Background
A virtual reality (VR) tour of the operating theatre before anaesthesia could provide a realistic experience for children. This study was designed to determine whether a preoperative VR ...tour could reduce preoperative anxiety in children.
Methods
Children scheduled for elective surgery under general anaesthesia were randomized into a control or VR group. The control group received conventional information regarding anaesthesia and surgery. The VR group watched a 4‐min video showing Pororo, the famous little penguin, visiting the operating theatre and explaining what is in it. The main outcome was preoperative anxiety, assessed using the modified Yale Preoperative Anxiety Scale (m‐YPAS) before entering the operating theatre. Secondary outcomes included induction compliance checklist (ICC) and procedural behaviour rating scale (PBRS) scores during anaesthesia.
Results
A total of 69 children were included in the analysis, 35 in the control group and 34 in the VR group. Demographic data and induction time were similar in the two groups. Children in the VR group had a significantly lower m‐YPAS score than those in the control group (median 31·7 (i.q.r. 23·3–37·9) and 51·7 (28·3–63·3) respectively; P < 0·001). During anaesthesia, the VR group had lower ICC and PBRS scores than the control group.
Conclusion
This preoperative VR tour of the operating theatre was effective in alleviating preoperative anxiety and increasing compliance during induction of anaesthesia in children undergoing elective surgery. Registration number: UMIN000025232 (http://www.umin.ac.jp/ctr).
Reduces anxiety
Abstract Objectives The pathogenesis of late preterm birth remains elusive for the mechanisms of disease responsible. Placental examination can often provide important clues for the pathogenesis of ...pregnancy complications. This study was conducted to determine placental pathologic findings according to the gestational age and the clinical circumstances of preterm birth. Study design Placental pathologic findings and obstetrical and neonatal outcomes were reviewed in a consecutive preterm birth cohort from a single tertiary center ( N = 1206). Placentas of term births ( N = 300) were used as normal controls. Results Acute chorioamnionitis (22.7% vs. 16.7%), maternal vascular underperfusion (6.4% vs. 0.5%), and chronic chorioamnionitis (20.8% vs. 10.5%) were significantly more frequent in preterm births than in term births ( P < 0.05, for each). Among preterm births, chronic chorioamnionitis was the most common pathology of late preterm birth (gestational age <37 and ≥34 weeks), while acute chorioamnionitis was the most common lesion of extremely preterm birth (gestational age <28 weeks). While the frequency of acute chorioamnionitis decreased with advancing gestation, that of chronic chorioamnionitis increased ( P < 0.001, for each). The upward trend of the frequency of chronic chorioamnionitis was related to advancing gestation in both spontaneous and indicated preterm births ( P < 0.001, for each). Conclusions Chronic chorioamnionitis is a common pathology of late preterm birth. It is suggested that chronic chorioamnionitis, a feature of maternal anti-fetal rejection, is an important etiology of preterm birth, especially of late preterm birth.
Aim: To evaluate the efficacy and safety of a newly developed formulation of phentermine diffuse-controlled release (DCR) in patients with obesity. Methods: This was a randomized, double-blind, ...placebo-controlled trial of 12 weeks of treatment with phentermine DCR 30 mg (n = 37) or placebo (n = 37), administered once daily in patients with obesity with controlled diabetes, hypertension or dyslipidaemia. The efficacy was evaluated by changes in body weight and waist circumference from baseline at 12 weeks and also changes in metabolic parameters, including lipid profiles and blood pressure. Results: The participants in the phentermine DCR group showed significant reductions in body weight (-8.1 ± 3.9 vs. -1.7 ± 2.9 kg, p < 0.001) and waist circumference (7.2 ± 0.5 vs. 2.1 ± 0.6 cm, p < 0.001) compared with those in the placebo group. Weight reductions of 5% or greater from the baseline (95.8 vs. 20.8%, p < 0.001) and 10% or more (62.5 vs. 4.7%, p < 0.001) were achieved in the DCR phentermine group and placebo group, respectively. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels were significantly improved in the phentermine DCR group. However, there were no significant differences in systolic and diastolic blood pressure between the groups. Dry mouth and insomnia were the most common adverse events, but these were mild to moderate and transient. Conclusions: Short-term phentermine DCR treatment resulted in significant reduction in weight and improvement of metabolic parameters, including waist circumference and some lipid profiles, without clinically severe adverse events. Further study is needed to show long-term efficacy and safety of phentermine DCR in Korean patients with obesity.
