Treatment Patterns in Patients with Locally Advanced or Metastatic Non-Small-Cell Lung Cancer Treated with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors: Analysis of US Insurance Claims Databases.

BACKGROUND: Most patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC) acquire resistance to first-line (1L) first- or second-generation (1G/2G) EGFR-TKIs; therefore, it is important to optimize 1L treatment to improve patient outcomes. OBJECTIVE: To retrospectively examine treatment patterns in locally advanced/metastatic NSCLC using MarketScan® Commercial and Medicare Supplemental Databases (all US census regions). PATIENTS AND METHODS: Adults with a lung cancer diagnosis code between 1 January 2015-31 March 2018 were analyzed from diagnosis (index) through a variable-length follow-up. Patients had ≥ 1 pharmacy claim for 1G/2G EGFR-TKIs on or within 60 days post-index. Data were stratified by presence or absence of central nervous system (CNS) metastases (30 days pre-index through study end). RESULTS: 578 patients were included (median age 63 years, 64% female). Median follow-up was 13.5 months. The most frequently prescribed 1L EGFR-TKI was erlotinib (414/578, 72%). Median time to 1L treatment discontinuation was 8.2 (95% confidence interval (CI) 6.9, 9.0) months in patients diagnosed with CNS metastases at any time, and 7.7 (95% CI 6.9, 8.9) months in patients without CNS metastases. 270/578 patients (47%) discontinued 1L EGFR-TKIs; 209/270 (77%) initiated second-line (2L) therapy, most frequently osimertinib (96/209, 46%). CONCLUSIONS: In an analysis of US claims data, nearly half of patients discontinued 1L EGFR-TKIs, and 46% who initiated 2L received osimertinib. As nearly a quarter of patients who discontinued 1L EGFR-TKIs did not receive 2L treatment, this study highlights the need for optimal 1L treatment in EGFRm locally advanced/metastatic NSCLC.

European and US Real-World Treatment Patterns in Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Retrospective Medical Record Review.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line (1L) therapy for EGFR mutation-positive (EGFRm) advanced/metastatic non-small cell lung cancer (NSCLC). OBJECTIVE: Our objective was to describe real-world treatment patterns and T790M testing practices in patients with 1L disease progression (Europe/USA) following treatment with first- or second-generation EGFR-TKIs. METHODS: This was a retrospective, non-interventional medical record review of patients with EGFRm locally advanced/metastatic NSCLC from routine clinical practice (EGFR-TKI initiation: 1 January 2015 to 31 December 2017; follow-up: last available medical record). Endpoints were demographic/clinical characteristics, incidence of central nervous system (CNS) metastases/leptomeningeal disease, second-line (2L) treatment, T790M mutation testing, and osimertinib treatment prevalence. RESULTS: Among 469 patients, 73% (n = 341/469) progressed on 1L EGFR-TKI treatment. Of those who progressed, 74% (n = 252/341) were tested for T790M, with 50% (n = 126/252) testing positive; 75% (n = 94/126) of T790M-positive patients received osimertinib (mostly 2L). Of the patients with progression, 24% (n = 83/341) did not receive 2L treatment, and 88% (n = 73/83) of these patients died. At diagnosis of advanced disease, 9% of patients (n = 41) had CNS metastases; at EGFR-TKI initiation, 14% of patients (n = 68) had CNS metastases. Over the study period, 11% of patients (n = 42) developed CNS metastases not detected at NSCLC diagnosis. CONCLUSIONS: Rates of resistance mutation testing and subsequent utilization of recommended 2L therapies could be improved. As more targeted therapies are developed, it will be crucial to improve the molecular testing rates to ensure patients receive appropriate, effective, and timely treatment.

On-chip second-order spatial derivative of an optical beam by a periodic ridge.

In this paper, a very simple periodic ridge on a symmetric slab waveguide is used for implementing an on-chip CMOS-compatible second-order spatial differentiator. The reflection and transmission coefficients of this structure show that the second derivative is performed in the transmission when the optical beam normally incidents on the periodic ridge. Simulations confirm that the reason behind the second-order spatial differentiation of the incoming beam is the excitation of the guided mode of the periodic ridge. A Maxwell's equation solver that utilizes the finite element method (FEM) is used to simulate this structure, and an eigenmode solver is utilized for the validation. The results of both methods have a very good agreement with each other.

Spin-polarized unidirectional cylindrical waveguide in bianisotropic media.

