Gender differences in lung cancer epidemiology - do Austrian male lung cancer patients still die earlier in life?

Objective: Previous analyses reported an unexpected decline of mean age of death of Austrian male lung cancer patients until 1996 and a subsequent turnaround of this epidemiological trend after the mid-1990s until 2007. In light of ongoing changes in smoking behavior of men and women, this study aims to investigate the development of mean age of death from lung cancer in Austria during the past three decades. Materials and methods: This study used data about the annual mean age of death from lung cancer, including malignant neoplasm of trachea, bronchus and lung, between 1992 and 2021 obtained from Statistics Austria, Federal Institution under Public Law. One-way analysis of variance (ANOVA) and independent samples t-tests were applied to explore any significant differences of mean values in the course of time as well as between men and women. Results: Overall, mean age of death of male lung cancer patients increased consistently throughout the observed time periods, whereas women did not show any statistically significant change in the last decades. Conclusion: Possible reasons for the reported epidemiological development are discussed in this article. Research and Public Health measures should increasingly focus on smoking behaviors of female adolescents.

Price Policy and Taxation as Effective Strategies for Tobacco Control.

Objective: Only 13% of the world's population are living in countries imposing appropriate tobacco tax-rates. This study aims to promote the implementation of price policy measures as a striking tobacco control strategy in Austria and to encourage other countries to further increase their taxes to WHO best-practice levels. Method: This study used the yearly economic data from Austria from 1997 to 2015. Applying a model for regression analysis, the price elasticity of total tobacco consumption was estimated. Results: Between 1997 and 2015 the price elasticity of demand for tobacco products (including cigarettes, cigars, and other tobaccos) was -0.661, however, the result is statistically insignificant. When excluding 2 anomalous years and removing a variable of the regression model the elasticity was -0.691 and statistically significant, indicating that a 1% increase in tobacco prices will result in a 0.691% decrease of tobacco consumption. Conclusion: The responsiveness of Austrian smokers to price changes has increased during the last decades. Because other activities showed no significance in the analysis, this study should encourage countries world-wide to use price policy and taxation more intensively in order to reduce smoking rates effectively.

Highly aminated iron oxide nanoworms for simultaneous manufacturing and labeling of chimeric antigen receptor T cells.

Cell based therapies including chimeric antigen receptor (CAR) T cells are promising for treating leukemias and solid cancers. At the same time, there is interest in enhancing the functionality of these cells via surface decoration with nanoparticles (backpacking). Magnetic nanoparticle cell labeling is of particular interest due to opportunities for magnetic separation, in vivo manipulation, drug delivery and magnetic resonance imaging (MRI). While modification of T cells with magnetic nanoparticles (MNPs) was explored before, we questioned whether MNPs are compatible with CAR-T cells when introduced during the manufacturing process. We chose highly aminated 120 nm crosslinked iron oxide nanoworms (CLIO NWs, ~36,000 amines per NW) that could efficiently label different adherent cell lines and we used CD123 CAR-T cells as the labeling model. The CD123 CAR-T cells were produced in the presence of CLIO NWs, CLIO NWs plus protamine sulfate (PS), or PS only. The transduction efficiency of lentiviral CD123 CAR with only NWs was ~23% lower than NW+PS and PS groups (~33% and 35%, respectively). The cell viability from these three transduction conditions was not reduced within CAR-T cell groups, though lower compared to non-transduced T cells (mock T). Use of CLIO NWs instead of, or together with cationic protamine sulfate for enhancement of lentiviral transduction resulted in comparable levels of CAR expression and viability but decreased the proportion of CD8+ cells and increased the proportion of CD4+ cells. CD123 CAR-T transduced in the presence of CLIO NWs, CLIO NWs plus PS, or PS only, showed similar level of cytotoxicity against leukemic cell lines. Furthermore, fluorescence microscopy imaging demonstrated that CD123 CAR-T cells labeled with CLIO NW formed rosettes with CD123+ leukemic cells as the non-labeled CAR-T cells, indicating that the CAR-T targeting to tumor cells has maintained after CLIO NW labeling. The in vivo trafficking of the NW labeled CAR-T cells showed the accumulation of CAR-T labeled with NWs primarily in the bone marrow and spleen. CAR-T cells can be magnetically labeled during their production while maintaining functionality using the positively charged iron oxide NWs, which enable the in vivo biodistribution and tracking of CAR-T cells.

