T-Cell–Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028

Abstract: PURPOSEBiomarkers that can predict response to anti–programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell–inflamed gene-expression profile (GEP), programmed death liga...

A bioprinted human-glioblastoma-on-a-chip for the identification of patient-specific responses to chemoradiotherapy

Abstract: Patient-specific ex vivo models of human tumours that recapitulate the pathological characteristics and complex ecology of native tumours could help determine the most appropriate cancer treatment for individual patients. Here, we show that bioprinted reconstituted glioblastoma tumours consisting of patient-derived tumour cells, vascular endothelial cells and decellularized extracellular matrix from brain tissue in a compartmentalized cancer–stroma concentric-ring structure that sustains a radial oxygen gradient, recapitulate the structural, biochemical and biophysical properties of the native tumours. We also show that the glioblastoma-on-a-chip reproduces clinically observed patient-specific resistances to treatment with concurrent chemoradiation and temozolomide, and that the model can be used to determine drug combinations associated with superior tumour killing. The patient-specific tumour-on-a-chip model might be useful for the identification of effective treatments for glioblastoma patients resistant to the standard first-line treatment. A tumour-on-a-chip model featuring patient-derived glioblastoma cells, vascular endothelial cells and decellularized extracellular matrix from brain tissue can be used to identify patient-specific resistance to standard chemoradiotherapy.

Effect of Laparoscopic Distal Gastrectomy vs Open Distal Gastrectomy on Long-term Survival Among Patients With Stage I Gastric Cancer The KLASS-01 Randomized Clinical Trial

Abstract: Importance Laparoscopic distal gastrectomy is gaining popularity over open distal gastrectomy for gastric cancer because of better early postoperative outcomes. However, to our knowledge, no studies have proved whether laparoscopic distal gastrectomy is oncologically equivalent to open distal gastrectomy. Objective To examine whether the long-term survival among patients with stage I gastric cancer undergoing laparoscopic distal gastrectomy is noninferior to that among patients undergoing open distal gastrectomy. Design The Korean Laparoendoscopic Gastrointestinal Surgery Study (KLASS) group, which includes 15 surgeons from 13 institutes, conducted a phase 3, multicenter, open-label, noninferiority, prospective randomized clinical trial (KLASS-01) of patients with histologically proven, preoperative clinical stage I gastric adenocarcinoma from January 5, 2006, to August 23, 2010. Survival and recurrence status of the patients was determined in December 2016. Interventions Patients were randomly assigned (1:1) to laparoscopic distal gastrectomy (n = 705) or open distal gastrectomy (n = 711). Of these patients, 85 received a surgical approach opposite the one to which they were randomized (63 randomized to the open surgery group and 22 to the laparoscopic group). Main Outcomes and Measures Difference in 5-year overall survival between the laparoscopic and open distal gastrectomy groups. The noninferiority margin was prespecified as −5% (corresponding hazard ratio of 1.54), with an assumed survival of 90% after 5 years in the open surgery group. Results Among the 1416 patients (mean [SD] age, 57.3 [11.1] years; 940 [66.4%] male) included in the study, the 5-year overall survival rates were 94.2% in the laparoscopic group and 93.3% in the open surgery group (log-rankP = .64). Intention-to-treat analysis confirmed the noninferiority of the laparoscopic approach compared with the open approach (difference, 0.9 percentage points; 1-sided 97.5% CI, −1.6 to infinity). The 5-year cancer-specific survival rates were similar between the 2 groups (97.1% in the laparoscopic group and 97.2% in the open surgery group, log-rankP = .91; difference, −0.03 percentage points; 1-sided 97.5% CI, −1.8 to infinity). Per-protocol analysis results were consistent with the intention-to-treat results for overall and cancer-specific survival rates. Conclusions and Relevance The KLASS-01 trial revealed similar overall and cancer-specific survival rates between patients receiving laparoscopic and open distal gastrectomy. Laparoscopic distal gastrectomy is an oncologically safe alternative to open surgery for stage I gastric cancer. Trial Registration ClinicalTrials.gov identifier:NCT00452751

Molecular Mechanisms of Dermal Aging and Antiaging Approaches.

