Different Characteristics and Clinical Outcomes between Early-Onset and Late-Onset Asthma: A Prospective Cohort Study.

Late-onset asthma (LOA) differs from early-onset asthma (EOA) in terms of prognosis and the treatment response because it has a much worse prognosis and a poorer response to standard asthma treatment. This study sought to investigate the characteristics and clinical outcomes of asthma patients with phenotypes distinguished by age at onset and atopy status. We prospectively recruited patients with asthma who were registered in a pay-for-performance program operated by Taiwan's National Health Insurance Administration (NHIA). These patients received regular outpatient treatment for at least 1 year at every outpatient clinic visit since 2019. Baseline characteristics and clinical outcomes were compared between patients with LOA (≥40 years) and those with EOA (<40 years). Of the consecutive 101 patients with asthma, 21 patients (20.7%) had EOA and 80 (79.3%) had LOA. In the 12-month period, patients with EOA had higher declines in forced expiratory volume in one second (FEV1; −2.1 ± 8.4 vs. 6.8 ± 13.1, % of predicted value, p = 0.037) and forced vital capacity (FVC; −4.6 ± 12.0 vs. 6.1 ± 13.6, % of predicted value, p = 0.023) than patients with LOA. Patients with nonatopic EOA had a significantly higher exacerbation rate at 12 months than patients with nonatopic LOA (50% vs. 11.8%, p = 0.012). Identification of different phenotypes of asthma is important in clinical practice because treatment responses may differ.

Prior EGFR-TKI Treatment in EGFR-Mutated NSCLC Affects the Allele Frequency Fraction of Acquired T790M and the Subsequent Efficacy of Osimertinib.

BACKGROUND: The first (1G) and second (2G) generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show differential inhibitory capacities towards EGFR T790M-mutated non-small-cell lung cancer (NSCLC) cells. OBJECTIVE: To assess the ratio of the allele fractions of T790M (AFT790M) to EGFR-activating mutations (AFmEGFR) in patients treated with 1G and 2G EGFR TKIs who acquired T790M-mediated resistance and to determine the relationship between AF and the later efficacy of osimertinib. PATIENTS AND METHODS: The efficacy of osimertinib was reviewed for 54 T790M-positive EGFR-mutated NSCLC patients grouped by the generation of prior EGFR TKI use (1G vs. 2G). AFmEGFR and AFT790M were determined by QuantStudio digital PCR using tissues obtained upon acquired resistance. RESULTS: The progression-free survival (PFS; 20.3 vs. 11.6 months, p = 0.031) and the 1-year PFS rate (63.2 vs. 37.5%, p = 0.029) for osimertinib were significantly better for group 1G compared to group 2G. The ratio of AFT790M to AFmEGFR in group 1G was significantly higher than in group 2G (46.16 ± 5.40% vs. 25.86 ± 4.25%, p = 0.009). An unbiased analysis revealed three AF-associated clusters (ARCs) suggesting the ratio of AFT790M to AFmEGFR correlates with the efficacy of osimertinib. We found all patients in ARC2 having the highest ratio of AFT790M to AFmEGFR to have previously been treated with a 1G EGFR TKI and to show the longest osimertinib PFS compared to ARC3 (NR vs. 11.9 months, p = 0.060) and ARC1 (NR vs. 12.4 month, p = 0.045). CONCLUSIONS: Acquired T790M fraction of EGFR-mutated NSCLC is linked to different generations of prior EGFR TKI use and the later efficacy of osimertinib.

