Prescription Pathways from Initial Medication Use to Triple Therapy in Older COPD Patients: A Real-World Population Study.

BACKGROUND AND OBJECTIVE: Triple therapy with an inhaled corticosteroid (ICS), a long-acting ß2-agonist bronchodilator (LABA) and a long-acting muscarinic antagonist (LAMA) is recommended as step-up therapy for chronic obstructive pulmonary disease (COPD) patients who continue to have persistent symptoms and increased risk of exacerbation despite treatment with dual therapy. We sought to evaluate different treatment pathways through which COPD patients were escalated to triple therapy. METHODS: We used population health databases from Ontario, Canada to identify individuals aged 66 or older with COPD who started triple therapy between 2014 and 2017. Median time from diagnosis to triple therapy was estimated using the Kaplan-Meier method. We classified treatment pathways based on treatments received prior to triple therapy and evaluated whether pathways differed by exacerbation history, blood eosinophil counts or time period. RESULTS: Among 4108 COPD patients initiating triple therapy, only 41.2% had a COPD exacerbation in the year prior. The three most common pathways were triple therapy as initial treatment (32.5%), LAMA to triple therapy (29.8%), and ICS + LABA to triple therapy (15.4%). Median time from diagnosis to triple therapy was 362 days (95% confidence interval:331-393 days) overall, but 14 days (95% CI 12-17 days) in the triple therapy as initial treatment pathway. This pathway was least likely to contain patients with frequent or severe exacerbations (22.0% vs. 31.5%, p < 0.001) or with blood eosinophil counts ≥300 cells/µL (18.9% vs. 22.0%, p < 0.001). CONCLUSION: Real-world prescription of triple therapy often does not follow COPD guidelines in terms of disease severity and prior treatments attempted.

Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities.

PURPOSE: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFR T790M-negative resistance. EXPERIMENTAL DESIGN: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M+) and -negative (T790M-) disease. RESULTS: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M- tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M- tumors. Almost half of resistant tumors were further classified as immunehot, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M- and T790M+ disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. CONCLUSIONS: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.

Tea Consumption and Risk of Chronic Obstructive Pulmonary Disease in Middle-Aged and Older Singaporean Adults.

Objective: The anti-oxidant and anti-inflammatory actions of phytochemicals and the smooth muscle relaxant actions of theophylline present in tea may confer pulmonary protection and reduce COPD risk. We investigated tea consumption (black, oolong, or green) association with COPD risks in a population-based cohort study of older adults aged ≥55. Methods: GOLD criteria was used to identify prevalent and incident cases of COPD (FEV1/FVC <0.70) among 4617 participants and 920 participants free of COPD at baseline who were assessed at follow-up 4.5 years later. Results: Prevalent cases of COPD consumed less tea than their non-COPD counterparts. Estimated odds ratio (OR) and 95% confidence intervals (95% CI) of association with prevalent COPD, adjusted for age, sex, ethnicity, housing type, smoking, alcohol, physical activity and BMI declined across tea consumption levels (p-trend=0.048), and was lowest for ≥3 cups/day (OR=0.77, 95% CI=0.61-0.96). The cumulated incidence of COPD declined across tea consumption categories (p-trend=0.012) and the lowest OR of association (OR=0.35, 95% CI=0.17-0.69) with consuming ≥3 cups/day after co-variate adjustment. Conclusion: Different kinds of tea showed similar non-significant trends of associations but appeared to be strongest for green tea. Tea consumption in this Asian population was associated with lowered COPD prevalence and incidence.