Abstract: The dermis is primarily composed of the extracellular matrix (ECM) and fibroblasts. During the aging process, the dermis undergoes significant changes. Collagen, which is a major component of ECM, becomes fragmented and coarsely distributed, and its total amount decreases. This is mainly due to increased activity of matrix metalloproteinases, and impaired transforming growth factor-β signaling induced by reactive oxygen species generated during aging. The reduction in the amount of collagen hinders the mechanical interaction between fibroblasts and the ECM, and consequently leads to the deterioration of fibroblast function and further decrease in the amount of dermal collagen. Other ECM components, including elastic fibers, glycosaminglycans (GAGs), and proteoglycans (PGs), also change during aging, ultimately leading to a reduction in the amount of functional components. Elastic fibers decrease in intrinsically aged skin, but accumulate abnormally in photoaged skin. The changes in the levels of GAGs and PGs are highly diverse, and previous studies have reported conflicting results. A reduction in the levels of functional dermal components results in the emergence of clinical aging features, such as wrinkles and reduced elasticity. Various antiaging approaches, including topicals, energy-based procedures, and dermal fillers, can restore the molecular features of dermal aging with clinical efficacy. This review summarizes the current understanding of skin aging at the molecular level, and associated treatments, to put some of the new antiaging technology that has emerged in this rapidly expanding field into molecular context.

Development and Validation of a Deep Learning-Based Automated Detection Algorithm for Major Thoracic Diseases on Chest Radiographs.

Abstract: Importance Interpretation of chest radiographs is a challenging task prone to errors, requiring expert readers. An automated system that can accurately classify chest radiographs may help streamline the clinical workflow. Objectives To develop a deep learning–based algorithm that can classify normal and abnormal results from chest radiographs with major thoracic diseases including pulmonary malignant neoplasm, active tuberculosis, pneumonia, and pneumothorax and to validate the algorithm’s performance using independent data sets. Design, Setting, and Participants This diagnostic study developed a deep learning–based algorithm using single-center data collected between November 1, 2016, and January 31, 2017. The algorithm was externally validated with multicenter data collected between May 1 and July 31, 2018. A total of 54 221 chest radiographs with normal findings from 47 917 individuals (21 556 men and 26 361 women; mean [SD] age, 51 [16] years) and 35 613 chest radiographs with abnormal findings from 14 102 individuals (8373 men and 5729 women; mean [SD] age, 62 [15] years) were used to develop the algorithm. A total of 486 chest radiographs with normal results and 529 with abnormal results (1 from each participant; 628 men and 387 women; mean [SD] age, 53 [18] years) from 5 institutions were used for external validation. Fifteen physicians, including nonradiology physicians, board-certified radiologists, and thoracic radiologists, participated in observer performance testing. Data were analyzed in August 2018. Exposures Deep learning–based algorithm. Main Outcomes and Measures Image-wise classification performances measured by area under the receiver operating characteristic curve; lesion-wise localization performances measured by area under the alternative free-response receiver operating characteristic curve. Results The algorithm demonstrated a median (range) area under the curve of 0.979 (0.973-1.000) for image-wise classification and 0.972 (0.923-0.985) for lesion-wise localization; the algorithm demonstrated significantly higher performance than all 3 physician groups in both image-wise classification (0.983 vs 0.814-0.932; allP Conclusions and Relevance The algorithm consistently outperformed physicians, including thoracic radiologists, in the discrimination of chest radiographs with major thoracic diseases, demonstrating its potential to improve the quality and efficiency of clinical practice.

Safety and immunogenicity of an anti-Middle East respiratory syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation trial.

