In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus ...gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data.
LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases.
Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.
In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.
NCT01466660.
Migraine carries an increased risk for cardiovascular and cerebrovascular diseases that cannot be explained by traditional cardiovascular risk factors. The circulating endothelial progenitor cell ...(EPC) number is a surrogate biologic marker of vascular function, and diminished EPC counts are associated with higher cardiovascular risk. We investigated whether abnormalities in EPC levels and functions are present in migraine patients.
Consecutive headache patients (n =166) were enrolled, including those with tension type headache (TTH; n = 74), migraine without aura (MO; n = 67), and migraine with aura (MA; n = 25). EPC colony-forming units in peripheral blood samples and migratory capacity to chemoattractants (stromal cell-derived factor 1 and vascular endothelial growth factor) and cellular senescence levels were assayed in risk factor-matched subjects (n = 6 per group).
The TTH group had more cardiovascular risk factors, more headache days, and higher Framingham risk scores than the other two groups. Mean numbers of EPC colony-forming units were 47.8 +/- 24.3 in TTH, 20.4 +/-22.2 in MO, and 8.6 +/- 10.1 in MA patients (p < 0.001 in TTH vs MO; p = 0.001 in MO vs MA). EPC colony counts of normal subjects (n = 37) were not significantly different from those with TTH. Multiple linear regression models identified only MO, MA, and the presence of migraine (MO + MA) as significant predictors of EPC levels. In addition, EPCs from migraine patients (MO and MA) showed reduced migratory capacity and increased cellular senescence compared with EPCs from TTH or normal subjects.
Circulating endothelial progenitor cell (EPC) numbers and functions are reduced in migraine patients, suggesting that EPCs can be an underlying link between migraine and cardiovascular risk.
Tumour-infiltrating lymphocytes (TILs) are known to be associated with response to primary systemic therapy (PST) in breast cancer. This study was conducted to assess the association of TIL subsets ...with pathological complete response (pCR) after PST in breast cancer in relation to breast cancer subtype, breast cancer stem cell (BCSC) phenotype and epithelial-mesenchymal transition (EMT).
The pre-chemotherapeutic biopsy specimens of 153 breast cancer patients who underwent surgical resection after anthracycline- or anthracycline/taxane-based PST were analysed. TIL subsets (CD4+, CD8+, and FOXP3+ TILs), BCSC phenotype, and the expression of EMT markers were evaluated by immunohistochemistry and were correlated with pCR after PST.
Infiltration of CD4+ and CD8+ T lymphocytes was closely correlated with BCSC phenotype and EMT. High levels of CD4+, CD8+, and FOXP3+ TILs were associated with pCR, and CD8+ TILs were found to be an independent predictive factor for pCR. In addition, CD8+ TILs were associated with pCR irrespective of breast cancer subtype, CD44+/CD24- phenotype, EMT, and chemotherapeutic regimen in subgroup analyses.
These findings indicate that CD8+ cytotoxic T lymphocytes are a key component of TILs associated with chemo-response and can be used as a reliable predictor of response to anthracycline- or anthracycline/taxane-based PST in breast cancer.
Summary
Background
Recent studies suggest that Staphylococcus aureus enterotoxin sensitization is a risk factor for asthma. However, there is a paucity of epidemiologic evidence on adult‐onset asthma ...in community‐based populations.
Objective
We sought to evaluate the epidemiology and the clinical significance of staphylococcal enterotoxin sensitization in community‐based adult populations.
Methods
The present analyses were performed using the baseline data set of Korean adult population surveys, consisting of 1080 adults (mean age = 60.2 years) recruited from an urban and a rural community. Questionnaires, methacholine challenge tests, and allergen skin tests were performed for defining clinical phenotypes. Sera were analysed for total IgE and enterotoxin‐specific IgE using ImmunoCAP.
Results
Staphylococcal enterotoxin sensitization (≥ 0.35 kU/L) had a prevalence of 27.0%. Risk factors were identified as male sex, current smoking, advanced age (≥ 61 years), and inhalant allergen sensitization. Current asthma was mostly adult onset (≥ 18 years old) and showed independent associations with high enterotoxin‐specific IgE levels in multivariate logistic regression tests. In multivariate linear regressions, staphylococcal enterotoxin‐specific IgE level was identified as the major determinant factor for total IgE level.
Conclusions and Clinical Relevance
Staphylococcal enterotoxin sensitization was independently associated with adult‐onset asthma in adult community populations. Strong correlations between the enterotoxin‐specific IgE and total IgE levels support the clinical significance. The present findings warrant further studies for the precise roles of staphylococcal enterotoxin sensitization in the asthma pathogenesis.
