Prognostic impact of gross tumor volume during radical radiochemotherapy of locally advanced non-small cell lung cancer-results from the NCT03055715 multicenter cohort study of the Young DEGRO Trial Group.

BACKGROUND: In radical radiochemotherapy (RCT) of inoperable non-small-cell lung cancer (NSCLC) typical prognostic factors include T- and N-stage, while there are still conflicting data on the prognostic relevance of gross tumor volume (GTV) and particularly its changes during RCT. The NCT03055715 study of the Young DEGRO working group of the German Society of Radiation Oncology (DEGRO) evaluated the prognostic impact of GTV and its changes during RCT. METHODS: A total of 21 university centers for radiation oncology from five different European countries (Germany, Switzerland, Spain, Belgium, and Austria) participated in the study which evaluated n = 347 patients with confirmed (biopsy) inoperable NSCLC in UICC stage III A/B who received radical curative-intent RCT between 2010 and 2013. Patient and disease data were collected anonymously via electronic case report forms and entered into the multi-institutional RadPlanBio platform for central data analysis. GTV before RCT (initial planning CT, GTV1) and at 40-50 Gy (re-planning CT for radiation boost, GTV2) was delineated. Absolute GTV before/during RCT and relative GTV changes were correlated with overall survival as the primary endpoint. Hazard ratios (HR) of survival analysis were estimated by means of adjusted Cox regression models. RESULTS: GTV1 was found to have a mean of 154.4 ml (95%CI: 1.5-877) and GTV2 of 106.2 ml (95% CI: 0.5-589.5), resulting in an estimated reduction of 48.2 ml (p < 0.001). Median overall survival (OS) was 18.8 months with a median of 22.1, 20.9, and 12.6 months for patients with high, intermediate, and low GTV before RT. Considering all patients, in one survival model of overall mortality, GTV2 (2.75 (1.12-6.75, p = 0.03) was found to be a stronger survival predictor than GTV1 (1.34 (0.9-2, p > 0.05). In patients with available data on both GTV1 and GTV2, absolute GTV1 before RT was not significantly associated with survival (HR 0-69, 0.32-1.49, p > 0.05) but GTV2 significantly predicted OS in a model adjusted for age, T stage, and chemotherapy, with an HR of 3.7 (1.01-13.53, p = 0.04) per 300 ml. The absolute decrease from GTV1 to GTV2 was correlated to survival, where every decrease by 50 ml reduced the HR by 0.8 (CI 0.64-0.99, p = 0.04). There was no evidence for a survival effect of the relative change between GTV1 and GTV2. CONCLUSION: Our results indicate that independently of T stage, the re-planning GTV during RCT is a significant and superior survival predictor compared to baseline GTV before RT. Patients with a high absolute (rather than relative) change in GTV during RT show a superior survival outcome after RCT.

Customizing hydrothermal properties of inkjet printed sensitive films by functionalization of carbon nanotubes.

Multiwalled carbon nanotubes (MWCNTs) are attractive materials for realizing sensors, owing to their high aspect ratio associated with excellent mechanical, electronic, and thermal properties. Moreover, their sensing properties can be tuned by introducing functional groups on their framework and adjusting the processing conditions. In this paper, we investigate the potential of functionalized CNTs for humidity and temperature sensing by optimization of the functionalization, the processing conditions and the printing conditions. The morphology of the differently functionalized MWCNTs is investigated by infrared spectroscopy (IR), scanning electron microscopy, thermogravimetry (TG) and TG-coupled mass-spectrometric studies. Using the functionalized MWCNTs, films were fabricated with different numbers of layers (4, 6, 8, 10 layers) via inkjet printing on a flexible polyimide substrate containing an interdigital microelectrode. The influence of hydrothermal effects was investigated. The sensitivity to humidity is higher for films prepared with MWCNTs functionalized with a high sonication amplitude and a bigger number of layers due to enhancements of hydrophilicity and water mobility. A higher sensitivity to temperature is achieved by a low sonication amplitude and a small number of layers. For the encapsulation of the temperature sensor against humidity, a Bectron layer is proposed, which reduces also the hysteresis effect. This study demonstrates the efficiency of carboxylic functionalized MWCNTs deposit by inkjet printing for realization of sensitive and cost-effective humidity and temperature sensors. It provides a real example for the interesting contribution of functionalization procedures to the sensing properties of MWCNTs films.