Abstract: Summary Background Middle East respiratory syndrome (MERS) coronavirus causes a highly fatal lower-respiratory tract infection. There are as yet no licensed MERS vaccines or therapeutics. This study (WRAIR-2274) assessed the safety, tolerability, and immunogenicity of the GLS-5300 MERS coronavirus DNA vaccine in healthy adults. Methods This study was a phase 1, open-label, single-arm, dose-escalation study of GLS-5300 done at the Walter Reed Army Institute for Research Clinical Trials Center (Silver Spring, MD, USA). We enrolled healthy adults aged 18–50 years; exclusion criteria included previous infection or treatment of MERS. Eligible participants were enrolled sequentially using a dose-escalation protocol to receive 0·67 mg, 2 mg, or 6 mg GLS-5300 administered by trained clinical site staff via a single intramuscular 1 mL injection at each vaccination at baseline, week 4, and week 12 followed immediately by co-localised intramuscular electroporation. Enrolment into the higher dose groups occurred after a safety monitoring committee reviewed the data following vaccination of the first five participants at the previous lower dose in each group. The primary outcome of the study was safety, assessed in all participants who received at least one study treatment and for whom post-dose study data were available, during the vaccination period with follow-up through to 48 weeks after dose 3. Safety was measured by the incidence of adverse events; administration site reactions and pain; and changes in safety laboratory parameters. The secondary outcome was immunogenicity. This trial is registered at ClinicalTrials.gov (number NCT02670187) and is completed. Findings Between Feb 17 and July 22, 2016, we enrolled 75 individuals and allocated 25 each to 0·67 mg, 2 mg, or 6 mg GLS-5300. No vaccine-associated serious adverse events were reported. The most common adverse events were injection-site reactions, reported in 70 participants (93%) of 75. Overall, 73 participants (97%) of 75 reported at least one solicited adverse event; the most common systemic symptoms were headache (five [20%] with 0·67 mg, 11 [44%] with 2 mg, and seven [28%] with 6 mg), and malaise or fatigue (five [20%] with 0·67 mg, seven [28%] with 2 mg, and two [8%] with 6 mg). The most common local solicited symptoms were administration site pain (23 [92%] with all three doses) and tenderness (21 [84%] with all three doses). Most solicited symptoms were reported as mild (19 [76%] with 0·67 mg, 20 [80%] with 2 mg, and 17 [68%] with 6 mg) and were self-limiting. Unsolicited symptoms were reported for 56 participants (75%) of 75 and were deemed treatment-related for 26 (35%). The most common unsolicited adverse events were infections, occurring in 27 participants (36%); six (8%) were deemed possibly related to study treatment. There were no laboratory abnormalities of grade 3 or higher that were related to study treatment; laboratory abnormalities were uncommon, except for 15 increases in creatine phosphokinase in 14 participants (three participants in the 0·67 mg group, three in the 2 mg group, and seven in the 6 mg group). Of these 15 increases, five (33%) were deemed possibly related to study treatment (one in the 2 mg group and four in the 6 mg group). Seroconversion measured by S1-ELISA occurred in 59 (86%) of 69 participants and 61 (94%) of 65 participants after two and three vaccinations, respectively. Neutralising antibodies were detected in 34 (50%) of 68 participants. T-cell responses were detected in 47 (71%) of 66 participants after two vaccinations and in 44 (76%) of 58 participants after three vaccinations. There were no differences in immune responses between dose groups after 6 weeks. At week 60, vaccine-induced humoral and cellular responses were detected in 51 (77%) of 66 participants and 42 (64%) of 66, respectively. Interpretation The GLS-5300 MERS coronavirus vaccine was well tolerated with no vaccine-associated serious adverse events. Immune responses were dose-independent, detected in more than 85% of participants after two vaccinations, and durable through 1 year of follow-up. The data support further development of the GLS-5300 vaccine, including additional studies to test the efficacy of GLS-5300 in a region endemic for MERS coronavirus. Funding US Department of the Army and GeneOne Life Science.

Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations

Abstract: Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

Pulse Wave Velocity in Atherosclerosis.

Abstract: Early detection of subclinical atherosclerosis is important to reduce patients' cardiovascular risk. However, current diagnostic strategy focusing on traditional risk factors or using risk scoring is not satisfactory. Non-invasive imaging tools also have limitations such as cost, time, radiation hazard, renal toxicity, and requirement for specialized techniques or instruments. There is a close interaction between arterial stiffness and atherosclerosis. Increased luminal pressure and shear stress by arterial stiffening causes endothelial dysfunction, accelerates the formation of atheroma, and stimulates excessive collagen production and deposition in the arterial wall, leading to the progression of atherosclerosis. Pulse wave velocity (PWV), the most widely used measure of arterial stiffness, has emerged as a useful tool for the diagnosis and risk stratification of cardiovascular disease (CVD). The measurement of PWV is simple, non-invasive, and reproducible. There have been many clinical studies and meta-analyses showing the association between PWV and coronary/cerebral/carotid atherosclerosis. More importantly, longitudinal studies have shown that PWV is a significant risk factor for future CVD independent of well-known cardiovascular risk factors. The measurement of PWV may be a useful tool to select subjects at high risk of developing subclinical atherosclerosis or CVD especially in mass screening.

Identification of High-Risk Plaques Destined to Cause Acute Coronary Syndrome Using Coronary Computed Tomographic Angiography and Computational Fluid Dynamics.