Summary
Background
Asthma in the elderly (aged ≥ 65 years old) is a significant concern with high morbidity, but the pathophysiology remains unclear particularly in late‐onset asthma. Recent studies ...suggest staphylococcal enterotoxin IgE (SE‐IgE) sensitization to be a risk factor for asthma in general populations; however, the associations have not been examined in late‐onset elderly asthma.
Objective
We aimed to examine the associations of SE‐IgE sensitization with late‐onset asthma in the elderly, using a database of elderly asthma cohort study.
Methods
A total of 249 elderly patients with asthma and 98 controls were analysed. At baseline, patients were assessed for demographics, atopy, induced sputum profiles and comorbidities including chronic rhinosinusitis (CRS). Serum total IgE and SE‐IgE levels were measured. Asthma severity was assessed on the basis of asthma outcomes during a 12‐month follow‐up period.
Results
At baseline, serum SE‐IgE concentrations were significantly higher in patients with asthma than in controls median 0.16 (interquartile range 0.04–0.53) vs. 0.10 (0.01–0.19), P < 0.001. Elderly asthma patients with high SE‐IgE levels had specific characteristics of having more severe asthma, sputum eosinophilia and CRS, compared to those with lower SE‐IgE levels. In multivariate logistic regression analyses, the associations between serum SE‐IgE concentrations and severe asthma were significant, independently of covariables SE‐IgE‐high (≥ 0.35 kU/L) vs. negative (< 0.10 kU/L) group: odds ratio 7.47, 95% confidence interval 1.86–30.03, P = 0.005. Multiple correspondence analyses also showed that high serum SE‐IgE level had close relationships with severe asthma, CRS and sputum eosinophilia together.
Conclusions and Clinical Relevance
This is the first report on the significant associations of SE‐IgE sensitization with late‐onset asthma in the elderly, particularly severe eosinophilic asthma with CRS comorbidity. Our findings indicate a potential implication of SE in the high morbidity burden of elderly asthma and suggest clues to the pathogenesis of severe late‐onset eosinophilic asthma in the elderly.
Patients who complete neoadjuvant chemotherapy for breast cancer without a pathological complete response have a high risk of relapse. A randomized trial comparing capecitabine with no additional ...adjuvant therapy showed that capecitabine prolonged disease-free and overall survival.
Patients who have residual invasive breast cancer after the receipt of neoadjuvant chemotherapy have a high risk of relapse.
1
The rate of complete response as assessed on pathological testing (hereafter, pathological complete response) ranges from 13 to 22% among patients with human epidermal growth factor receptor 2 (HER2)–negative primary breast cancer.
1
Patients who do not have a pathological complete response after the receipt of neoadjuvant taxane and anthracycline chemotherapy have a 20 to 30% risk of relapse.
2
Patients with HER2-negative cancer who receive neoadjuvant chemotherapy often receive postoperative radiation therapy, whereas endocrine therapy is administered to patients with hormone-receptor–positive disease . . .
Immune checkpoint inhibitors (ICIs) have been shown to be beneficial for some patients with advanced non-small-cell lung cancer (NSCLC). However, the underlying mechanisms mediating the limited ...response to ICIs remain unclear.
We carried out whole-exome sequencing on 198 advanced NSCLC tumors that had been sampled before anti-programmed cell death 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) therapy. Detailed clinical characteristics were collected on these patients. We designed a new method to estimate human leukocyte antigen (HLA)-corrected tumor mutation burden (TMB), a modification which considers the loss of heterozygosity of HLA from conventional TMB. We carried out external validation of our findings utilizing 89 NSCLC samples and 110 melanoma samples from two independent cohorts of immunotherapy-treated patients.
