Showing papers by "New Generation University College published in 2020"

Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma

Abstract: Background The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinom...

Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.

Abstract: PURPOSEGenomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential ne...

Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.

Abstract: Summary Background Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours. Methods In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing. Findings Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status ( Interpretation tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours. Funding Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial.

Abstract: Importance Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need. Objective To evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater. Design, Setting, and Participants The phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017. Interventions Patients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2twice daily), or chemotherapy plus placebo, every 3 weeks. Main Outcomes and Measures Primary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater. Results A total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03;P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17;P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02;P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively. Conclusions and Relevance This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested. Trial Registration ClinicalTrials.gov Identifier:NCT02494583

HER2-targeted therapies — a role beyond breast cancer

Abstract: HER2 is an established therapeutic target in a large subset of women with breast cancer; a variety of agents including trastuzumab, pertuzumab, lapatinib, neratinib and trastuzumab emtansine (T-DM1) have been approved for the treatment of HER2-positive breast cancer. HER2 is also overexpressed in subsets of patients with other solid tumours. Notably, the addition of trastuzumab to first-line chemotherapy has improved the overall survival of patients with HER2-positive gastric cancer, and has become the standard-of-care treatment for this group of patients. However, trials involving pertuzumab, lapatinib and T-DM1 have failed to provide significant improvements in the outcomes of patients with HER2-positive gastric cancer. HER2-targeted therapies are also being tested in patients with other solid tumours harbouring HER2 overexpression, and/or amplifications or other mutations of the gene encoding HER2 (ERBB2), including biliary tract, colorectal, non-small-cell lung and bladder cancers. The experience with gastric cancer suggests that the successes observed in HER2-positive breast cancer might not be replicated in these other tumour types, owing to differences in the level of HER2 overexpression and other aspects of disease biology. In this Review, we describe the current role of HER2-targeted therapies beyond breast cancer and also highlight the potential of novel HER2-targeted agents that are currently in clinical development.

Diagnostic Performance of CT and Reverse Transcriptase Polymerase Chain Reaction for Coronavirus Disease 2019: A Meta-Analysis.

Abstract: Background Recent studies have suggested that chest CT scans could be used as a primary screening or diagnostic tool for coronavirus disease 2019 (COVID-19) in epidemic areas. Purpose To perform a meta-analysis to evaluate diagnostic performance measures, including predictive values of chest CT and initial reverse transcriptase polymerase chain reaction (RT-PCR). Materials and Methods Medline and Embase were searched from January 1, 2020, to April 3, 2020, for studies on COVID-19 that reported the sensitivity, specificity, or both of CT scans, RT-PCR assays, or both. The pooled sensitivity and specificity were estimated by using random-effects models. The actual prevalence (ie, the proportion of confirmed patients among those tested) in eight countries was obtained from web sources, and the predictive values were calculated. Meta-regression was performed to reveal the effect of potential explanatory factors on the diagnostic performance measures. Results The pooled sensitivity was 94% (95% confidence interval [CI]: 91%, 96%; I2 = 95%) for chest CT and 89% (95% CI: 81%, 94%; I2 = 90%) for RT-PCR. The pooled specificity was 37% (95% CI: 26%, 50%; I2 = 83%) for chest CT. The prevalence of COVID-19 outside China ranged from 1.0% to 22.9%. For chest CT scans, the positive predictive value (PPV) ranged from 1.5% to 30.7%, and the negative predictive value (NPV) ranged from 95.4% to 99.8%. For RT-PCR, the PPV ranged from 47.3% to 96.4%, whereas the NPV ranged from 96.8% to 99.9%. The sensitivity of CT was affected by the distribution of disease severity, the proportion of patients with comorbidities, and the proportion of asymptomatic patients (all P < .05). The sensitivity of RT-PCR was negatively associated with the proportion of elderly patients (P = .01). Conclusion Outside of China where there is a low prevalence of coronavirus disease 2019 (range, 1%-22.9%), chest CT screening of patients with suspected disease had low positive predictive value (range, 1.5%-30.7%). © RSNA, 2020 Online supplemental material is available for this article.