Aviation Contrail Cirrus and Radiative Forcing Over Europe During 6 Months of COVID-19.

The COVID-19 pandemic led to a 72% reduction of air traffic over Europe in March-August 2020 compared to 2019. Modeled contrail cover declined similarly, and computed mean instantaneous radiative contrail forcing dropped regionally by up to 0.7 W m-2. Here, model predictions of cirrus optical thickness and the top-of-atmosphere outgoing longwave and reflected shortwave irradiances are tested by comparison to Meteosat-SEVIRI-derived data. The agreement between observations and modeled data is slightly better when modeled contrail cirrus contributions are included. The spatial distributions and diurnal cycles of the differences in these data between 2019 and 2020 are partially caused by differences in atmospheric and surface conditions, particularly for solar radiation in the spring of 2020. Aviation signals become discernible in the observed differences of these data between 2019 and 2020 when subtracting numerical weather prediction model results that approximate the atmosphere and surface conditions without contrails.

DEGRO practical guideline for partial-breast irradiation.

PURPOSE: This consensus statement from the Breast Cancer Working Group of the German Society for Radiation Oncology (DEGRO) aims to define practical guidelines for accelerated partial-breast irradiation (APBI). METHODS: Recent recommendations for relevant aspects of APBI were summarized and a panel of experts reviewed all the relevant literature. Panel members of the DEGRO experts participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for implementing APBI in clinical routine, focusing on patient selection, target definition, and treatment technique. RESULTS: Appropriate patient selection, target definition for different APBI techniques, and basic rules for appropriate APBI techniques for clinical routine outside of clinical trials are described. Detailed recommendations for APBI in daily practice, including dose constraints, are given. CONCLUSION: Guidelines are mandatory to assure optimal results of APBI using different techniques.

[Description of a Multidimensional Health Program for Informal Caregivers]. / Beschreibung eines mehrdimensionalen Gesundheitsprogramms für pflegende Angehörige.

The aim of this study is to describe the concept of a prevention program for informal caregivers and its fit into stress theory and quality criteria. The program combines a 4-day group intervention outside the home with individual professional care in familiar domestic surroundings (family health care for persons with high burden, home training for specific care aspects). The program applies strategies focusing on problems and emotions. The program can be financed by social security funds. The 4-day respite service closes a gap in health services for informal caregivers.

[Prediction and Prevention of Dropouts in Vocational Retraining]. / Prognose und Verhinderung von Abbrüchen bei Qualifizierungen in der beruflichen Rehabilitation.

UNLABELLED: Principal objective: To verify if a psychological intervention targeting individuals with high resignation tendency prevents dropouts in vocational retraining. For individuals with high resignation tendency a high risk of dropping out was assumed under regular conditions. METHOD: Data was collected at 2 adult education institutes. At the beginning of vocational training the occupational inventory Work-related Behaviour and Experience Patterns (AVEM) was used. The questionnaire allows to classify 4 types of coping behaviour. G: healthy-ambitious, S: unambitious, A: excessively ambitious, B: resigned. Using a quasi-experimental design, the effect of resilience building was verified by comparing a treatment group with a control group. Control group was offered the usual treatment of the education institute. The treatment group was additionally offered two individual meetings and a work-related group treatment focussing on coping behaviour. RESULTS: Given a very high resignation tendency in both groups, dropping out of rehabilitation was less frequent in the treatment group. Other individuals tended to drop out more frequently, but this is not statistically significant. CONCLUSION: The study shows that work-related resilience building helps to minimize risk of dropping out of vocational rehabilitation in the case of extremely resigned coping behaviour.

A simple and inexpensive method to control oxygen concentrations within physiological and neoplastic ranges.

Traditional methods for regulating oxygen concentration ([O2]) in in vitro experiments over the range found in normal and tumor tissues require the use of expensive equipment to generate controlled gas atmospheres or the purchase of a range of gas cylinders with certified O2 percentages. Here we describe a simple and inexpensive enzymatic method for generating low, precise steady-state [O2] levels that are stable for several hours. This method is particularly applicable to the in vitro study of some classes of hypoxia-targeted antitumor prodrugs and bioreductively activated agents.