Methylation of the MGMT gene promoter is associated with a favorable prognosis in adult patients with GBM treated with TMZ. We determined the incidence of pseudoprogression according to the MGMT ...methylation status and the potential value of DSC perfusion MR images for predicting pseudoprogression.
New or enlarged enhancing lesions after CCRT in adult patients with newly diagnosed GBMs were prospectively assessed by measuring their rCBV by using DSC perfusion MR images. Tumor tissue was assayed to determine MGMT promoter methylation status. All patients were regularly followed up at an interval of 2 months by MR images, including DSC perfusion MR images.
Ninety eligible patients were enrolled in this study. After CCRT, new or enlarged enhanced lesions were found in 59 of 90 patients, which were subsequently classified as pseudoprogression (26 patients, 28.9%) and real progression (33 patients, 36.7%). Overall, there was a significant difference in the mean rCBV between pseudoprogression and real tumor progression (P = .003). The ROC curve revealed that an rCBV ratio >1.47 had an 81.5% sensitivity and a 77.8% specificity. The unmethylated MGMT promoter group had a significant difference of mean rCBV between pseudoprogression and real progression (P = .009), though the methylated MGMT promoter group had no significant difference (P = .258).
The current study suggests that rCBV measured by DSC perfusion MR images has a differential impact on the predictability of pseudoprogression in patients with GBM.
A memory cell consisting of a Pt/VO2/Pt switch element and a Pt/NiO/Pt memory element connected in series. By applying a voltage higher than Vth of 0.6 V, the switch element reaches the on state and ...the cell can be accessed. Since reset and set voltages are higher than Vth, information can be written by simply applying an appropriate voltage to a selected cell. By applying a voltage lower than Vth to the other cells, we can keep the other cells in the off state and prevent interference between the selected cell and the others.
Background and purpose: Lipid rafts and caveolae are membrane microdomains with important roles in cell survival signalling involving the Akt pathway. Cholesterol is important for the structure and ...function of these microdomains. The ginsenoside Rh2 exhibits anti‐tumour activity. Because Rh2 is structurally similar to cholesterol, we investigated the possibility that Rh2 exerted its anti‐tumour effect by modulating rafts and caveolae.
Experimental approach: A431 cells (human epidermoid carcinoma cell line) were treated with Rh2 and the effects on cell apoptosis, raft localization and Akt activation measured. We also examined the effects of over‐expression of Akt and active‐Akt on Rh2‐induced cell death.
Key results: Rh2 induced apoptosis concentration‐ and time‐dependently. Rh2 reduced the levels of rafts and caveolae in the plasma membrane and increased their internalization. Furthermore, Akt activity was decreased and consequently, Akt‐dependent phosphorylation of Bad, a pro‐survival protein, was decreased whereas the pro‐apoptotic proteins, Bim and Bax, were increased upon Rh2 treatment. Unlike microdomain internalization induce by cholesterol depletion, Rh2‐mediated internalization of rafts and caveolae was not reversed by cholesterol addition. Also, cholesterol addition did not restore Akt activation or rescue cells from Rh2‐induced cell death. Rh2‐induced cell death was attenuated in MDA‐MB‐231 cells over‐expressing either wild‐type or dominant‐active Akt.
Conclusions and implications: Rh2 induced internalization of rafts and caveolae, leading to Akt inactivation, and ultimately apoptosis. Because elevated levels of membrane rafts and caveolae, and Akt activation have been correlated with cancer development, internalization of these microdomains by Rh2 could potentially be used as an anti‐cancer therapy.
The cancer stem cell (CSC) hypothesis has important clinical implications for cancer therapeutics because of the proposed role of CSCs in chemoresistance. The aim of this study was to investigate ...changes in the CSC populations before and after primary systemic therapy (PST) and their prognostic role in human breast cancer.
Paired samples (before and after PST) of breast cancer tissue were obtained from clinical stage II or III patients (n=92) undergoing PST with the regimen of doxorubicin plus docetaxel (AD) (n=50) or doxorubicin plus cyclophosphamide (AC) (n=42) and subsequent breast resection. The proportions of putative CSCs with CD44+/CD24- or aldehyde dehydrogenase 1+ (ALDH1+) phenotypes were determined by immunohistochemistry.