Epidemiology, virology, and clinical features of severe acute respiratory syndrome -coronavirus-2 (SARS-CoV-2; Coronavirus Disease-19).

Abstract: A cluster of severe pneumonia of unknown etiology in Wuhan City, Hubei province in China emerged in December 2019. A novel coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was isolated from lower respiratory tract sample as the causative agent. The current outbreak of infections with SARS-CoV-2 is termed Coronavirus Disease 2019 (COVID-19) by the World Health Organization (WHO). COVID-19 rapidly spread into at least 114 countries and killed more than 4,000 people by March 11 2020. WHO officially declared COVID-19 a pandemic on March 11, 2020. There have been 2 novel coronavirus outbreaks in the past 2 decades. The outbreak of severe acute respiratory syndrome (SARS) in 2002-2003 caused by SARS-CoV had a case fatality rate of around 10% (8,098 confirmed cases and 774 deaths), while Middle East respiratory syndrome (MERS) caused by MERSCoV killed 861 people out of a total 2,502 confirmed cases between 2012 and 2019. The purpose of this review is to summarize known-to-date information about SARS-CoV-2, transmission of SARS-CoV-2, and clinical features.

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

Abstract: This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

The First Case of 2019 Novel Coronavirus Pneumonia Imported into Korea from Wuhan, China: Implication for Infection Prevention and Control Measures.

Abstract: In December 2019, a viral pneumonia outbreak caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV), began in Wuhan, China. We report the epidemiological and clinical features of the first patient with 2019-nCoV pneumonia imported into Korea from Wuhan. This report suggests that in the early phase of 2019-nCoV pneumonia, chest radiography would miss patients with pneumonia and highlights taking travel history is of paramount importance for early detection and isolation of 2019-nCoV cases.

Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer.

Abstract: Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Abstract: Objective Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive. Design Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis. Results Composition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice. Conclusion These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

Clinical Course and Outcomes of Patients with Severe Acute Respiratory Syndrome Coronavirus 2 Infection: a Preliminary Report of the First 28 Patients from the Korean Cohort Study on COVID-19

Abstract: Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pneumonia emerged in Wuhan, China in December 2019. In this retrospective multicenter study, we investigated the clinical course and outcomes of novel coronavirus disease 2019 (COVID-19) from early cases in Republic of Korea. Methods All of the cases confirmed by real time polymerase chain reaction were enrolled from the 1st to the 28th patient nationwide. Clinical data were collected and analyzed for changes in clinical severity including laboratory, radiological, and virologic dynamics during the progression of illness. Results The median age was 40 years (range, 20-73 years) and 15 (53.6%) patients were male. The most common symptoms were cough (28.6%) and sore throat (28.6%), followed by fever (25.0%). Diarrhea was not common (10.7%). Two patients had no symptoms. Initial chest X-ray (CXR) showed infiltration in 46.4% of the patients, but computed tomography scan confirmed pneumonia in 88.9% (16/18) of the patients. Six patients (21.4%) required supplemental oxygen therapy, but no one needed mechanical ventilation. Lymphopenia was more common in severe cases. Higher level of C-reactive protein and worsening of chest radiographic score was observed during the 5-7 day period after symptom onset. Viral shedding was high from day 1 of illness, especially from the upper respiratory tract (URT). Conclusion The prodromal symptoms of COVID-19 were mild and most patients did not have limitations of daily activity. Viral shedding from URT was high from the prodromal phase. Radiological pneumonia was common from the early days of illness, but it was frequently not evident in simple CXR. These findings could be plausible explanations for the easy and rapid spread of SARS-CoV-2 in the community.

Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound (CEUS) in the Liver-Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS.