Predicting HCC Response to Multikinase Inhibitors With In Vivo Cirrhotic Mouse Model for Personalized Therapy.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) arises in a cirrhotic, pro-angiogenic microenvironment. Inhibiting angiogenesis is a key mode of action of multikinase inhibitors and current non-cirrhotic models are unable to predict treatment response. We present a novel mouse cirrhotic model of xenotransplant that predicts the natural biology of HCC and allows personalized therapy. METHODS: Cirrhosis was induced in NOD Scid gamma mice with 4 months of thioacetamide administration. Patient derived xenografts (PDXs) were created by transplant of human HCC subcutaneously into non-cirrhotic mice and intra-hepatically into both cirrhotic and non-cirrhotic mice. The applicability of cirrhotic PDXs for drug testing was tested with 16 days of either sorafenib or lenvatinib. Treatment response was evaluated by MRI. RESULTS: 8 out of 19 (42%) human HCC engrafted in the cirrhotic model compared with only 3 out of 19 (16%) that engrafted in the subcutaneous non-cirrhotic model. Tumor vasculature was preserved in the cirrhotic model but was diminished in the non-cirrhotic models. Metastasis developed in 3 cirrhotic PDX lines and was associated with early HCC recurrence in all 3 corresponding patients (100%), compared with only 5 out of 16 (31%) of the other PDX lines, P = .027. The cirrhotic model was able to predict response and non-response to lenvatinib and sorafenib respectively in the corresponding patients. Response to lenvatinib in the cirrhotic PDX was associated with reduction in CD34, VEGFR2 and CLEC4G immunofluorescence area and intensity (all P ≤ .03). CONCLUSIONS: A clinically relevant cirrhotic PDX model preserves tumor angiogenesis and allows prediction of response to multikinase inhibitors for personalized therapy.

Dietary and supplemental antioxidant and anti-inflammatory nutrient intakes and pulmonary function.

OBJECTIVE: A limited but growing body of evidence supports a significant role of antioxidant and anti-inflammatory micronutrients in pulmonary health. We investigated the associations of dietary and supplemental intakes of vitamins A, C, E and D, Se and n-3 PUFA with pulmonary function in a population-based study. DESIGN: Population-based, cross-sectional study and data analysis of fruits and vegetables, dairy products and fish, vitamins A, C, E and D, Se and n-3 PUFA supplemental intakes, pulmonary risk factors and spirometry. SUBJECTS: Chinese older adults (n 2478) aged 55 years and above in the Singapore Longitudinal Ageing Studies. RESULTS: In multiple regression models that controlled simultaneously for gender, age, height, smoking, occupational exposure and history of asthma/chronic obstructive pulmonary disease, BMI, physical activity, and in the presence of other nutrient variables, daily supplementary vitamins A/C/E (b = 0·044, SE = 0·022, P = 0·04), dietary fish intake at least thrice weekly (b = 0·058, SE = 0·016, P < 0·0001) and daily supplementary n-3 PUFA (b = 0·068, SE = 0·032, P = 0·034) were individually associated with forced expiratory volume in the first second. Supplemental n-3 PUFA was also positively associated with forced vital capacity (b = 0·091, SE = 0·045, P = 0·045). No significant association with daily dairy product intake, vitamin D or Se supplements was observed. CONCLUSIONS: The findings support the roles of antioxidant vitamins and n-3 PUFA in the pulmonary health of older persons.

Complementary and alternative asthma treatments and their association with asthma control: a population-based study.

OBJECTIVES: Many patients with asthma spend time and resources consuming complementary and alternative medicines (CAMs). This study explores whether CAM utilisation is associated with asthma control and the intake of asthma controller medications. DESIGN: Population-based, prospective cross-sectional study. SETTING: General population residing in two census areas in the province of British Columbia, Canada. Recruitment was based on random-digit dialling of both landlines and cell phones. PARTICIPANTS: 486 patients with self-reported physician diagnosis of asthma (mean age 52 years; 67.3% woman). PRIMARY AND SECONDARY OUTCOME MEASURES: We assessed CAM use over the previous 12 months, level of asthma control as defined by the Global Initiative for Asthma and the self-reported intake of controller medications. Multivariate logistic regression was performed to study the relationship between any usage of CAMs (outcome), asthma control and controller medication usage, adjusted for potential confounders. RESULTS: A total of 179 (36.8%) of the sample reported CAM usage in the past 12 months. Breathing exercises (17.7%), herbal medicines (10.1%) and vitamins (9.7%) were the most popular CAMs reported. After adjustment, female sex (OR 1.66; 95% CI 1.09 to 2.52) and uncontrolled asthma (vs controlled asthma, OR 2.25, 95% CI 1.30 to 3.89) were associated with a higher likelihood of using any CAMs in the past 12 months. Controller medication use was not associated with CAM usage in general and in the subgroups defined by asthma control. CONCLUSIONS: Clinicians and policy makers need to be aware of the high prevalence of CAM use in patients with asthma and its association with lack of asthma control.