In this paper, we analyze a cylindrical waveguide consisting of two layers of bianisotropic material with anti-symmetric magnetoelectric coupling tensors. The analysis is carried out in terms of pseudo-electric and pseudo-magnetic fields which satisfy Maxwells' equations with gyrotropic permittivity and permeability tensors. We show that the rotationally symmetric modes of the waveguide are unidirectional with transverse pseudo-electric and transverse pseudo-magnetic modes propagating in opposite directions. These modes are surface waves whose electromagnetic field is concentrated near the interface between the two anisotropic materials. They follow the contour of the interface even in the case of sharp discontinuities and pass through an obstacle without backscattering if the obstacle does not change the polarization of the wave. Higher-order modes of the waveguide are also investigated. Although these modes are hybrid modes and not, strictly speaking, unidirectional, they practically behave as the rotationally symmetric mode.

Fundamental limit for gain and resolution in analog optical edge detection.

In this paper, the relation between gain and resolution of an ideal analog optical differentiator in two different cases and their fundamental limits are investigated. Based on this relation, a figure of merit for comparison of the designed differentiators in recent papers is proposed. The differentiators are optimized using this figure of merit, and they are compared with each other to determine the best one. Also, a new differentiator is presented based on the dielectric slab waveguide in which the trade-off between its gain and resolution is easily controllable, and its best operating point is determined.

Prediagnostic circulating inflammation biomarkers and esophageal squamous cell carcinoma: A case-cohort study in Japan.

Esophageal squamous cell carcinoma (ESCC) is the predominant histologic subtype of esophageal cancer worldwide. Measurements of circulating inflammation-related biomarkers may inform etiology or provide noninvasive signatures for early diagnosis. We therefore examined levels of inflammation molecules for associations with ESCC risk. Using a case-cohort study designed within the Japan Public Health Center-based Prospective Study, we measured baseline plasma levels of 92 biomarkers using a multiplex assay in a subcohort of 410 randomly selected participants and 66 participants with incident ESCC (including four cases that occurred in the subcohort). ESCC hazard ratios (HRs) were calculated for 2-4 quantiles of each biomarker by Cox proportional hazards regression models with age as the time metric, adjusted for sex, smoking and alcohol use. Twenty analytes were undetectable in nearly all samples. Of the remaining 72, 12 biomarkers (FGF19, ST1A1, STAMBP, AXIN1, CASP8, NT3, CD6, CDCP1, CD5, SLAMF1, OPG and CSF1) were associated with increased ESCC risk (ptrend < 0.05) with HRs per quantile 1.28-1.65. Seven biomarkers (CXCL6, CCL23, CXCL5, TGFA, CXCL1, OSM and CCL4) were inversely associated with HRs 0.57-0.72. FGF19, CASP8, STAMBP, ST1A1 and CCL-4 met statistical significance with false discovery rate correction. Associations did not differ <5 vs. ≥5 years between blood collection and ESCC diagnosis. CASP8, STAMBP and ST1A1 were strongly correlated (p < 0.05). Our study expands the range of inflammation molecules associated with the development of this highly lethal neoplasia. Correlations among these novel biomarkers suggest a possible shared pathway. These findings need replication and could further delineate ESCCs molecular mechanisms of carcinogenesis.

Risk factors for Burkitt lymphoma: a nested case-control study in the UK Clinical Practice Research Datalink.

Burkitt lymphoma (BL) occurs as three subtypes: endemic BL, immunosuppression-related BL and sporadic BL. Descriptive studies of BL age-specific incidence patterns have suggested multimodal peaks near 10, 40 and 70 years of age, but the risk factors for BL at different ages are unknown. We investigated risk factors for BL in the United Kingdom among 156 BL cases and 608 matched BL-free controls identified in the Clinical Practice Research Datalink (CPRD) between 1992 and 2016. Associations with pre-diagnostic body mass index, cigarette smoking, alcohol consumption, hepatitis, Epstein-Barr virus (EBV), human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS), malaria, allergic and autoimmune conditions, and prednisone use were evaluated. Overall, we identified inverse associations between smoking and BL risk, and positive associations between prior EBV infection, HIV/AIDS and prescription or use of prednisone with BL risk. In age-group stratified analyses, BL was associated with malaria exposure (vs. no exposure, odds ratio [OR] 8·00, 95% confidence interval [CI] 1·46-43·7) among those aged 20-59 years old and with hepatitis infection (vs. no infection, OR 3·41, 95% CI 1·01-11·5) among those aged 60+ years old. The effects of EBV, malaria, HIV/AIDS, prednisone and hepatitis on BL remained significant in mutually-adjusted age-group-specific analyses. No risk factors were associated with childhood BL. We report novel associations for BL in non-endemic settings.