Homology-dependent recombination deficiency was identified in 37 patients (18.7%) and was associated with longer progression-free survival (PFS; P = 0.049). Using the HLA-corrected TMB, non-responders to ICIs were identified, despite having a high TMB (top 25%). Ten patients (21.3% of the high TMB group) were reclassified from the high TMB group into the low TMB group. The objective response rate (ORR), PFS, and overall survival (OS) were all lower in these patients compared with those of the high TMB group (ORR: 20% versus 59%, P = 0.0363; PFS: hazard ratio = 2.91, P = 0.007; OS: hazard ratio = 3.43, P = 0.004). Multivariate analyses showed that high HLA-corrected TMB was associated with a significant survival advantage (hazard ratio = 0.44, P = 0.015), whereas high conventional TMB was not associated with a survival advantage (hazard ratio = 0.63, P = 0.118). Applying this approach to the independent cohorts of 89 NSCLC patients and 110 melanoma patients, TMB-based survival prediction was significantly improved.
HLA-corrected TMB can reconcile the observed disparity in relationships between TMB and ICI responses, and is of predictive and prognostic value for ICI therapies.
•TMB alone is not sufficiently reliable or accurate as a biomarker of response to ICIs in NSCLC.•TMB-based survival prediction is improved by using the HLA-corrected TMB algorithm (TMB in combination with loss of heterozygosity of HLA).•Notably, additional predictive and prognostic value of the HLA-corrected TMB is not limited to certain types of cancer.•The HLA-corrected TMB could be a new strategy for selecting patients who may benefit from immunotherapy.
Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic ...breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 95% CI 0·437–0·994, one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 75% of 92 vs 14 16% of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.
Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.
Pfizer, Shinpoong, and Daewoong Korea and Takeda.
To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics.
We prospectively evaluated the ...efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples.
Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P=0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P=0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications.
The present study showed that HER2+GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.
Aims
For the effective production of 146S particles, which determines foot‐and‐mouth disease (FMD) vaccine efficacy, we aimed to identify the optimal medium that is easy‐to‐use, productive and ...economically affordable for the large‐scale production of FMD vaccine.
Methods and Results
Nine combinations of cell growth media and replacement media were tested for virus propagation. Apart from the replacement strategy, we tested a simple addition strategy involving the addition of 30% v/v of fresh medium to the total spent medium using the Cellvento BHK‐200 (Vento). Unlike other tested media that produced poor yields of 146S particles when the spent media were not eliminated, Vento exhibited high productivity with the 30% addition strategy.
Conclusions
Considering its lower price and media consumption compared to those of other media that require media replacement, the 30% addition strategy of Vento is highly effective. Furthermore, owing to its simple application strategy, it makes the scale‐up process easy and helps in saving the time and labour involved in spent media removal.
Significance and Impact of the Study
Through the first comparative assessment of commercial media for the 146S particle recovery, this study suggests the best practical medium for the industrial‐scale production of FMD vaccines.
Modulating the DNA damage response and repair (DDR) pathways is a promising strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral inhibitor of the serine/threonine protein ...kinase ataxia telangiectasia and Rad3-related protein, which is crucial for DDR.
This phase II trial evaluated ceralasertib plus durvalumab for the treatment of patients with metastatic melanoma who had failed anti-programmed cell death protein 1 therapy.
Among the 30 patients, we observed an overall response rate of 31.0% and a disease control rate of 63.3%. Responses were evident across patients with acral, mucosal, and cutaneous melanoma. The median duration of response was 8.8 months (range, 3.8-11.7 months). The median progression-free survival was 7.1 months (95% confidence interval, 3.6-10.6 months), and the median overall survival was 14.2 months (95% confidence interval, 9.3-19.1 months). Common adverse events were largely hematologic and manageable with dose interruptions and reductions. Exploratory biomarker analysis suggested that tumors with an immune-enriched microenvironment or alterations in the DDR pathway were more likely to respond to the study treatment.
We conclude that ceralasertib in combination with durvalumab has promising antitumor activity among patients with metastatic melanoma who have failed anti-programmed cell death protein 1 therapy, and constitute a population with unmet needs.
•Combination of ceralasertib and durvalumab had a tolerable safety profile in patients with metastatic melanoma.•Combination treatment resulted in median progression-free survival of 7.1 months and median overall survival of 14.2 months.•Our data suggest that this combination could be used to salvage patients with immunotherapy-resistant melanoma.•Ceralasertib plus durvalumab is worthy of further investigation for melanoma after failure of frontline immunotherapy.
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