Complement Inhibitors Block Complement C3 Opsonization and Improve Targeting Selectivity of Nanoparticles in Blood.

Complement is one of the critical branches of innate immunity that determines the recognition of engineered nanoparticles by immune cells. Antibody-targeted iron oxide nanoparticles are a popular platform for magnetic separations, in vitro diagnostics, and molecular imaging. We used 60 nm cross-linked iron oxide nanoworms (CLIO NWs) modified with antibodies against Her2/neu and EpCAM, which are common markers of blood-borne cancer cells, to understand the role of complement in the selectivity of targeting of tumor cells in whole blood. CLIO NWs showed highly efficient targeting and magnetic isolation of tumor cells spiked in lepirudin-anticoagulated blood, but specificity was low due to high uptake by neutrophils, monocytes, and lymphocytes. Complement C3 opsonization in plasma was predominantly via the alternative pathway regardless of the presence of antibody, PEG, or fluorescent tag, but was higher for antibody-conjugated CLIO NWs. Addition of various soluble inhibitors of complement convertase (compstatin, soluble CD35, and soluble CD55) to whole human blood blocked up to 99% of the uptake of targeted CLIO NWs by leukocytes, which resulted in a more selective magnetic isolation of tumor cells. Using well-characterized nanomaterials, we demonstrate here that complement therapeutics can be used to improve targeting selectivity.

Feraheme (Ferumoxytol) Is Recognized by Proinflammatory and Anti-inflammatory Macrophages via Scavenger Receptor Type AI/II.

Feraheme (ferumoxytol), a negatively charged, carboxymethyl dextran-coated ultrasmall superparamagnetic iron oxide nanoparticle (USPIO, 30 nm, -16 mV), is clinically approved as an iron supplement and is used off-label for magnetic resonance imaging (MRI) of macrophage-rich lesions, but the mechanism of recognition is not known. We investigated mechanisms of uptake of Feraheme by various types of macrophages in vitro and in vivo. The uptake by mouse peritoneal macrophages was not inhibited in complement-deficient serum. In contrast, the uptake of larger and less charged SPIO nanoworms (60 nm, -5 mV; 120 nm, -5 mV, respectively) was completely inhibited in complement deficient serum, which could be attributed to more C3 molecules bound per nanoparticle than Feraheme. The uptake of Feraheme in vitro was blocked by scavenger receptor (SR) inhibitor polyinosinic acid (PIA) and by antibody against scavenger receptor type A I/II (SR-AI/II). Antibodies against other SRs including MARCO, CD14, SR-BI, and CD11b had no effect on Feraheme uptake. Intraperitoneally administered PIA inhibited the peritoneal macrophage uptake of Feraheme in vivo. Nonmacrophage cells transfected with SR-AI plasmid efficiently internalized Feraheme but not noncharged ultrasmall SPIO of the same size (26 nm, -6 mV), suggesting that the anionic carboxymethyl groups of Feraheme are responsible for the SR-AI recognition. The uptake by nondifferentiated bone marrow derived macrophages (BMDM) and by BMDM differentiated into M1 (proinflammatory) and M2 (anti-inflammatory) types was efficiently inhibited by PIA and anti-SR-AI/II antibody. Interestingly, all BMDM types expressed similar levels of SR-AI/II. In conclusion, Feraheme is efficiently recognized via SR-AI/II but not via complement by different macrophage types. The recognition by the common phagocytic receptor has implications for specificity of imaging of macrophage subtypes.

Brain Iron Distribution after Multiple Doses of Ultra-small Superparamagnetic Iron Oxide Particles in Rats.

The purpose of this study is to determine the effects of high cumulative doses of ultra-small paramagnetic iron oxide (USPIO) used in neuroimaging studies. We intravenously administered 8 mg/kg of 2 USPIO compounds daily for 4 wk to male Sprague-Dawley rats (Crl:SD). Multiecho gradient-echo MRI, serum iron levels, and histology were performed at the end of dosing and after a 7-d washout period. R2* maps and quantitative susceptibility maps (QSM) were generated from multiecho gradient-echo data. R2* maps and QSM showed iron accumulation in brain ventricles on MR images acquired at the 4- and 5-wk time points. Estimates from QSM data showed ventricular iron concentration was equal to or higher than serum iron concentration. Histologic analysis revealed choroid plexus hemosiderosis and midbrain vacuolation, without iron deposition in brain parenchyma. Serum iron levels increased with administration of both compounds, and a 7-d washout period effectively reduced serum iron levels of one but not both of the compounds. High cumulative doses from multiple, frequent administrations of USPIO can lead to iron deposition in brain ventricles, resulting in persistent signal loss on T2*-weighted images. Techniques such as QSM are helpful in quantifying iron biodistribution in this situation.

