The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood.
...Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome.
The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs.
We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.
Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant ...chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC.
The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146).
A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable.
In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.
•In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy.•The addition of radiotherapy to chemotherapy did not significantly reduce the rate of recurrence after D2 gastrectomy.•DFS between patients treated with adjuvant chemotherapy and chemoradiotherapy was similar across all subgroups, including Lauren classification.
This study aimed to evaluate endogenous metabolic markers of hepatic cytochrome P450 (CYP)3A activity in healthy subjects using a metabolomics approach. Twenty‐four subjects received the following ...medication during the following three study periods: 1 mg of i.v. midazolam alone (control phase), 1 mg of i.v. midazolam after 4 days of pretreatment with 400 mg of ketoconazole once daily (CYP3A‐inhibited phase), and 2.5 mg of i.v. midazolam after 10 days of pretreatment with 600 mg of rifampicin once daily (CYP3A‐induced phase). During each study period, 24 h before and after the administration of midazolam, urine samples were collected at 12‐h intervals for metabolomic analyses. We derived an equation to predict midazolam clearance (CL) based on several of these markers. We demonstrated that a combination of the concentrations and ratios of several endogenous metabolites and the CYP3A5*3 genotype is a reliable predictive marker of hepatic CYP3A activity as assessed by i.v. administration of midazolam.
Clinical Pharmacology & Therapeutics (2013); 94 5, 601–609. doi:10.1038/clpt.2013.128
The presence of a di-unsaturated highly branched isoprenoid (HBI) lipid biomarker (diene II) in Southern Ocean sediments has previously been proposed as a proxy measure of palaeo Antarctic sea ice. ...Here we show that a source of diene II is the sympagic diatom Berkeleya adeliensis Medlin. Furthermore, the propensity for B. adeliensis to flourish in platelet ice is reflected by an offshore downward gradient in diene II concentration in >100 surface sediments from Antarctic coastal and near-coastal environments. Since platelet ice formation is strongly associated with super-cooled freshwater inflow, we further hypothesize that sedimentary diene II provides a potentially sensitive proxy indicator of landfast sea ice influenced by meltwater discharge from nearby glaciers and ice shelves, and re-examination of some previous diene II downcore records supports this hypothesis. The term IPSO25-Ice Proxy for the Southern Ocean with 25 carbon atoms-is proposed as a proxy name for diene II.
Rectal carcinoids are low-grade malignancies that are usually treated by endoscopic resection. However, on pathologic examination, resection margins that are positive for carcinoid cells are ...frequently found. Patient outcomes were reviewed after endoscopic resection of rectal carcinoids and the clinical significance of possible residual disease, as defined by pathologic and endoscopic examination, was evaluated.
The medical records and endoscopic findings of 347 patients presenting with rectal carcinoids to 14 university hospitals in Korea between January 1999 and June 2007 were retrospectively analyzed.
A total of 304 patients were treated with endoscopic resection, and 43 patents were treated with surgery. In the endoscopic resection group, the complete resection rate was 88.2% based on endoscopic appearance (CR-E) and 60.2% based on pathologic evaluation (CR-P). The agreement between CR-E and CR-P was low (κ=0.192). No residual tumors were found in 77 of 85 patients (90.6%) who were CR-E but not CR-P and who had endoscopic biopsy taken at 24-month follow-up. The receiver-operating characteristic curve identified an optimal cut-off value of 10.5 mm, at which the sensitivity and the specificity for metastasis were 100% and 89%, respectively. The risk factors for metastasis by multivariate analysis were tumor size, increased mitotic rate, and lymphovascular invasion.
Endoscopic resection is a safe and effective modality for treating well-differentiated rectal carcinoids smaller than 10 mm in diameter. Discrepancies were observed between CR-E and CR-P. The risk factors for metastasis were tumor size, increased mitotic rate, and lymphovascular invasion.
Summary
Sarcopenia is the age-related reduction of skeletal muscle mass in older individuals. Respiratory muscle strength may be related to skeletal muscle mass and, thus, the present study attempted ...to estimate the risk of sarcopenia relative to decreased pulmonary function. The present findings demonstrated that low pulmonary function was associated with low muscle mass in community-dwelling older adults.
Introduction
Lean body mass is related to pulmonary function in patients with chronic obstructive pulmonary disease (COPD). However, the relationship between muscle mass and pulmonary function in healthy older adults has yet to be clarified. Thus, the present study investigated the association of pulmonary function with muscle mass in an older community-dwelling Korean population.