Abstract: The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast-enhanced ultrasound, first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology. The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications. The 2012 guideline requires updating as, previously, the differences in the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including U.S. Food and Drug Administration approval and the extensive Asian experience, to produce a truly international perspective. These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCAs) and are intended to create standard protocols for the use and administration of UCAs in liver applications on an international basis to improve the management of patients.

Identification of type 2 diabetes loci in 433,540 East Asian individuals

Abstract: Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.

Virus Isolation from the First Patient with SARS-CoV-2 in Korea.

Abstract: Novel coronavirus (SARS-CoV-2) is found to cause a large outbreak started from Wuhan since December 2019 in China and SARS-CoV-2 infections have been reported with epidemiological linkage to China in 25 countries until now. We isolated SARS-CoV-2 from the oropharyngeal sample obtained from the patient with the first laboratory-confirmed SARS-CoV-2 infection in Korea. Cytopathic effects of SARS-CoV-2 in the Vero cell cultures were confluent 3 days after the first blind passage of the sample. Coronavirus was confirmed with spherical particle having a fringe reminiscent of crown on transmission electron microscopy. Phylogenetic analyses of whole genome sequences showed that it clustered with other SARS-CoV-2 reported from Wuhan.

Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1–2 trial

Abstract: Summary Background Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer. Methods KEYNOTE-051 is an ongoing phase 1–2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov , number NCT02332668 . Findings Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8–15). Median follow-up was 8·6 months (IQR 2·5–16·4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3–5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3–5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60·0%; 95% CI 32·3–83·7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5·9% (95% CI 2·6–11·3). Interpretation Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co.

National Response to COVID-19 in the Republic of Korea and Lessons Learned for Other Countries.

Abstract: In the first two months of the COVID-19 pandemic, the Republic of Korea (South Korea) had the second highest number of cases globally yet was able to dramatically lower the incidence of new cases and sustain a low mortality rate, making it a promising example of strong national response. We describe the main strategies undertaken and selected facilitators and challenges in order to identify transferable lessons for other countries working to control the spread and impact of COVID-19. Identified strategies included early recognition of the threat and rapid activation of national response protocols led by national leadership; rapid establishment of diagnostic capacity; scale-up of measures for preventing community transmission; and redesigning the triage and treatment systems, mobilizing the necessary resources for clinical care. Facilitators included existing hospital capacity, the epidemiology of the COVID-19 outbreak, and strong national leadership despite political changes and population sensitization due to the 2015 Middle East respiratory syndrome-related coronavirus (MERS-CoV) epidemic. Challenges included sustaining adequate human resources and supplies in high-caseload areas. Key recommendations include (1) recognize the problem, (2) establish diagnostic capacity, (3) implement aggressive measures to prevent community transmission, (4) redesign and reallocate clinical resources for the new environment, and (5) work to limit economic impact through and while prioritizing controlling the spread and impact of COVID-19. South Korea's strategies to prevent, detect, and respond to the pandemic represent applicable knowledge that can be adopted by other countries and the global community facing the enormous COVID-19 challenges ahead.

Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma

Abstract: Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.

First Pediatric Case of Coronavirus Disease 2019 in Korea

Abstract: The large outbreak of coronavirus disease 2019 (COVID-19) that started in Wuhan, China has now spread to many countries worldwide. Current epidemiologic knowledge suggests that relatively few cases are seen among children, which limits opportunities to address pediatric specific issues on infection control and the children's contribution to viral spread in the community. Here, we report the first pediatric case of COVID-19 in Korea. The 10-year-old girl was a close contact of her uncle and her mother who were confirmed to have COVID-19. In this report, we present mild clinical course of her pneumonia that did not require antiviral treatment and serial viral test results from multiple specimens. Lastly, we raise concerns on the optimal strategy of self-quarantine and patient care in a negative isolation room for children.

Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver - Update 2020 - WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS

Abstract: The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS), first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications. The 2012 guideline requires updating as previously the differences of the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including the United States Food and Drug Administration (FDA) approval as well as the extensive Asian experience, to produce a truly international perspective. These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCA) and are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis to improve the management of patients.

Impact of Public Health Interventions on Seasonal Influenza Activity During the COVID-19 Outbreak in Korea.

Abstract: BACKGROUND: COVID-19 was introduced in Korea early and experienced a large outbreak in mid-February. We aimed to review the public health interventions used during the COVID-19 outbreak and describe the impact on seasonal influenza activity in Korea. METHODS: National response strategies and public health interventions, along with daily COVID-19 confirmed cases in Korea were reviewed during the pandemic. National influenza surveillance data were compared between seven sequential seasons. Characteristics of each season, including the rate of influenza-like illness (ILI), duration of epidemic, date of termination of epidemic, distribution of influenza virus strain and hospitalization were analyzed. RESULTS: After various public health interventions including enforced public education on hand hygiene, cough etiquette and staying at home with respiratory symptoms, universal mask use in public places, refrain from non-essential social activities and school closure, the duration of the influenza epidemic in 2019/2020 decreased by 6-12 weeks and the influenza activity peak rated 49.8 ILI/1,000 visits compared to 71.9-86.2 ILI/1,000 visits of previous seasons. During the period of enforced social distancing from week 9 to 17 of 2020, influenza hospitalization cases were 11.9-26.9-fold lower compared with previous seasons. During the 2019/2020 season, influenza B accounted for only 4%, in contrast with previous seasons in which influenza B accounted for 26.6% to 54.9% of all cases. CONCLUSIONS: Efforts to activate high level national response not only led to a decrease in COVID-19, but also substantial decrease in seasonal influenza activity. Interventions applied to control COVID-19 may serve as useful strategies for prevention and control of influenza in upcoming seasons.

Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial.

Abstract: Summary Background Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma. Methods CP-MGAH22–05 was a single-arm, open-label, phase 1b–2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov , NCT02689284 . Recruitment for the trial has completed and follow-up is ongoing. Findings Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7–23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3–4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15–27·93) of 92 evaluable patients. Interpretation These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab). Funding MacroGenics.

Posttraumatic stress disorder and depression of survivors 12 months after the outbreak of Middle East respiratory syndrome in South Korea.

Abstract: The 2015 outbreak of Middle East Respiratory Syndrome (MERS) in the Republic of Korea is a recent and representative occurrence of nationwide outbreaks of Emerging Infectious Diseases (EIDs). In addition to physical symptoms, posttraumatic stress disorder (PTSD) and depression are common following outbreaks of EID. The present study investigated the long-term mental health outcomes and related risk factors in survivors of MERS. A prospective nationwide cohort study was conducted 12 months after the MERS outbreak at multi-centers throughout Korea. PTSD and depression as the main mental health outcomes were assessed with the Impact of Event Scale-Revised Korean version (IES-R-K) and the Patient Health Questionnaire-9 (PHQ-9) respectively. 42.9% of survivors reported PTSD (IES-R-K ≥ 25) and 27.0% reported depression (PHQ-9 ≥ 10) at 12 months post-MERS. A multivariate analysis revealed that anxiety (adjusted odds ratio [aOR], 5.76; 95%CI, 1.29–25.58; P = 0.021), and a greater recognition of stigma (aOR, 11.09, 95%CI, 2.28–53.90; P = 0.003) during the MERS-affected period were independent predictors of PTSD at 12 months after the MERS outbreak. Having a family member who died from MERS predicted the development of depression (aOR, 12.08, 95%CI, 1.47–99.19; P = 0.020). This finding implies that psychosocial factors, particularly during the outbreak phase, influenced the mental health of patients over a long-term period. Mental health support among the infected subjects and efforts to reduce stigma may improve recovery from psychological distress in an EID outbreak.