Nasal levels of soluble IL-33R ST2 and IL-16 in allergic rhinitis: inverse correlation trends with disease severity.

BACKGROUND: Serum levels of IL-16, IL-33 and the decoy receptor of IL-33, soluble ST2, are elevated in allergic rhinitis. Recent studies show that IL-16, soluble ST2 or anti-IL-33 reduce type 2 cytokines (such as IL-5) and eosinophilia in murine models of allergic asthma or allergic rhinitis respectively. OBJECTIVE: In this study, we studied the release of IL-5, IL-16, IL-33 and soluble ST2 in allergic rhinitis patients after nasal allergen challenge and natural pollen exposure. METHODS: The nasal lavages of 15 allergic and 14 non-allergic volunteers were collected during the pollen allergy season. In addition, six allergic volunteers underwent unilateral nasal allergen and control challenge out of season and nasal secretions and sera were collected. IL-5, IL-16, IL-33 and soluble ST2 in nasal secretions and sera were measured by electrochemiluminescent assay or ELISA, respectively. RESULTS: Nasal IL-5, IL-16 and soluble ST2 levels were significantly increased in seasonally pollen exposed allergic volunteers compared to control subjects (P < 0.001, P = 0.018 and P = 0.002 respectively), whereas IL-33 remained undetectable. Nasal IL-16 showed a weak inverse correlation trend with nasal symptoms (r = -0.48, P = 0.07). Nasal soluble ST2 concentrations were inversely correlated with nasal symptoms (r = -0.61, P = 0.02) and positively correlated with IL-16 (r = 0.56, P = 0.03). Significant increases of nasal IL-5, IL-16 and ST2 but not IL-33 were observed after nasal allergen challenge. At 24 h after allergen challenge, local ST2 and IL-5 concentrations showed an inverse correlation trend (r = -0.83, P = 0.04). Serum levels of IL-5, IL-16 and soluble ST2 rose in at least five of six volunteers tested at 5 or 24 h post-challenge. CONCLUSIONS AND CLINICAL RELEVANCE: The observed upregulation of soluble ST2 and IL-16 after nasal allergen challenge and during peak pollination season suggests potential regulatory roles of these cytokines in the inflammatory reaction in allergic rhinitis.

HDR brachytherapy: an option for preventing nonmalignant obstruction in patients after lung transplantation.

PURPOSE: Interventional bronchoscopy is the main treatment modality in managing benign airway obstructions following lung transplantation. We analyzed the effect of intraluminal brachytherapy on preventing recurrence of hyperplastic tissue. PATIENTS AND METHODS: From September 2002 to September 2004, a total of 24 intraluminal brachytherapy applications were carried out on 12 lung transplant patients in 15 different locations. A single dose of 3 Gy was calculated at a 5-mm distance from the catheter surface; the target volume included a stenosis plus safety interval of 0.5-1.0 cm. RESULTS: All patients had a mean 10.6 local interventions (Argon plasma coagulation, balloon dilatations, stenting) over 4.4 months before the first application of endobronchial brachytherapy, with a mean amount of 2.4 applications per month. The mean forced expiratory volume in 1 s (FEV1) was 2,219 ml in the 3 months before application of brachytherapy. After endobronchial brachytherapy, all patients experienced improvement in clinical status and respiratory function. The mean level of FEV1 in the 3 months after application was 2,435 ml (p = 0.02), and the number of invasive interventions dropped to a mean rate of 5.2 interventions in the 5.1 months after the first intervention, with an amount of 1 application per month. No treatment-related complications were seen. Four patients were treated twice, 1 patient three times, and 1 patient four times at the same localization. CONCLUSIONS: Recurrent symptomatic benign airway obstruction from hyperplastic tissue in the bronchus after lung transplantation can be successfully treated with intraluminal high-dose-rate brachytherapy with a dose of 3 Gy at a 5-mm distance from the catheter surface and a longitudinal safety margin of 1 cm.

pH-dependent bending in and out of purple membranes comprising BR-D85T.

