Background and purpose
Physical activity is associated with a reduced incidence of first‐time stroke. However, few studies have examined the effect of pre‐stroke physical activity on post‐stroke ...complications and clinical outcomes.
Methods
A total of 39 835 cases of stroke registered in the nationwide stroke registry system of Taiwan between 2006 and 2009 were analyzed according to five levels of severity as determined by National Institutes of Health Stroke Scale score upon hospital admission. Pre‐stroke physical activity was defined in the Taiwan Stroke Registry as dedicated leisure‐time physical activity for at least 30 min/day for 3 days/week for more than 6 months. A Cox model was used to compare complications and outcomes between active and inactive groups.
Results
The active and inactive groups were similar in age distribution and stroke type distribution, but the active group had better National Institutes of Health Stroke Scale scores upon admission. The active group also had significantly fewer post‐stroke complications. Active patients had lower hospital mortality and better functional outcomes upon discharge as per the modified Rankin Scale. Improved functional status in the active group was significant at 1, 3 and 6 months post‐stroke.
Conclusion
Dedicated leisure‐time physical activity for at least 30 min/day, at least three times per week for more than 6 months was associated with decreased stroke severity, fewer post‐stroke complications, lower mortality and better outcomes.
Abstract
Front-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy is the standard of care for lung cancer patients with sensitising EGFR mutations (exon 19 deletion or ...L858R mutation). Several phase III studies have demonstrated the superiority of gefitinib, erlotinib (first generation of TKIs) or afatinib (second generation) to chemotherapy in progression-free survival and response rates. Drug-related toxicities, such as diarrhoea, acneiform skin rash, mucositis, and paronychia, are frequently encountered in patients who receive EGFR TKIs. Other rare side-effects, such as hepatic impairment and interstitial lung disease, should be identified early and managed carefully. Patients with uncommon EGFR mutations, such as G719X, S768I, and L861Q, may require special selection of EGFR TKIs. The combination of erlotinib plus bevacizumab has been accepted in certain parts of the world as an alternative front-line treatment. This review article summarizes the studies leading to the establishment of EGFR TKIs in EGFR-mutant lung cancer patients. The side-effect profiles of the current EGFR TKIs in these large trials are listed, and the management of uncommon EGFR mutations is discussed. Finally, the potential role of combination front-line treatment is discussed.
Background: Mutations of the epidermal growth factor receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) patients predict the patients who will respond to EGFR tyrosine kinase inhibitor (TKI) ...treatment. A recent study has suggested that 33% of NSCLC showed primary tumor/metastasis discordance of EGFR expression by immunohistochemistry analysis. We intended to find out whether the EGFR mutations of primary lung cancers are concordant to that of corresponding metastatic tumors. Materials and methods: We analyzed EGFR exons 18–21 from paired primary and metastatic tumors in 67 lung cancer patients who had not received TKI before tissues were sampled. Results: Using the direct sequencing method, 9 of 18 (50%) patients with EGFR mutation-positive primary lung tumors had lost the mutations in metastases. For 26 patients who were EGFR mutation positive in the metastatic tumors, 17 (65%) were negative in the primary tumors. We analyzed these paired tissues with discrepant EGFR mutations by the Scorpion Amplified Refractory Mutation System assay. Finally, the discordant rate reached 27% (18 of 67 cases). Conclusion: EGFR mutations in primary lung tumors do not always reflect the same situation in metastases. Analysis of EGFR mutations in the primary lung tumor would be inadequate for planning the use of TKI for advanced NSCLC.
Summary
Bone mineral density (BMD) may be increased due to vertebral compression fractures (VCF). Our study showed trabecular bone scores (TBS) was less affected than BMD by fractured vertebrae. The ...TBS of most compression fractures, including old and recent VCF with mild or moderate deformity and old VCF with severe deformity, could still be used in predicting fracture risk.
Introduction
Trabecular bone score (TBS), a noninvasive tool estimating bone microarchitecture, provides complementary information to lumbar spine bone mineral density (BMD). Lumbar spine BMD might be increased due to both degenerative disease and vertebral compression fractures (VCF). Lumbar spine TBS has been confirmed not influenced by osteoarthrosis, but the effects of VCF are still not been well evaluated. This study aimed to investigate whether lumbar spine TBS was affected by fractured vertebrae.
Methods
We studied postmenopausal women and men above 50 years old who underwent DXA between January 1, 2017, and May 31, 2019. By calculating the difference of BMD and TBS between L1 and the mean of L2-3, the study compared the difference of values between the control group and fracture group to determine the effects of fractured vertebrae on BMD and TBS.
Results
A total of 377 participants were enrolled with 202 in the control group (157 females; age: 68.06 ± 6.47 years) and 175 in the fracture group (147 females; age: 71.71 ± 9.44 years). The mean BMD of the L1 vertebrae in the fracture group was significantly higher than that in the control group (
p
< 0.0001). There was no significant difference between the mean differences of TBS between L1 and the means of L2-3 vertebrae in the control group and the most compression fractures, including old and recent VCF with mild or moderate deformity and old VCF with severe deformity.