Determining 1-Yr Prosthetic Use for Mobility Prognoses for Community-Dwelling Adults with Lower-Limb Amputation: Development of a Clinical Prediction Rule.

OBJECTIVE: The objective of this study was to develop a prognostic clinical prediction rule to identify people not achieving community walking level prosthetic use after 1 yr. DESIGN: This is a prospective longitudinal cohort study of community-dwelling adults with lower-limb amputations recruited from support groups and prosthetic clinics. Participants completed Activities-specific Balance Confidence and Houghton prosthetic use for mobility self-report scales and the Berg Balance Scale. The clinical prediction rule was developed using multivariate logistic regression, receiver operating curves, and probability statistics to identify people not achieving community walking level prosthetic use (Houghton scores <9) at 1 yr. RESULTS: Forty (74.1%) of 54 participants provided follow-up data. Participants averaged 57.0 ± 11.9 yrs old, and the most recent amputation had occurred an average of 6.6 ± 11.0 yrs ago. Seventy percent had vascular amputations and 52.5% had transtibial amputations. The clinical prediction rule predicted who would not reach the community prosthetic walking level with excellent accuracy (area under the curve >0.96) using four criteria: initial Houghton, Activities-specific Balance Confidence, and Berg Balance Scale tasks 9 (retrieve object from floor) and 10 (look behind over shoulders). Failure to exceed cutoff scores in two or more criteria yielded posttest probability of not reaching community walking prosthetic use 1 yr later for 90% of participants or higher. CONCLUSIONS: Accurate 1-yr prosthetic use for mobility prognoses can be obtained by screening prosthetic use, balance confidence, and balance ability to identify community-dwelling people with lower-limb amputations unlikely to achieve community walking prosthetic use.

Sperm Aneuploidy in Faroese Men with Lifetime Exposure to Dichlorodiphenyldichloroethylene (p,p´-DDE) and Polychlorinated Biphenyl (PCB) Pollutants.

BACKGROUND: Although it is known that sperm aneuploidy contributes to early pregnancy losses and congenital abnormalities, the causes are unknown and environmental contaminants are suspected. OBJECTIVES: Our goal was to evaluate associations between lifetime exposure to organochlorines, specifically dichlorodiphenyldicholorethylene (p,p´-DDE) and polychlorinated biphenyls (PCBs), and sperm aneuploidy in men from the general population of the Faroe Islands, a population with a known history of organochlorine exposures. METHODS: Serum and semen samples from men (n = 90) 22-44 years old who participated in Faroe Islands health studies were analyzed for p,p´-DDE and PCBs 118, 138, 153, and 180 and adjusted for total lipids. Cord blood and age-14 serum were available for a subgroup (n = 40) and were also analyzed for p,p´-DDE and PCBs. Sperm fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine rates of XX18, XY18, YY18, and total disomy. Multivariable adjusted Poisson models were used to estimate the relationship between organochlorine exposure and sperm disomy outcomes. RESULTS: Adult p,p´-DDE and total PCB serum concentrations were both associated with significantly increased rates of XX18, XY18, and total disomy. Age-14 p,p´-DDE and PCB concentrations were both associated with significantly increased rates of XX, XY, and total disomy in adulthood. Associations between cord blood concentrations of p,p´-DDE and PCBs and sperm disomy in adulthood were not consistently significant. CONCLUSIONS: Organochlorine exposures measured at age 14 and in adulthood were associated with sperm disomy in this sample of high-exposure men, suggesting that the impacts of persistent pollutants on testicular maturation and function require further investigation. CITATION: Perry MJ, Young HA, Grandjean P, Halling J, Petersen MS, Martenies SE, Karimi P, Weihe P. 2016. Sperm aneuploidy in Faroese men with lifetime exposure to dichlorodiphenyldichloroethylene (p,p´-DDE) and polychlorinated biphenyl (PCB) pollutants. Environ Health Perspect 124:951-956; http://dx.doi.org/10.1289/ehp.1509779.

Polycyclic aromatic hydrocarbons and childhood asthma.