Variability of Complement Response toward Preclinical and Clinical Nanocarriers in the General Population.

Opsonization (coating) of nanoparticles with complement C3 component is an important mechanism that triggers immune clearance and downstream anaphylactic and proinflammatory responses. The variability of complement C3 binding to nanoparticles in the general population has not been studied. We examined complement C3 binding to dextran superparamagnetic iron oxide nanoparticles (superparamagnetic iron oxide nanoworms, SPIO NWs, 58 and 110 nm) and clinically approved nanoparticles (carboxymethyl dextran iron oxide ferumoxytol (Feraheme, 28 nm), highly PEGylated liposomal doxorubicin (LipoDox, 88 nm), and minimally PEGylated liposomal irinotecan (Onivyde, 120 nm)) in sera from healthy human individuals. SPIO NWs had the highest variation in C3 binding (n = 47) between subjects, with a 15-30 fold range in levels of C3. LipoDox (n = 12) and Feraheme (n = 18) had the lowest levels of variation between subjects (an approximately 1.5-fold range), whereas Onivyde (n = 18) had intermediate between-subject variation (2-fold range). There was no statistical difference between males and females and no correlation with age. There was a significant correlation in complement response between small and large SPIO NWs, which are similar structurally and chemically, but the correlations between SPIO NWs and other types of nanoparticles, and between LipoDox and Onivyde, were not significant. The calculated average number of C3 molecules bound per nanoparticle correlated with the hydrodynamic diameter but was decreased in LipoDox, likely due to the PEG coating. The conclusions of this study are (1) all nanoparticles show variability of C3 opsonization in the general population; (2) an individual's response toward one nanoparticle cannot be reliably predicted based on another nanoparticle; and (3) the average number of C3 molecules per nanoparticle depends on size and surface coating. These results provide new strategies to improve nanomedicine safety.

SIRB, sans iron oxide rhodamine B, a novel cross-linked dextran nanoparticle, labels human neuroprogenitor and SH-SY5Y neuroblastoma cells and serves as a USPIO cell labeling control.

This is the first report of the synthesis of a new nanoparticle, sans iron oxide rhodamine B (SIRB), an example of a new class of nanoparticles. SIRB is designed to provide all of the cell labeling properties of the ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle Molday ION Rhodamine B (MIRB) without containing the iron oxide core. MIRB was developed to label cells and allow them to be tracked by MRI or to be manipulated by magnetic gradients. SIRB possesses a similar size, charge and cross-linked dextran coating as MIRB. Of great interest is understanding the biological and physiological changes in cells after they are labeled with a USPIO. Whether these effects are due to the iron oxide buried within the nanoparticle or to the surface coating surrounding the iron oxide core has not been considered previously. MIRB and SIRB represent an ideal pairing of nanoparticles to identify nanoparticle anatomy responsible for post-labeling cytotoxicity. Here we report the effects of SIRB labeling on the SH-SY5Y neuroblastoma cell line and primary human neuroprogenitor cells (hNPCs). These effects are contrasted with the effects of labeling SH-SY5Y cells and hNPCs with MIRB. We find that SIRB labeling, like MIRB labeling, (i) occurs without the use of transfection reagents, (ii) is packaged within lysosomes distributed within cell cytoplasm, (iii) is retained within cells with no loss of label after cell storage, and (iv) does not alter cellular viability or proliferation, and (v) SIRB labeled hNPCs differentiate normally into neurons or astrocytes. Copyright © 2016 John Wiley & Sons, Ltd.

Predictors of short-term success in smoking cessation in relation to attendance at a smoking cessation program.