Oral vinorelbine plus cisplatin with concomitant radiotherapy as induction therapy for stage III non-small cell lung cancer: Results of a single-arm prospective cohort study.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is an optimal recommended treatment for stage III non-small cell lung cancer (NSCLC). Herein, we aimed to investigate the efficacy and safety of oral vinorelbine plus cisplatin with concomitant radiotherapy for stage III NSCLC. METHODS: This prospective, open-label, single-arm, observational cohort study was performed between January 2010 and September 2016. Patients were treated with two cycles of chemotherapy with 60 mg/m2 intravenous cisplatin on day 1 and 50 mg/m2 oral vinorelbine on days 1, 8, and 15; radiotherapy was administered concurrently from day 1 when chemotherapy was initiated. A total dose of 66-70 Gy radiotherapy was delivered in daily fractions of 2 Gy for 6.5-7 consecutive weeks. The tumor response was assessed after completing concomitant treatment. RESULTS: A total of 58 patients were enrolled and analyzed; 31 patients had stage IIIA NSCLC and 27 had stage IIIB NSCLC. After induction CCRT, 31 patients achieved an objective response (complete response in one and partial response in 30; the response rate was 53.4%). The median progression-free survival was 6.73 months (95% confidence interval [CI], 5.42-7.91), duration of response was 12.30 months (95% CI, 5.59-19.01), and overall survival was 24.83 months (95% CI, 19.26-30.21). No treatment-related mortality was observed, and neutropenia was the most common grade 3 and 4 treatment-related toxicity (11 patients; 18.9%). CONCLUSIONS: CCRT with the weekly regimen of oral vinorelbine plus triweekly cisplatin was effective and safe for stage III NSCLC.

Comparison of a combination of chemotherapy and immune checkpoint inhibitors and immune checkpoint inhibitors alone for the treatment of advanced and metastatic non-small cell lung cancer.

BACKGROUND: Single agent immune checkpoint inhibitors (ICIs) improve survival outcomes compared to chemotherapy for advanced non-small cell lung cancer (NSCLC), but treatment efficacy widely varies. The combination of ICIs with chemotherapy has shown promising efficacy over chemotherapy alone; however, whether this strategy is superior to single agent ICIs for the treatment of advanced NSCLC remains unknown. METHODS: The records of 109 patients with advanced NSCLC who were administered at least one cycle of ICIs were retrospectively reviewed. Patients were grouped based on the presence or absence of a chemotherapy treatment combination. Efficacy and survival outcomes were analyzed. RESULT: Sixty-nine (58.0%) patients received single agent ICIs (ICI group) and 50 (42.0%) received ICIs and chemotherapy (ICC group). The median (3.2 vs. 3.0 months; P = 0.025) and one-year (34.5 vs. 9.6%; P = 0.026) progression-free survival (PFS) rates were significantly better in the ICC than in the ICI group. The superior efficacy of ICC remained in the propensity score matched pairs (median PFS 3.2 vs. 2.6 months, P = 0.032; 1-year PFS 35.2 vs. 7.6%; P = 0.035). Eastern Cooperative Oncology Group performance status 0-1 (HR 0.37, 95% CI 0.22-0.62; P < 0.001) and the ICC group (HR 0.56, 95% CI 0.34-0.94; P = 0.028) were predictive of PFS. Subgroup-to-chemotherapy interaction revealed improved risk reduction for adenocarcinoma and EGFR mutation. CONCLUSION: Combing chemotherapy with ICIs improved treatment efficacy over ICIs alone. The additional efficacy of chemotherapy may differ between histological subtypes and EGFR mutation status.

Distribution of colon neoplasia in Chinese patients: implications for endoscopic screening strategies.

OBJECTIVES: Our aim was to measure the prevalence and distribution of colonic neoplasia in Chinese adults, and to estimate the sensitivity of sigmoidoscopic screening strategies for detecting those with advanced neoplasia. METHODS: Asymptomatic, average-risk Chinese adults aged 50 years or older underwent screening colonoscopy. The prevalence and distribution of colonic neoplasia and advanced neoplasia (defined as an adenoma >or=10 mm or with villous, high-grade dysplastic, or malignant features) were reviewed retrospectively and the outcomes of various sigmoidoscopic screening strategies estimated. RESULTS: Of 1,382 individuals (833 men, 549 women; mean age 58.8 years) included, 243 (18%) had colorectal neoplasia and 72 (5.2%) had advanced neoplasia. Neoplasia prevalence was significantly higher in male and older patients. No significant differences were observed in neoplasia distribution between men and women. Overall, 24 patients had advanced neoplasia in the proximal colon, of whom four had synchronous distal neoplasia. The estimated sensitivity for detecting patients with advanced neoplasia was 72% if we assumed screening sigmoidoscopy was performed, with follow-up colonoscopy for those with distal neoplasia; 165 patients would need to undergo colonoscopy. If, instead, we assumed follow-up colonoscopy was done only for patients with distal advanced neoplasia, the estimated sensitivity would decrease slightly to 71%, but the number of colonoscopies would decrease substantially to 51. CONCLUSION: In average-risk Chinese adults, screening sigmoidoscopy is estimated to detect more than two-thirds of patients with advanced neoplasia. In Chinese societies with limited health-care resources, performing colonoscopy only on patients with distal advanced neoplasia is a screening approach that optimizes the return rate on colonoscopic capacity.