Methods
This study included 463 disease-free subjects over 65 years of age who underwent anthropometric measurements, laboratory tests, spirometry, and the estimation of appendicular skeletal muscle (ASM) mass in the 2008–2011 Korea National Health and Nutrition Examination Survey (KNHANES). Low muscle mass was defined as the value of ASM divided by height squared (ASM/height
2
) that was less than two standard deviations (SD) below the sex-specific mean of the young reference group.
Results
Forced expiratory volume in 1 s (FEV1L) and forced vital capacity (FVCL) were positively correlated with ASM/height
2
in males (
p
< 0.001 and
p
= 0.001, respectively) but not in females (
p
= 0.360 and
p
= 0.779, respectively). A univariate logistic regression analysis revealed that males with low FEV1 or FVC were more likely to have low muscle mass (odds ratio OR = 3.11, 95 % confidence interval CI 1.62–5.99 for FEV1; OR = 1.99, 95 % CI 1.13–3.53 for FVC); similar results were found for females, but the significance was lower (OR = 11.37, 95 % CI 0.97–132.91 for FEV1; OR = 7.31, 95 % CI 1.25–42.74 for FVC). After adjusting for age, smoking, and moderate physical activity, a low FEV1 value was associated with low muscle mass in both males (OR = 2.90, 95 % CI 1.50–5.63) and females (OR = 9.15, 95 % CI 1.53–54.77).
Conclusions
Using nationally representative data from the 2008–2011 KNHANES, low pulmonary function was found to be associated with low muscle mass in community-dwelling older Korean adults.
The kinetic roughening of polymer films grown by vapor deposition polymerization was analyzed using the widely accepted classification framework of “generic scaling ansatz” given for the structure ...factor. Over the past two decades, this method has played a pivotal role in classifying diverse forms of dynamic scaling and understanding the mechanisms driving interface roughening. The roughness exponents of the polymer films were consistently determined as α=1.25±0.09, αloc=0.73±0.02, and αs=0.99±0.06. However, the inability to unambiguously assign these roughness exponent values to a specific scaling subclass prompts the proposal of a practical alternative. This report illustrates how all potential dynamic scaling can be consistently identified and classified based on the relationship between two temporal scaling exponents measured in real space: the average local slope and the global slope of the interface. The intrinsic anomalous roughening class is conclusively assigned to polymer film growth characterized by anomalous “native (background slope-removed) local height fluctuations”. Moreover, the new analysis reveals that interfaces exhibiting anomalous scaling, previously classified as intrinsic anomalous roughening, could potentially belong to the super-rough class, particularly when the spectral roughness exponent αs is equal to 1.
Summary Background The CLASSIC trial was done to compare adjuvant capecitabine plus oxaliplatin versus observation after D2 gastrectomy for patients with stage II or III gastric cancer. The planned ...interim analysis of CLASSIC (median follow-up 34 months) showed that adjuvant capecitabine plus oxaliplatin significantly improved disease-free survival, the primary endpoint, compared with observation after D2 gastrectomy. We report the 5-year follow-up data from the trial. Methods CLASSIC was a phase 3, randomised, open-label study done at 35 cancer centres, medical centres, and hospitals in China, South Korea, and Taiwan. Patients with stage II–IIIB gastric cancer who underwent curative D2 gastrectomy were randomly assigned (1:1) after surgery to receive adjuvant chemotherapy with capecitabine and oxaliplatin (eight 3-week cycles of oral capecitabine 1000 mg/m2 twice daily on days 1–14 plus intravenous oxaliplatin 130 mg/m2 on day 1) for 6 months or observation alone. Randomisation was stratified by country and disease stage with a permuted block (size four) design. Neither patients nor investigators were masked to treatment assignment. The primary outcome was 3-year disease-free survival in the intention-to-treat population. This analysis presents the final preplanned assessment of outcomes after 5 years. The study is registered with ClinicalTrials.gov , NCT00411229. Findings We enrolled 1035 patients: 520 were randomly assigned to adjuvant capecitabine and oxaliplatin, and 515 to observation. Median follow-up for this analysis in the intention-to-treat population was 62·4 months (IQR 54–70). 139 (27%) patients had disease-free survival events in the adjuvant capecitabine and oxaliplatin group versus 203 (39%) patients in the observation group (stratified hazard ratio HR 0·58, 95% CI 0·47–0·72; p<0·0001). Estimated 5-year disease-free survival was 68% (95% CI 63–73) in the adjuvant capecitabine and oxaliplatin group versus 53% (47–58) in the observation alone group. By the clinical cutoff date, 103 patients (20%) had died in the adjuvant capecitabine and oxaliplatin group versus 141 patients (27%) in the observation group (stratified HR 0·66, 95% CI 0·51–0·85; p=0·0015). Estimated 5-year overall survival was 78% (95% CI 74–82) in the adjuvant capecitabine and oxaliplatin group versus 69% (64–73) in the observation group. Adverse event data were not collected after the primary analysis. Interpretation Adjuvant treatment with capecitabine plus oxaliplatin after D2 gastrectomy should be considered for patients with operable stage II or III gastric cancer. Funding F Hoffmann La-Roche and Sanofi.