Abstract: Objectives The authors investigated the utility of noninvasive hemodynamic assessment in the identification of high-risk plaques that caused subsequent acute coronary syndrome (ACS). Background ACS is a critical event that impacts the prognosis of patients with coronary artery disease. However, the role of hemodynamic factors in the development of ACS is not well-known. Methods Seventy-two patients with clearly documented ACS and available coronary computed tomographic angiography (CTA) acquired between 1 month and 2 years before the development of ACS were included. In 66 culprit and 150 nonculprit lesions as a case-control design, the presence of adverse plaque characteristics (APC) was assessed and hemodynamic parameters (fractional flow reserve derived by coronary computed tomographic angiography [FFRCT], change in FFRCT across the lesion [△FFRCT], wall shear stress [WSS], and axial plaque stress) were analyzed using computational fluid dynamics. The best cut-off values for FFRCT, △FFRCT, WSS, and axial plaque stress were used to define the presence of adverse hemodynamic characteristics (AHC). The incremental discriminant and reclassification abilities for ACS prediction were compared among 3 models (model 1: percent diameter stenosis [%DS] and lesion length, model 2: model 1 + APC, and model 3: model 2 + AHC). Results The culprit lesions showed higher %DS (55.5 ± 15.4% vs. 43.1 ± 15.0%; p Conclusions Noninvasive hemodynamic assessment enhanced the identification of high-risk plaques that subsequently caused ACS. The integration of noninvasive hemodynamic assessments may improve the identification of culprit lesions for future ACS. (Exploring the Mechanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary CT Angiography and Computational Fluid Dynamic [EMERALD]; NCT02374775)

2018 Korean Society of Hypertension Guidelines for the management of hypertension: part II-diagnosis and treatment of hypertension

Abstract: The standardized techniques of blood pressure (BP) measurement in the clinic are emphasized and it is recommended to replace the mercury sphygmomanometer by a non-mercury sphygmomanometer. Out-of-office BP measurement using home BP monitoring (HBPM) or ambulatory BP monitoring (ABPM) and even automated office BP (AOBP) are recommended to correctly measure the patient’s genuine BP. Hypertension (HTN) treatment should be individualized based on cardiovascular (CV) risk and the level of BP. Based on the recent clinical study data proving benefits of intensive BP lowering in the high risk patients, the revised guideline recommends the more intensive BP lowering in high risk patients including the elderly population. Lifestyle modifications, mostly low salt diet and weight reduction, are strongly recommended in the population with elevated BP and prehypertension and all hypertensive patients. In patients with BP higher than 160/100 mmHg or more than 20/10 mmHg above the target BP, two drugs can be prescribed in combination to maximize the antihypertensive effect and to achieve rapid BP control. Especially, single pill combination drugs have multiple benefits, including maximizing reduction of BP, minimizing adverse effects, increasing adherence, and preventing cardiovascular disease (CVD) and target organ damage.

2019 Clinical Practice Guidelines for Type 2 Diabetes Mellitus in Korea

Abstract: The Committee of Clinical Practice Guidelines of the Korean Diabetes Association revised and updated the 6th Clinical Practice Guidelines in 2019. Targets of glycemic, blood pressure, and lipid control in type 2 diabetes mellitus (T2DM) were updated. The obese and overweight population is increasing steadily in Korea, and half of the Koreans with diabetes are obese. Evidence-based recommendations for weight-loss therapy for obesity management as treatment for hyperglycemia in T2DM were provided. In addition, evidence from large clinical studies assessing cardiovascular outcomes following the use of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists in patients with T2DM were incorporated into the recommendations.

Highlighted STAT3 as a potential drug target for cancer therapy.

Abstract: Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that regulates cell proliferation, differentiation, apoptosis, angiogenesis, inflammation and immune responses. Aberrant STAT3 activation triggers tumor progression through oncogenic gene expression in numerous human cancers, leading to promote tumor malignancy. On the contrary, STAT3 activation in immune cells cause elevation of immunosuppressive factors. Accumulating evidence suggests that the tumor microenvironment closely interacts with the STAT3 signaling pathway. So, targeting STAT3 may improve tumor progression, and anti-cancer immune response. In this review, we summarized the role of STAT3 in cancer and the tumor microenvironment, and present inhibitors of STAT3 signaling cascades. [BMB Reports 2019; 52(7): 415-423]

Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis

Abstract: Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non-small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFα to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy. SIGNIFICANCE: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.