Impact of prolonged and early bevacizumab treatment on the overall survival of EGFR-mutant and EGFR-wild type nonsquamous non-small cell lung cancer.

BACKGROUND: VEGF plays a key role in tumor angiogenesis and immunosuppression. VEGF-blocking has proven beneficial for EGFR mutant and wild-type nonsquamous non-small cell lung cancer (nonsq-NSCLC); however, the number of cycles and treatment line yielding the optimal benefit are unknown. METHODS: We retrospectively analyzed the data of 115 patients with advanced/metastatic nonsq-NSCLC administered at least one cycle of bevacizumab. The number of bevacizumab cycles was treated as a time-dependent covariate. Predictors of overall survival (OS) were investigated. RESULTS: Bevacizumab was used as first-line treatment in 47 (40.9%) patients, with a median of five cycles (range: 1-31). Eastern Cooperative Oncology Group performance status ≥ 2 (hazard ratio [HR] 4.78, 95% confidence interval [CI] 2.68-8.51; P < 0.001), wild-type EGFR (HR 2.61, 95% CI 1.45-4.70; P = 0.001), and bleeding during bevacizumab treatment (HR 3.63, 95% CI 1.77-7.45; P < 0.001) were predictive of poor OS; the number of bevacizumab cycles and first-line administration were not. In the wild-type EGFR subgroup, the number of bevacizumab cycles (≥ 5 vs. 1-4) was associated with a significant OS benefit (HR 0.28, 95% CI 0.08-0.98; P = 0.044); first-line administration also showed an OS benefit (HR 0.48, 95% CI 0.20-1.17; P = 0.105). A significant association between the number of cycles and EGFR status was identified (P = 0.046). CONCLUSION: OS benefit is negatively affected by bleeding events in bevacizumab-treated patients. Prolonged and early introduction of bevacizumab may provide an OS benefit for patients with wild-type EGFR nonsq-NSCLC.

Unique Immune Gene Expression Patterns in Bronchoalveolar Lavage and Tumor Adjacent Non-Neoplastic Lung Tissue in Non-Small Cell Lung Cancer.

Background: The immune cells in the local environments surrounding non-small cell lung cancer (NSCLC) implicate the balance of pro- and antitumor immunity; however, their transcriptomic profiles remain poorly understood. Methods: A transcriptomic microarray study of bronchoalveolar lavage (BAL) cells harvested from tumor-bearing lung segments was performed in a discovery group. The findings were validated (1) in published microarray datasets, (2) in an independent group by RT-qPCR, and (3) in non-diseased and tumor adjacent non-neoplastic lung tissue by immunohistochemistry and in BAL cell lysates by immunoblotting. Result: The differential expression of 129 genes was identified in the discovery group. These genes revealed functional enrichment in Fc gamma receptor-dependent phagocytosis and circulating immunoglobulin complex among others. Microarray datasets analysis (n = 607) showed that gene expression of BAL cells of tumor-bearing lung segment was also the unique transcriptomic profile of tumor adjacent non-neoplastic lung of early stage NSCLC and a significantly gradient increase of immunoglobulin genes' expression for non-diseased lungs, tumor adjacent non-neoplastic lungs, and tumors was identified (ANOVA, p < 2 × 10-16). A 53-gene signature was determined with significant correlation with inhibitory checkpoint PDCD1 (r = 0.59, p = 0.0078) among others, where the nine top genes including IGJ and IGKC were RT-qPCR validated with high diagnostic performance (AUC: 0.920, 95% CI: 0.831-0.985, p = 2.98 × 10-7). Increased staining and expression of IGKC revealed by immunohistochemistry and immunoblotting in tumor adjacent non-neoplastic lung tissues (Wilcoxon signed-rank test, p < 0.001) and in BAL cell lysates (p < 0.01) of NSCLC, respectively, were noted. Conclusion: The BAL cells of tumor-bearing lung segments and tumor adjacent non-neoplastic lung tissues present a unique gene expression characterized by IGKC in relation to inhibitory checkpoints. Further study of humoral immune responses to NSCLC is warranted.