INTRODUCTION: The identification of individual characteristics that predict success in smoking cessation is necessary to improve the effectiveness of smoking cessation efforts. The aim of this study was to identify the factors that predict success in smoking cessation in people who attended 2, 3, 4, or 5 sessions of a smoking cessation program. METHODS: The participants comprised 2,471 people who attended at least 2 consultations during a 5-week smoking cessation program. Success in smoking cessation was defined as self-reported abstinence and having an exhaled carbon monoxide level ≤10 parts per million at the final consultation. Baseline characteristics were compared using univariate analysis of variance and the chi-square test. A stepwise multivariate logistic regression model was used to analyze the effect of baseline characteristics and the slopes of the withdrawal symptoms on the success in smoking cessation. RESULTS: Participating in a higher number of sessions gradually increased the chance of smoking cessation from 12.1% to 61.2% (p < .0001). Logistic regression analysis revealed that the independent predictors of success in smoking cessation were being male; low nicotine dependence; smoking few cigarettes per day at baseline; having no history of depression; having low values for craving for cigarettes, irritability, frustration, anger, or nocturnal awakening at baseline; decreased craving for cigarettes and restlessness with time; and use of nicotine replacement therapy (NRT). People who attended more sessions tended to be older. CONCLUSIONS: Attending more sessions of a smoking cessation program, NRT, and coping with withdrawal and psychosocial symptoms increases the chance of short-term success in smoking cessation.

Trends in mortality and mean age at death from lung cancer in Austria (1975-2007).

OBJECTIVE: To investigate trends in mortality and mean age at death from lung cancer (MADLC) compared to mean age at death from all causes (MAD) over the period 1975 - 2007 in Austria. Results are assessed with respect to secular trends in smoking habits. METHODS: MAD and MADLC were computed by year and gender as the expected value of a fitted Weibull distribution. Age-period-cohort effects on lung cancer death rates were estimated by hierarchical Poisson models. RESULTS: In females MADLC was on average about 2 years higher than in males and tended to decrease since the mid 1980s, while after the mid 1990s MADLC in males increased such that the difference between men and women shrank to about half a year in 2007. Females dying from lung cancer lost about 6 years of life during the late 1970s but more than 10 years after 2000, while males lost 2 years in the 1970s and 5 years after 2000. Males demonstrated a decreasing risk with increasing year of birth, with the exception of cohorts born during or immediately after the World Wars that showed peak relative risks (RR). Females did not show pronounced birth cohort effect except for a peak RR for cohorts born during and after World War II. CONCLUSIONS: MADLC provides additional information about secular trends in addition to incidence data. The declining trend of MADLC in females and in males up to the mid 1990s points to a change of smoking habits with an earlier onset of smoking in both genders. The subsequent increase in males during the last decade may be attributed to an increasing proportion of quitters because smoking cessation delays onset of lung cancer.

[Outpatient smoking cessation: a report on 3,260 cases]. / Ambulante Raucherentwöhnung: Ein Bericht über 3.260 Fälle.

A total number of 3,260 smokers were included into a 4-week smoking cessation programme of the Regional Sickness Fund of Lower Austria in which participants were coached by health care professionals. The smoking status of each subject, as determined by measuring expired CO, resulted in a success rate of 70.6% (non-smokers and persons with smoking reduction). Success rates were emerged to increase with decreasing level of baseline nicotine dependence (determined with the Fagerström Test for Nicotine Dependence = FTND). Even in the group of heavily dependent smokers, however, (FTND Score 8-10) a non-smoking rate of 33.9% was achieved. Moreover, an additional 27.6% of the persons of this group had reduced the number of cigarettes smoked daily. The positive effect of nicotine replacement therapy (NRT) could be demonstrated by the high rate of 69.3% non-smokers in this group of participants, which was clearly higher than in participants who did not use NRT.

[Varenicline - pharmacological therapy of tobacco dependence]. / Vareniclin - medikamentöse Therapie der Tabakabhängigkeit.

Every year about 1.2 million deaths attributable to smoking occur in Europe. Effective smoking cessation, therefore, is essential. Varenicline is the first medication specifically developed for smoking cessation. The efficacy of varenicline in smoking cessation is due to its role as a partial agonist/antagonist at the alpha4beta2 nicotine receptors. This dual action causes a reduction in cigarette craving as well as withdrawal symptoms; moreover, it decreases the pleasurable and reinforcing effects of smoking. This article discusses the current clinical data regarding efficacy and safety of varenicline and its role in smoking cessation.

Assessing smoking behaviour among medical students by the measurement of expired carbon monoxide (CO).