L-ascorbate (L-ascorbic acid, vitamin C) clearly has an inhibitory effect on cancer cells. However, the mechanism underlying differential sensitivity of cancer cells from same tissue to L-ascorbate ...is yet to be clarified. Here, we demonstrate that L-ascorbate has a selective killing effect, which is influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human breast cancer cells. Treatment of human breast cancer cells with L-ascorbate differentially induced cell death, dependent on the SVCT-2 protein level. Moreover, knockdown of endogenous SVCT-2 via RNA interference in breast cancer cells expressing high levels of the protein induced resistance to L-ascorbate treatment, whereas transfection with SVCT-2 expression plasmids led to enhanced L-ascorbate chemosensitivity. Surprisingly, tumor regression by L-ascorbate administration in mice bearing tumor cell xenograft also corresponded to the SVCT-2 protein level. Interestingly, SVCT-2 expression was absent or weak in normal tissues, but strongly detected in tumor samples obtained from breast cancer patients. In addition, enhanced chemosensitivity to L-ascorbate occurred as a result of caspase-independent autophagy, which was mediated by beclin-1 and LC3 II. In addition, treatment with N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, suppressed the induction of beclin-1 and LC3 II, implying that the differential SVCT-2 protein-dependent L-ascorbate uptake was attributable to intracellular ROS induced by L-ascorbate, subsequently leading to autophagy. These results suggest that functional SVCT-2 sensitizes breast cancer cells to autophagic damage by increasing the L-ascorbate concentration and intracellular ROS production and furthermore, SVCT-2 in breast cancer may act as an indicator for commencing L-ascorbate treatment.
Objectives
The relationship between consuming ≥2 servings of fruits and ≥3 servings of vegetables a day, which has been identified as optimal for health (i.e., adequate fruit/vegetable consumption), ...and non-communicable diseases (NCDs) in low- and middle-income countries (LMICs) is largely unknown. Therefore, using data from six LMICs, we investigated the independent association between inadequate fruit/vegetable consumption and 12 NCDs, and estimated the prevalence of inadequate fruit/vegetable consumption among people with NCDs.
Design and Setting
Cross-sectional, nationally representative data from the WHO Study on global AGEing and adult health (SAGE) were analyzed.
Participants
Data on 34129 individuals aged ≥50 years were analyzed mean (SD) age 62.4 (16.0); maximum age 114 years; 52.1% females.
Measurements
Information on the number of servings of fruits and vegetables consumed on a typical day was self-reported. Twelve NCDs were assessed. Multivariable logistic regression analysis was conducted.
Results
Overall, 67.2% had inadequate fruit/vegetable consumption. Inadequate fruit/vegetable consumption was independently associated with significantly higher odds for chronic lung disease (OR=1.25), diabetes (OR=1.45), hearing problems (OR=1.75), and visual impairment (OR=2.50). The prevalence of inadequate fruit/vegetable consumption was particularly high among people with visual impairment (92.5%), depression (90.5%), asthma (79.8%), and hearing problems (78.4%).
Conclusion
Promotion of fruit and vegetable consumption (≥2 servings of fruits and ≥3 servings of vegetables a day) in LMICs may lead to prevention of some NCDs (e.g., diabetes, chronic lung disease). Furthermore, people with certain NCDs (e.g., visual impairment, depression) had particularly high prevalence of inadequate fruit/vegetable consumption, and it is thus important to target this population to increase fruit/vegetable consumption.
PDF