Asthma is the most common chronic illness in children living in developed countries and the leading cause of childhood hospitalization and school absenteeism. Prevalence rates of asthma are increasing and show disparities across gender, geographic regions, and ethnic/racial groups. Common risk factors for developing childhood asthma include exposure to tobacco smoke, previous allergic reactions, a family history of asthma, allergic rhinitis or eczema, living in an urban environment, obesity and lack of physical exercise, severe lower respiratory tract infections, and male gender. Asthma exacerbation in children can be triggered by a variety of factors, including allergens (e.g., pollen, dust mites, and animal dander), viral and bacterial infections, exercise, and exposure to airway irritants. Recent studies have shown that exposure to polycyclic aromatic hydrocarbons (PAHs), a major component of fine particulate matter from combustion sources, is also associated with onset of asthma, and increasing asthmatic symptoms. In this paper, we review sources of childhood PAH exposure and the association between airborne PAH exposure and childhood asthma prevalence and exacerbation.

Implementation of proteomics for cancer research: past, present, and future.

Cancer is the leading cause of the death, accounts for about 13% of all annual deaths worldwide. Many different fields of science are collaborating together studying cancer to improve our knowledge of this lethal disease, and find better solutions for diagnosis and treatment. Proteomics is one of the most recent and rapidly growing areas in molecular biology that helps understanding cancer from an omics data analysis point of view. The human proteome project was officially initiated in 2008. Proteomics enables the scientists to interrogate a variety of biospecimens for their protein contents and measure the concentrations of these proteins. Current necessary equipment and technologies for cancer proteomics are mass spectrometry, protein microarrays, nanotechnology and bioinformatics. In this paper, we provide a brief review on proteomics and its application in cancer research. After a brief introduction including its definition, we summarize the history of major previous work conducted by researchers, followed by an overview on the role of proteomics in cancer studies. We also provide a list of different utilities in cancer proteomics and investigate their advantages and shortcomings from theoretical and practical angles. Finally, we explore some of the main challenges and conclude the paper with future directions in this field.

Strain counterstrain technique to decrease tender point palpation pain compared to control conditions: a systematic review with meta-analysis.

BACKGROUND: Strain counterstrain (SCS) is an indirect osteopathic manipulative technique that uses passive positioning to relieve tender point (TP) palpation pain and associated dysfunction. OBJECTIVE: The purposes of this systematic review with meta-analysis were to 1) determine the pooled effect of SCS on TP palpation pain compared to a control condition and 2) assess the quality of the overall evidence. DATA SOURCE: A search conducted using the MEDLINE with AMED, PUBMED, CINAHL, and SCOPUS databases for publications from January 2002 and April 2012 yielded 29 articles for eligibility screening. STUDY SELECTION: Included studies were limited to randomized control trials comparing TP palpation pain after isolated SCS treatment compared to control conditions assessed with a visual analog scale. Other study designs or manipulative treatments were excluded. DATA EXTRACTION: Two reviewers adhered to a predetermined study protocol following current Cochrane Collaboration recommendations to independently extract the data with standardized extraction forms and assess studies for methodological quality and determine risks of bias. RESULTS: Five randomized control trials were included for qualitative and quantitative analysis. The pooled effect of SCS was a reduction of TP palpation pain (p < 0.001, 95% CI -0.291 to -0.825). The overall evidence quality was low: while all studies met at least 8 of 12 methodological quality criteria, most were low quality. CONCLUSIONS: This systematic review and meta-analysis found low quality evidence suggesting that SCS may reduce TP palpation pain. Future studies with larger samples of better quality studies with patient populations that assess long-term pain, impairment, and dysfunction outcomes could enrich the literature.

Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention.

Less than a century ago, gastric cancer was the most common cancer in the United States and perhaps throughout the world. Despite its worldwide decline in incidence over the past century, gastric cancer remains a major killer across the globe. This article reviews the epidemiology, screening, and prevention of gastric cancer. We first discuss the descriptive epidemiology of gastric cancer, including its incidence, survival, mortality, and trends over time. Next, we characterize the risk factors for gastric cancer, both environmental and genetic. Serologic markers and histological precursor lesions of gastric cancer and early detection of gastric cancer using these markers are reviewed. Finally, we discuss prevention strategies and provide suggestions for further research.

The state of nutritional epidemiology: why we are still unsure of what we should eat?