Pericardial and thoracic peri-aortic adipose tissues contribute to systemic inflammation and calcified coronary atherosclerosis independent of body fat composition, anthropometric measures and traditional cardiovascular risks.

BACKGROUND: Coronary atherosclerosis has traditionally been proposed to be associated with several cardiovascular risk factors and anthropometric measures. However, clinical data regarding the independent value of visceral adipose tissue in addition to such traditional predictors remains obscure. MATERIALS AND METHODS: We subsequently studied 719 subjects (age: 48.1±8.3 years, 25% females) who underwent multidetector computed tomography (MDCT) for coronary calcium score (CCS) quantification. Baseline demographic data and anthropometric measures were taken with simultaneous body fat composition estimated. Visceral adipose tissue of pericardial and thoracic peri-aortic fat was quantified by MDCT using TeraRecon Aquarius workstation (San Mateo, CA). Traditional cardiovascular risk stratification was calculated by metabolic (NCEP ATP III) and Framingham (FRS) scores and high-sensitivity CRP (Hs-CRP) was taken to represent systemic inflammation. The independent value of visceral adipose tissue to systemic inflammation and CCS was assessed by utilizing multivariable regression analysis. RESULTS: Of all subjects enrolled in this study, the mean values for pericardial and peri-aortic adipose tissue were 74.23±27.51 and 7.23±3.69ml, respectively. Higher visceral fat quartile groups were associated with graded increase of risks for cardiovascular diseases. Both adipose burdens strongly correlated with anthropometric measures including waist circumference, body weight and body mass index (all p<0.001). In addition, both visceral amount correlates well with ATP and FRS scores, all lipid profiles and systemic inflammation marker in terms of Hs-CRP (all p<0.001). After adjustment for baseline variables, both visceral fat were independently related to Hs-CRP levels (all p<0.05), but only pericardial fat exerted independent role in coronary calcium deposit. CONCLUSION: Both visceral adipose tissues strongly correlated with systemic inflammation beyond traditional cardiovascular risks and anthropometric measures, though only pericardial fat exerted independent role in coronary calcium deposit. Our data suggested that visceral adipose tissue may thus contribute to systemic inflammation and play an independent role in the pathogenesis of atherosclerosis.

Epicardial adipose tissue relating to anthropometrics, metabolic derangements and fatty liver disease independently contributes to serum high-sensitivity C-reactive protein beyond body fat composition: a study validated with computed tomography.

BACKGROUND: Epicardial adipose tissue (EAT) measured by echocardiography has been proposed to be associated with metabolic syndrome and increased cardiovascular risks. However, its independent association with fatty liver disease and systemic inflammation beyond clinical variables and body fat remains less well known. METHODS: The relationships between EAT and various factors of metabolic derangement were retrospectively examined in consecutive 359 asymptomatic subjects (mean age, 51.6 years; 31% women) who participated in a cardiovascular health survey. Echocardiography-derived regional EAT thickness from parasternal long-axis and short-axis views was quantified. A subset of data from 178 randomly chosen participants were validated using 16-slice multidetector computed tomography. Body fat composition was evaluated using bioelectrical impedance from foot-to-foot measurements. RESULTS: Increased EAT was associated with increased waist circumference, body weight, and body mass index (all P values for trend = .005). Graded increases in serum fasting glucose, insulin resistance, and alanine transaminase levels were observed across higher EAT tertiles as well as a graded decrease of high-density lipoprotein (all P values for trend <.05). The areas under the receiver operating characteristic curves for identifying metabolic syndrome and fatty liver disease were 0.8 and 0.77, with odds ratio estimated at 3.65 and 2.63, respectively. In a multivariate model, EAT remained independently associated with higher high-sensitivity C-reactive protein and fatty liver disease. CONCLUSIONS: These data suggested that echocardiography-based epicardial fat measurement can be clinically feasible and was related to several metabolic abnormalities and independently associated fatty liver disease. In addition, EAT amount may contribute to systemic inflammation beyond traditional cardiovascular risks and body fat composition.