A higher proportion of CD44+/CD24- tumour cells and ALDH1 positivity in pre-chemotherapy tissue was correlated with higher histologic grade, oestrogen receptor (ER) negativity, high Ki-67 proliferation index and basal-like subtype of breast cancer. Aldehyde dehydrogenase 1 positivity in pre-chemotherapy biopsy was also associated with a higher rate of pathologic complete response following PST. In comparisons of putative CSC populations before and after PST, the proportions of CD44+/CD24- and ALDH1+ tumour cells were significantly increased after PST. The cases with increased CD44+/CD24- tumour cell populations after PST showed high Ki-67 proliferation index in post-chemotherapy specimens and those with increased ALDH1+ tumour cell population after PST were associated with ER negativity and p53 overexpression. Furthermore, cases showing such an increase had significantly shorter disease-free survival time than those with no change or a reduced number of CSCs, and the survival difference was most notable with regard to the changes of ALDH1+ tumour cell population in the patients who received AC regimen.
The present study provides the clinical evidence that the putative CSCs in breast cancer are chemoresistant and are associated with tumour progression, emphasising the need for targeting of CSCs in the breast cancer therapeutics.
Objectives
High salt intake results in various harmful effects on human health including hypertension, cardiovascular disease, and reduced bone density. Despite this, there are very few studies in ...the literature that have investigated the association between sodium intake and osteoarthritis (OA). Therefore, we aimed to explore these associations in a Korean population.
Methods
This study used cross-sectional data from adult subjects aged 50–75 years from two consecutive periods of the Korean National Health and Nutrition Examination Survey V–VII (2010–2011 and 2014–2016). The estimated 24-hour urinary sodium excretion (24HUNa) was used as a surrogate marker of salt intake. In the 2010–2011 dataset, knee OA (KOA) was defined as the presence of the radiographic features of OA and knee pain. The association between KOA and salt intake was analysed using univariable and multivariable logistic regression methods. For the sensitivity analysis, the same procedures were conducted on subjects with self-reported OA (SR-OA) with knee pain in the 2010–2011 dataset and any site SR-OA in the 2014–2016 dataset.
Results
Subjects with KOA had significantly lower energy intake, but higher 24HUNa than those without KOA. The restricted cubic spline plots demonstrated a J-shaped distribution between 24HUNa and prevalent KOA. When 24HUNa was stratified into five groups (<2, 2–3, 3–4, 4–5 and ≥5 g/day), subjects with high sodium intake (≥5 g/day) had a higher risk of KOA (odds ratio OR = 1.64, 95% confidence interval CI 1.03–2.62) compared to the reference group (3–4 g/day) after adjusting for covariates. The sensitivity analysis based on SR-OA with knee pain showed that high sodium intake was also significantly associated with increased prevalence of OA (OR = 1.84, 95% CI 1.10–3.10) compared with the reference group. Regarding SR-OA at any site in the 2014–2016 dataset, estimated 24HUNa showed a significantly positive association with the presence of SR-OA after adjusting for potential confounders.
Conclusions
This nationwide Korean representative study showed a significant association between symptomatic KOA and high sodium intake (≥5 g/day). Avoidance of a diet high in salt might be beneficial as a non-pharmacologic therapy for OA.
We aimed to compare tissue-specific expression profiles and biological pathways of RNA from amniocytes and amniotic fluid supernatant (AFS) from second-trimester pregnancies by using transcriptome ...analysis. Additionally, we wanted to explore whether cell-free RNA from AFS exhibits a unique gene expression signature that more adequately reflects the fetal developmental process than amniocyte RNA.
Amniotic fluid samples were prospectively collected in the second trimester of pregnancy from euploid fetuses. Total RNA was extracted from amniocytes and AFS and hybridized to Affymetrix GeneChip Human Arrays. Significantly differentially expressed transcripts between amniocytes and AFS were obtained by using Welch's t-test. Unsupervised hierarchical clustering was used to visualize overall expression characteristics and differences in transcripts between AFS and amniocytes. The biological functions of selected genes were analyzed using various online Gene Ontology databases.
A total of 3,072 and 15,633 transcripts were detected in the second-trimester AFS and amniocytes, respectively. Hierarchical clustering revealed differential transcript expression between AFS and amniocytes. We found 353 genes that were specifically enriched in the AFS only, and tissue expression analysis showed enrichment of brain-specific genes in the AFS. Biological pathway analysis revealed that AFS-specific transcripts were mainly involved in embryonic development, cardiovascular development, and cellular morphology pathways.
This study demonstrated differential tissue-specific gene expression profiles and biological pathways between AFS and amniocytes. The results suggested that AFS is the preferred RNA source to investigate potential biomarkers of fetal neurodevelopment.
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