Most people want to know how they can improve their health by implementation of a proper diet. Therefore nutritional epidemiology studies, which correlate the intake of specific nutrients, food items, or dietary patterns with health outcomes, receive substantial interest in the media. However, the results of many nutritional epidemiology studies have not been replicated in subsequent studies. This paper reviews the primary methodological problems in nutritional epidemiology that result in lack of replicability and inconsistency across studies. The problematic methodological issues include substantial measurement error, confounding, the variable effects of food items, variable reference groups, interactions, and multiple testing.

The relation of multiple sclerosis with allergy and atopy: a case control study.

Multiple Sclerosis (MS) and Allergy are believed to up regulate T helper cell type 1 (Th1) and T helper cell type 2 (Th2)  responses, respectively. It has been shown that disequilibrium in the ratio of Th1/Th2 activities may increase frequency of one disease and decrease the frequency of the other. The aim of this study was to investigate the relation of MS with allergy and atopy in new diagnosed MS patients. This case-control study was conducted on 40 new diagnosed MS patients and the same number of normal controls. All of the patients were diagnosed (according to McDonald criteria) at most 2 years prior to the study. Demographic data and clinical characteristics of both groups were recorded in a questionnaire. The total IgE and allergen specific IgE in the serum were measured in all the cases. Forty MS patients (female/male: 4.71) with mean age of 30.55±9.5 years and 40 healthy controls entered in this study. History of allergy was observed in 20(50%) of MS patients (including 15 (37.5%) rhinitis, 6 (15%) conjunctivitis, 3 (7.5%) urticaria and eczema, 1 (2.5%) asthma), and 20 (50%) of the controls (including 8 (20%) rhinitis, 4 (10%) conjunctivitis, 7 (17.5%) urticaria and eczema, 1 (2.5%) asthma). The differences between the two groups were not statistically significant. Neither the serum total IgE, nor the frequency of specific IgE against Weed mix, Grass Mix, Tree mix1, Tree mix 2, Dermatophagoides Farinae, Dermatophagoides pteronyssinus and Epidermal and animal proteins mix differed statistically between the two groups. There was also no significant relationship between MS clinical manifestations and allergy prevalence and also between MS and atopy. The results of this study as some other similar studies showed the same prevalence of allergy in MS patients and controls and also demonstrated no relation between MS and atopy.

Evidence for U.S. Preventive Services Task Force (USPSTF) recommendations against routine mammography for females between 40-49 years of age.

Breast cancer is the most common cancer among females, worldwide, accounting for 22.9% of all cancers (excluding non-melanoma skin cancer) in women. Mammography is a sensitive (77-95%) and specific (94-97%) screening method for breast cancer. Previously, females between the 40-50 years old were recommended to have mammograms every one to two years. However, based on current evidence, in 2009, USPSTF recommended that the decision to start regular, biennial screening mammography for females younger than 50 years should be an individual decision and take patient context into account, including patient values regarding specific benefits and harms. This decision was based on findings regarding radiation exposure, false-positive and false-negative rates, over-diagnosis, and pain and psychological responses. The goal of this paper is to focus on evidence for updating the U.S. Preventive Services Task Force (USPSTF) recommendation against routine mammography for females between 40-49 years of age.

Analysis of HLA DR2&DQ6 (DRB1*1501, DQA1*0102, DQB1*0602) haplotypes in Iranian patients with multiple sclerosis.

Multiple sclerosis (MS) is prototype of inflammatory demyelinating disease of the central nervous system .The etiology of MS remains unclear, but according to current data the disease develops in genetically susceptible individuals and may require additional environmental triggers. The human leukocyte antigen (HLA) class II alleles (DRB1*1501, DQA1*0102, DQB1*0602) may have the strongest genetic effect in MS. In this study, the role of these alleles were investigated in 183 Iranian patients with multiple sclerosis and compared with 100 healthy individuals. HLA typing for DRB1*1501, DQA1*0102, DQB1*0602 was performed by polymerase chain reaction (PCR) amplification with sequence-specific primers (PCR-SSP) method. The results show that, HLA DR B1*1501 was significantly more frequent among MS patients (46% vs. 20%, PV = 0.0006) but DQA1*0102 haplotype was negatively associated with MS (30% vs. 50%, PV = 0.0049) and no significant association was found with DQB1*0602 and MS patients in comparison with control group (24% and 30%, PV = 0.43). No significant correlation was observed among these alleles with sex, type of disease; initial symptoms, expanded disability status scale (EDSS), as well as age at onset and familial MS. This study therefore indicates that there is no association of above HLA haplotypes with clinical presentation, disease duration, and disability in Iranian patients with MS which is in line with other previous studies in different ethnic groups.