Conclusion
Lumbar spine TBS, unlike BMD, is less affected by fractured vertebrae. The TBS of most compression fractures, including old and recent VCF with mild or moderate deformity and old VCF with severe deformity, could still be used in predicting fracture risk.
Dual blockade of PD-L1 and VEGF has enhanced anticancer immunity through multiple mechanisms and augmented antitumour activity in multiple malignancies. We aimed to assess the efficacy and safety of ...atezolizumab (anti-PD-L1) alone and combined with bevacizumab (anti-VEGF) in patients with unresectable hepatocellular carcinoma.
GO30140 is an open-label, multicentre, multiarm, phase 1b study that enrolled patients at 26 academic centres and community oncology practices in seven countries worldwide. The study included five cohorts, and the two hepatocellular carcinoma cohorts, groups A and F, are described here. Inclusion criteria for these two groups included age 18 years and older; histologically, cytologically, or clinically (per American Association for the Study of Liver Diseases criteria) confirmed unresectable hepatocellular carcinoma that was not amenable to curative treatment; no previous systemic treatment; and Eastern Cooperative Oncology Group performance status of 0 or 1. In group A, all patients received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks. In group F, patients were randomly assigned (1:1) to receive intravenous atezolizumab (1200 mg) plus intravenous bevacizumab (15 mg/kg) every 3 weeks or atezolizumab alone by interactive voice-web response system using permuted block randomisation (block size of two) and stratification factors of geographical region; macrovascular invasion, extrahepatic spread, or both; and baseline α-fetoprotein concentration. Primary endpoints were confirmed objective response rate in all patients who received the combination treatment for group A and progression-free survival in the intention-to-treat population in group F, both assessed by an independent review facility according to Response Evaluation Criteria in Solid Tumors version 1.1. In both groups, safety was assessed in all patients who received at least one dose of any study treatment. This study is registered with ClinicalTrials.gov, NCT02715531, and is closed to enrolment.
In group A, 104 patients were enrolled between July 20, 2016, and July 31, 2018, and received atezolizumab plus bevacizumab. With a median follow-up of 12·4 months (IQR 8·0–16·2), 37 (36%; 95% CI 26–46) of 104 patients had a confirmed objective response. The most common grade 3–4 treatment-related adverse events were hypertension (13 13%) and proteinuria (seven 7%). Treatment-related serious adverse events occurred in 25 (24%) patients and treatment-related deaths in three (3%) patients (abnormal hepatic function, hepatic cirrhosis, and pneumonitis). In group F, 119 patients were enrolled and randomly assigned (60 to atezolizumab plus bevacizumab; 59 to atezolizumab monotherapy) between May 18, 2018, and March 7, 2019. With a median follow-up of 6·6 months (IQR 5·5–8·5) for the atezolizumab plus bevacizumab group and 6·7 months (4·2–8·2) for the atezolizumab monotherapy group, median progression-free survival was 5·6 months (95% CI 3·6–7·4) versus 3·4 months (1·9–5·2; hazard ratio 0·55; 80% CI 0·40–0·74; p=0·011). The most common grade 3–4 treatment-related adverse events in group F were hypertension (in three 5% patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group) and proteinuria (in two 3% patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group). Treatment-related serious adverse events occurred in seven (12%) patients in the atezolizumab plus bevacizumab group and two (3%) patients in the atezolizumab monotherapy group. There were no treatment-related deaths.
Our study shows longer progression-free survival with a combination of atezolizumab plus bevacizumab than with atezolizumab alone in patients with unresectable hepatocellular carcinoma not previously treated with systemic therapy. Therefore, atezolizumab plus bevacizumab might become a promising treatment option for these patients. This combination is being compared with standard-of-care sorafenib in a phase 3 trial.
F Hoffmann-La Roche/Genentech.
Activation of Akt signaling pathway has been suggested involving in chemoresistance, metastasis and tumorigenesis of gastric cancer. However, the mechanism of Akt regulation in gastric cancer is not ...fully understood. RUNX3, which was first identified as a transcription factor, suppresses gastric tumorigenesis through regulating expression of target genes. Here, we found that restoration of RUNX3 significantly downregulates the protein and mRNA expression of Akt1 in gastric cancer cell lines, AGS and SNU-1. Knockdown of RUNX3 upregulates protein and mRNA expression of Akt1 in normal gastric epithelial cell line, GES-1. The negative correlation of RUNX3 and Akt expression and downstream β-catenin/cyclin D1 effectors was further confirmed in AGS and GES-1 cell lines, as well as clinical specimens of gastric cancer. We identified two RUNX3-binding sites in Akt1 promoter and the binding of RUNX3 on Akt1 promoter significantly inhibits Akt1 expression. The RUNX3-mediated inhibition of Akt1 caused β-catenin protein degradation and then cyclin D1 downregulation. Restoration of cyclin D1 reverses cell growth inhibition and G1 phase arrest induced by RUNX3 in gastric cancer cells. Our results show that loss of RUNX3 expression can enhance the Akt1-mediated signaling pathway and promote the tumorigenesis process in human gastric cancer.
Objectives
This study aims to assess the effectiveness of a multidomain intervention program on the change in functional status of hospitalized older adults.