Phase I study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) administered with PD-L1 inhibitor (atezolizumab) in advanced solid tumors

Abstract: Purpose: IDO1 induces immune suppression in T cells through l-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer. Patients and Methods: The study consisted of a 3+3 dose-escalation stage (n = 66) and a tumor-specific expansion stage (n = 92). Navoximod was given orally every 12 hours continuously for 21 consecutive days of each cycle with the exception of cycle 1, where navoximod administration started on day −1 to characterize pharmacokinetics. Atezolizumab was administered by intravenous infusion 1,200 mg every 3 weeks on day 1 of each cycle. Results: Patients (n = 157) received navoximod at 6 dose levels (50–1,000 mg) in combination with atezolizumab. The maximum administered dose was 1,000 mg twice daily; the MTD was not reached. Navoximod demonstrated a linear pharmacokinetic profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, head and neck squamous cell carcinoma, cervical, neural sheath, non–small cell lung cancer, triple-negative breast cancer, renal cell carcinoma, urothelial bladder cancer): 6 (9%) dose-escalation patients achieved partial response, and 10 (11%) expansion patients achieved partial response or complete response. Conclusions: The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Although activity was observed, there was no clear evidence of benefit from adding navoximod to atezolizumab.

Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study

Abstract: The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab ± chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented. Patients ≥ 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score ≥ 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m2 on days 1–5 of each 3-week cycle (or capecitabine 1000 mg/m2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy). In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8–24.1) and 17.5 months (range 1.7–20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3–5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7–78.9] (combination therapy) and 25.8% (95% CI 11.9–44.6) (monotherapy). Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma. ClinicalTrials.gov NCT02335411

Executive Summary of Stroke Statistics in Korea 2018: A Report from the Epidemiology Research Council of the Korean Stroke Society

Abstract: Despite the great socioeconomic burden of stroke, there have been few reports of stroke statistics in Korea. In this scenario, the Epidemiologic Research Council of the Korean Stroke Society launched the “Stroke Statistics in Korea” project, aimed at writing a contemporary, comprehensive, and representative report on stroke epidemiology in Korea. This report contains general statistics of stroke, prevalence of behavioral and vascular risk factors, stroke characteristics, pre-hospital system of care, hospital management, quality of stroke care, and outcomes. In this report, we analyzed the most up-to-date and nationally representative databases, rather than performing a systematic review of existing evidence. In summary, one in 40 adults are patients with stroke and 232 subjects per 100,000 experience a stroke event every year. Among the 100 patients with stroke in 2014, 76 had ischemic stroke, 15 had intracerebral hemorrhage, and nine had subarachnoid hemorrhage. Stroke mortality is gradually declining, but it remains as high as 30 deaths per 100,000 individuals, with regional disparities. As for stroke risk factors, the prevalence of smoking is decreasing in men but not in women, and the prevalence of alcohol drinking is increasing in women but not in men. Population-attributable risk factors vary with age. Smoking plays a role in young-aged individuals, hypertension and diabetes in middle-aged individuals, and atrial fibrillation in the elderly. About four out of 10 hospitalized patients with stroke are visiting an emergency room within 3 hours of symptom onset, and only half use an ambulance. Regarding acute management, the proportion of patients with ischemic stroke receiving intravenous thrombolysis and endovascular treatment was 10.7% and 3.6%, respectively. Decompressive surgery was performed in 1.4% of patients with ischemic stroke and in 28.1% of those with intracerebral hemorrhage. The cumulative incidence of bleeding and fracture at 1 year after stroke was 8.9% and 4.7%, respectively. The direct costs of stroke were about ₩1.68 trillion (KRW), of which ₩1.11 trillion were for ischemic stroke and ₩540 billion for hemorrhagic stroke. The great burden of stroke in Korea can be reduced through more concentrated efforts to control major attributable risk factors for age and sex, reorganize emergency medical service systems to give patients with stroke more opportunities for reperfusion therapy, disseminate stroke unit care, and reduce regional disparities. We hope that this report can contribute to achieving these tasks.

Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study.

Abstract: LBA4007Background: KEYNOTE062 (NCT02494583) was a randomized, active controlled study of 1L P or P+C vs C in pts with PD-L1 combined positive score ≥1 (CPS ≥1), HER2-negative, advanced GC. Methods:...

Development and Validation of a Deep Learning-based Automatic Detection Algorithm for Active Pulmonary Tuberculosis on Chest Radiographs.