Smoking behaviour and prevalence rates among medical students and medical professionals are important public health issues, as physicians' attitudes and interventions are decisive for the patients' success in quitting smoking. Studies dealing with prevalence rates of smoking usually use only face-to-face interviews or self-administered questionnaires, which may induce vague findings. Additional measurement of exhaled carbon monoxide is an objective, easy, immediate, non-invasive and inexpensive mode of indicating smoking behaviour and will complement and at some stage replace the usual question regarding the number of cigarettes consumed. CO-measurement of 260 medical students was taken during compulsory public health training at the Medical University Vienna. Definite indication of active smoking was found in 12% of the students, 9.5% showed CO-levels between 6 and 10 ppm and 78% were definitely non-smokers with a CO level between 0 and 5 ppm. The students had the opportunity to get to know an important diagnostic technique and additionally learned about their own smoking habits.

[Smoking cessation with nicotine replacement therapy (NRT) - a scientific update]. / Rauchausstieg mit Nikotinersatztherapie - ein Update.

Nicotine replacement therapy (NRT) is available in various application forms for the treatment of tobacco addiction. All forms underwent a comprehensive clinical study program (approx. 132 trial) to research on efficacy, safety and influence of environmental conditions. Nicotine gum, patch, nasal spray, microtab, lozenge and inhaler are recommended based on evidence criteria (OR 1.5 to 3.6, variation based on usage conditions and application form. NRT forms are OTC medicines (Exception: Nicotine nasal spray). The quality and the certainty of the nicotine replacement therapy will be enhanced by reflecting considerations concerning the indication, correlation of single NRT form to the appropriate user as well as the right dosage and compliance matters.

Nocturnal sleep-disturbing nicotine craving and accomplishment with a smoking cessation program.

AIMS: To study nocturnal sleep-disturbing nicotine craving (NSDNC), described as a symptom of nicotine dependence, in 2884 patients. METHODS: All patients were part of a smoking cessation program of the Nicotine Institute in collaboration with the general sick fund of Lower Austria. During the study period, the program (which is ongoing) lasted five weeks and included individual counseling. At all appointments, patients received a questionnaire about smoking habits, illnesses, previous experience in smoking cessation and their motivation to complete the program with the help of an assistant. Carbon monoxide levels in expired air were also measured. RESULTS: Analysis of NSDNC showed that 22.4% (n = 647) of patients suffered from this symptom with varying intensity: 77.1% (n = 499) awoke rarely; 9.4% (n = 61) awoke several times per week; 6.8% (n = 44) awoke most days and 6.6% (n = 43) awoke daily. NSDNC was associated with nicotine dependence, the number of cigarettes smoked per day, CO level and the craving for cigarettes in general. Consequences for smoking cessation programs are complex. Success rates were influenced by the intensity of NSDNC. Patients who awoke most days or daily had the lowest chance to quit smoking and the lowest compliance with the program. CONCLUSIONS: Patients suffering from NSDNC, especially those who awoke most days or daily, formed a specific group among cigarette smokers. They can be classified as highly dependent smokers who have special needs regarding treatment strategies and medication. Further developments of specific cessation programs and strategies of tobacco harm reduction are recommended.

Synthesis of ultrasmall superparamagnetic iron oxides using reduced polysaccharides.

Investigation into the effect of the reducing sugar of dextran on formation and stability of dextran-coated ultrasmall superparamagnetic iron oxides (USPIO) has demonstrated that reduction of the terminal reducing sugar can have a significant effect on particle size, coating stability, and magnetic properties. Four aspects of polysaccharide-coated USPIO particle synthesis were investigated: (i) the effect reduction of the terminal polysaccharide sugar has upon polysaccharide usage, particle size, stability, and magnetic susceptibility; (ii) the effect an exogenous reducing sugar can have upon particle synthesis; (iii) the effect the molecular weight of the reduced polysaccharide has on particle synthesis; and (iv) the effectiveness of reduced and native dextrans in stabilizing a preformed magnetic sol. For low molecular weight dextrans (MW 20,000 x 10(-6) cgs). Similar results were obtained with a 12 kDa pullulan. The effect of polysaccharide molecular weight on particle size was studied, wherein higher molecular weight reduced dextrans produced larger particles. The effectiveness of the reduced and native dextrans in stabilizing a preformed magnetic sol was compared. Reduced dextrans were found to be superior for stabilizing the magnetic sol. The observed effects of reduction of the terminal sugar in dextran compared with the native dextran were modeled using the Langmuir adsorption isotherm. A good fit of experimental data with this model was found.