Design
This single-arm, prospective, ...non-randomized interventional study investigates the efficacy of a multidomain interventional program including cognitive stimulation activity, simple exercises, frailty education, and nutrition counseling.
Setting and Participants
At a tertiary hospital in southern Taiwan, 352 eligible patients were sequentially enrolled. Included patients were aged ≥65 years (mean age, 79.6 ± 9.0 years; 62% male), scored 3–7 on the Clinical Frailty Scale (CFS), and were hospitalized in the geriatric acute ward.
Intervention
Those receiving standard care (physical rehabilitation and nutrition counseling) during January–July 2019 composed the historical control group. Those receiving the multidomain intervention during August–December 2019 composed the intervention group.
Measurements
The primary outcome was the change in activities of daily life (ADL) and frailty status, as assessed by Katz Index and Clinical Frailty Scale, with using the generalized estimating equation model. The length of hospital stay, medical costs, and re-admission rates were secondary outcomes.
Results
Participants undergoing intervention (n = 101; 27.9%) showed greater improvements in the ADL and CFS during hospitalization (ADL adjusted estimate, 0.61; 95% CI, 0.11–1.11; p = 0.02; CFS adjusted estimate, −1.11; 95% CI, −1.42–−0.80; p < 0.01), shorter length of hospital stay (adjusted estimate, -5.00; 95% CI, −7.99–−2.47; p < 0.01), lower medical costs (adjusted estimate, 0.58; 95% CI, 0.49–0.69; p < 0.01), and lower 30- and 90-day readmission rates (30-day adjusted OR aOR, 0.12; 95% CI, 0.27–0.50; p < 0.01; 60-day aOR, 0.04; 95% CI, 0.01–0.33; p < 0.01) than did controls.
Conclusions
Participation in the multidomain intervention program during hospitalization improved the functional status and decreased the hospital stay length, medical costs, and readmission rates of frail older people.
This study proposed a computerized inquiry‐stage‐dependent argumentation assistance and investigated whether this can help improve elementary students' performance in science processes and the ...construction of quality arguments. Various argumentation assistances were developed and incorporated into each stage of scientific inquiry in a computer‐supported scientific inquiry system. A nonequivalent quasi‐experimental design was adopted to evaluate the effectiveness of this approach. Two intact sixth grade classes (N = 55) participated in this study, and each student used a tablet computer to accomplish the designated inquiry activities. One class of students was arranged to use the stage‐dependent argumentation assistance, and the other used a generic text‐based interface. The findings indicate that students who used the stage‐dependent argumentation assistance could acquire significantly better science process and argument construction skills than those using the generic text‐based interface.
Lay Description
What is already known about this topic:
Developing argument construction skills is crucial for learning and conducting scientific inquiry.
The required argument patterns and discourse processes should vary with each stage of scientific inquiry.
Teachers need to provide students with assistance to help them construct quality arguments.
What this paper adds:
This study developed a computerized argumentation assistance that complies with the features of each inquiry stage.
Various forms of augmentation assistance and scripted rules of reciprocal interaction were developed and incorporated into a scientific inquiry system.
This research focus on the effects of argumentation assistance on students' science process and argument construction skills.
Implications of study findings for practitioners:
Students can effectively practice the science process skills in argumentative scientific inquiry.
The argumentation assistance can increase the students' argumentative knowledge and engage them in intensive scientific argumentation.
This system can help teachers to implement scientific inquiry in the classroom and guide students to carry out scientific inquiry.
Background
Tryptophan metabolites have been suggested to play a role in immune modulation, wherein those have recently been shown to be endogenous ligands of aryl hydrocarbon receptor (AhR; a unique ...cellular chemical sensor). However, the involvement of tryptophan metabolites and AhR in modulating mast cell function remains to be fully defined. We therefore investigated that the functional impacts of tryptophan metabolites on human and mouse mast cell responses in vitro and their functional importance in vivo.
Methods
Three tryptophan metabolites, kynurenine (KYN), kynurenic acid (KA) and quinolinic acid (QA), were examined in terms of their effect on IgE‐mediated responses in mouse bone marrow‐derived mast cells (BMMCs) and in human peripheral blood‐derived cultured mast cells (HCMCs) and on in vivo anaphylactic responses. For evaluation of AhR involvement, we examined the responses of mast cells from AhR‐null or AhR‐wild‐type mice with the use of a known AhR antagonist, CH223191.
Results
Kynurenine, but not KA and QA, enhanced IgE‐mediated responses, including degranulation, LTC4 release, and IL‐13 production in BMMCs through the activation of PLCγ1, Akt, MAPK p38, and the increase of intracellular calcium. KYN also enhanced cutaneous anaphylaxis in vivo. These enhancing effects of KYN were not observed in AhR‐deficient BMMCs and could be inhibited by CH223191 in BMMCs. Further, KYN had similar enhancing effects on HCMCs, which were inhibited by CH223191.
Conclusion
The AhR‐KYN axis is potentially important in modulating mast cell responses and represents an example of AhR's critical involvement in the regulation of allergic responses.
A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact ...of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.
PDF