Anticancer activity of botanical alkyl hydroquinones attributed to topoisomerase II poisoning.

Cytotoxic alkyl hydroquinone compounds have been isolated from many plants. We previously isolated 3 structurally similar cytotoxic alkyl hydroquinone compounds from the sap of the lacquer tree Rhus succedanea L. belonging to the sumac family, which have a long history of medicinal use in Asia. Each has an unsaturated alkyl chain attached to the 2-position of a hydroquinone ring. One of these isolates, 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone [HQ17(3)], being the most cytotoxic, was chosen for studying the anticancer mechanism of these compounds. We found that HQ17(3) was a topoisomerase (Topo) II poison. It irreversibly inhibited Topo IIalpha activity through the accumulation of Topo II-DNA cleavable complexes. A cell-based assay showed that HQ17(3) inhibited the growth of leukemia HL-60 cells with an EC50 of 0.9 microM, inhibited the topoisomerase-II-deficient cells HL-60/MX2 with an EC50 of 9.6 microM, and exerted no effect on peripheral blood mononuclear cells at concentrations up to 50 microM. These results suggest that Topo II is the cellular drug target. In HL-60 cells, HQ17(3) promptly inhibited DNA synthesis, induced chromosomal breakage, and led to cell death with an EC50 about one-tenth that of hydroquinone. Pretreatment of the cells with N-acetylcysteine could not attenuate the cytotoxicity and DNA damage induced by HQ17(3). However, N-acetylcysteine did significantly reduce the cytotoxicity of hydroquinone. In F344 rats, intraperitoneal injection of HQ17(3) for 28 days induced no clinical signs of toxicity. These results indicated that HQ17(3) is a potential anticancer agent, and its structural features could be a model for anticancer drug design.

Screening colonoscopy in Chinese and Western patients: a comparative study.

OBJECTIVES: The aim of this study was to compare findings on screening colonoscopy in a Chinese cohort versus a concurrent Western cohort. METHODS: Asymptomatic adults aged 40 years or older concurrently underwent screening colonoscopy in two hospitals, one in Taiwan and the other in Seattle. The prevalence and distribution of colonic neoplasia and advanced neoplasia (defined as an adenoma >or=10 mm or with villous, high-grade dysplastic, or malignant features) were compared between the two groups. RESULTS: The Taiwan cohort was composed of 1,456 subjects. Colonic neoplasms were found in 214 (14.7%), advanced neoplasms in 58 (4%), and colon cancers in 4 subjects (0.3%). The Seattle cohort was composed of 3,403 subjects. Neoplasms were found in 705 (20.7%), advanced neoplasms in 166 (4.9%), and cancers in 11 subjects (0.3%). Age and male sex were risk factors for neoplasia in both groups. The adjusted risk ratio was 1.30 (95% confidence interval: 1.08-1.57) in Western versus Chinese patients. However, the prevalence of advanced neoplasms was not statistically different between the two cohorts. The Chinese cohort had a higher proportion of distal neoplasia (66.4%vs 52.6%; p= 0.0004). The sensitivity of a sigmoidoscopic screening strategy for detecting advanced neoplasia was higher in Chinese (79.3%) than in Western patients (67.5%). CONCLUSIONS: Compared to Westerners, Chinese patients have a slightly lower prevalence of colon neoplasia (but not advanced neoplasia), more distal distribution of neoplasia, and higher likelihood of concomitant proximal advanced neoplasia and distal neoplasia. Colonoscopy is safe, well-tolerated, and a viable screening option in Chinese patients, but its advantage over sigmoidoscopy as a screening tool may be smaller.