Abstract: Background Detection of active pulmonary tuberculosis on chest radiographs (CRs) is critical for the diagnosis and screening of tuberculosis. An automated system may help streamline the tuberculosis screening process and improve diagnostic performance. Methods We developed a deep learning-based automatic detection (DLAD) algorithm using 54c221 normal CRs and 6768 CRs with active pulmonary tuberculosis that were labeled and annotated by 13 board-certified radiologists. The performance of DLAD was validated using 6 external multicenter, multinational datasets. To compare the performances of DLAD with physicians, an observer performance test was conducted by 15 physicians including nonradiology physicians, board-certified radiologists, and thoracic radiologists. Image-wise classification and lesion-wise localization performances were measured using area under the receiver operating characteristic (ROC) curves and area under the alternative free-response ROC curves, respectively. Sensitivities and specificities of DLAD were calculated using 2 cutoffs (high sensitivity [98%] and high specificity [98%]) obtained through in-house validation. Results DLAD demonstrated classification performance of 0.977-1.000 and localization performance of 0.973-1.000. Sensitivities and specificities for classification were 94.3%-100% and 91.1%-100% using the high-sensitivity cutoff and 84.1%-99.0% and 99.1%-100% using the high-specificity cutoff. DLAD showed significantly higher performance in both classification (0.993 vs 0.746-0.971) and localization (0.993 vs 0.664-0.925) compared to all groups of physicians. Conclusions Our DLAD demonstrated excellent and consistent performance in the detection of active pulmonary tuberculosis on CR, outperforming physicians, including thoracic radiologists.

Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer

Abstract: Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAFV600E and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.

The molecular landscape of glioma in patients with Neurofibromatosis 1.

Abstract: Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors. An integrated analysis of glioma samples from patients with neurofibromatosis 1 annotates their mutational, epigenetic, transcriptional, and immunological features and uncovers similitudes with a subset of sporadic gliomas.

Incorporating diffusion- and perfusion-weighted MRI into a radiomics model improves diagnostic performance for pseudoprogression in glioblastoma patients.

Abstract: BACKGROUND Pseudoprogression is a diagnostic challenge in early posttreatment glioblastoma. We therefore developed and validated a radiomics model using multiparametric MRI to differentiate pseudoprogression from early tumor progression in patients with glioblastoma. METHODS The model was developed from the enlarging contrast-enhancing portions of 61 glioblastomas within 3 months after standard treatment with 6472 radiomic features being obtained from contrast-enhanced T1-weighted imaging, fluid-attenuated inversion recovery imaging, and apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) maps. Imaging features were selected using a LASSO (least absolute shrinkage and selection operator) logistic regression model with 10-fold cross-validation. Diagnostic performance for pseudoprogression was compared with that for single parameters (mean and minimum ADC and mean and maximum CBV) and single imaging radiomics models using the area under the receiver operating characteristics curve (AUC). The model was validated with an external cohort (n = 34) imaged on a different scanner and internal prospective registry data (n = 23). RESULTS Twelve significant radiomic features (3 from conventional, 2 from diffusion, and 7 from perfusion MRI) were selected for model construction. The multiparametric radiomics model (AUC, 0.90) showed significantly better performance than any single ADC or CBV parameter (AUC, 0.57-0.79, P < 0.05), and better than a single radiomics model using conventional MRI (AUC, 0.76, P = 0.012), ADC (AUC, 0.78, P = 0.014), or CBV (AUC, 0.80, P = 0.43). The multiparametric radiomics showed higher performance in the external validation (AUC, 0.85) and internal validation (AUC, 0.96) than any single approach, thus demonstrating robustness. CONCLUSIONS Incorporating diffusion- and perfusion-weighted MRI into a radiomics model improved diagnostic performance for identifying pseudoprogression and showed robustness in a multicenter setting.

Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis: Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors.

Abstract: Objective To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (SpA) and prior inadequate response to or intolerance of 1 or 2 tumor necrosis factor inhibitors (TNFi).

Flexible, sticky, and biodegradable wireless device for drug delivery to brain tumors.

Abstract: Implantation of biodegradable wafers near the brain surgery site to deliver anti-cancer agents which target residual tumor cells by bypassing the blood-brain barrier has been a promising method for brain tumor treatment. However, further improvement in the prognosis is still necessary. We herein present novel materials and device technologies for drug delivery to brain tumors, i.e., a flexible, sticky, and biodegradable drug-loaded patch integrated with wireless electronics for controlled intracranial drug delivery through mild-thermic actuation. The flexible and bifacially-designed sticky/hydrophobic device allows conformal adhesion on the brain surgery site and provides spatially-controlled and temporarily-extended drug delivery to brain tumors while minimizing unintended drug leakage to the cerebrospinal fluid. Biodegradation of the entire device minimizes potential neurological side-effects. Application of the device to the mouse model confirms tumor volume suppression and improved survival rate. Demonstration in a large animal model (canine model) exhibited its potential for human application.