The light-driven proton pump bacteriorhodopsin (BR) embedded in a purple membrane (PM) from Halobacterium salinarum undergoes a series of conformational changes while transporting a proton from the cytoplasmic to the extracellular side over the course of the so-called photocycle. Wild-type BR variant D85T, where aspartic acid 85 is replaced by threonine, allows for the study of structural intermediates of this photocycle that are formed in a light-dependent manner in the wild-type and in thermal equilibrium by tuning the pH of the D85T purple membrane suspension. Especially the last and least studied O-intermediate of the photocycle of bacteriorhodopsin has caught recent attention. First AFM images of D85T under acidic conditions resembling wild-type BR under physiological conditions in the O-photocycle-intermediate are presented. Bacteriorhodopsins embedded in the strongly bent purple membranes were analyzed by single molecule force spectroscopy (SMFS) providing the first single molecule force spectra of BR in the O-intermediate. SMFS was further employed to determine the absolute sign of membrane curvature. Complementary electrostatic force microscopy (EFM) was performed to support PM side discrimination and determination of the bending direction. Bending of PM-D85T was analyzed in more detail providing further insight into the structure-function relationship of the bacteriorhodopsin proton pump as well as PM behaviour at the solid-liquid junction. Findings reported here are of general interest to the field of chemomechanical transducers.

Bending of purple membranes in dependence on the pH analyzed by AFM and single molecule force spectroscopy.

The first AFM images of strongly bent purple membranes as well as the first single molecule force spectra of bacteriorhodopsins embedded therein are presented. AFM images of purple membranes to date always showed a flat membrane topology. Bacteriorhodopsin variants like BR-D85N and BR-D85T resemble an intermediate state of wild-type BR which is slightly 'wedge'-shaped. Due to the strong interaction within the 2-D crystalline lattice of the purple membrane, the geometrical anisotropy of the individual bacteriorhodopsins adds up to a macroscopic change in the geometry of the purple membranes. Instead of being flat they appear like domes at physiological conditions. Single molecule force spectroscopy was employed to determine the absolute sign of the membrane curvature. As the bacteriorhodopsins in the center of the dome-like purple membranes are not supported by any solid state substrate, the presented force spectra are the first of non-supported bacteriorhodopsin, resembling the natural occurrence in the halobacterial cell.

Mississippi deltaic wetland survival: sedimentation versus coastal submergence.

Seasonal sedimentation, measured with the aid of artificial marker horizons, was markedly different in deteriorating as compared with stable marshes in the Mississippi River deltaic plain. Deteriorating marshes receive most sediment during storm events, whereas stable marshes receive substantial amounts of sediments during the spring river flood. The deteriorating marshes are accreting at a faster rate (1.5 centimeters per year at streamside, 0.9 centimeter per year at inland areas) than the stable marshes (1.3 centimeters per year at streamside, 0.6 centimeter per year at inland areas). However, relative to local apparent sea-level rise as measured by tide gauges in each area, the deteriorating marshes are not maintaining their intertidal elevation as well as the stable marshes. These results indicate the importance of considering accretion relative to submergence.

Health-related quality of life in elderly cancer patients, elderly non-cancer patients and an elderly general population.

Health-related quality of life (QoL) is a major topic within the care for cancer patients (CP). Compared with the general population (GP), QoL of CP is worse in most dimensions; however, only few data comparing QoL of CP with that of other patients have been provided so far. We determined QoL with the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire in hospitalized patients aged 60 years and older: 195 CP and 130 patients treated for other medical disorders (MP). In addition, data were compared with an age- and gender-stratified German GP. Explorative statistical analyses were performed. The CP aged >or=70 years compared with those aged 60-69 years had decreased QoL in two scales, physical and cognitive functioning, MP in four scales, physical and role functioning, fatigue and dyspnoea respectively. Compared with the GP, both CP and MP had worse QoL in almost all scales. The CP and MP differed in two of 15 scales only, with CP having lower scores in emotional functioning and more loss of appetite. In conclusion, reduced QoL in elderly CP compared with GP cannot solely be attributed to the diagnosis of cancer, but also to a medical disorder requiring inpatient hospital care.

Systemic serum amyloid A as a biomarker for exposure to zinc and/or copper-containing metal fumes.

Zinc- and copper-containing welding fumes increase systemic C-reactive protein (CRP). The aim of this study was to investigate the performance of the biomarkers serum amyloid A (SAA) and soluble vascular cell adhesion molecule-1 (VCAM-1) in this regard. Fifteen male subjects were exposed under controlled conditions to welding fumes containing either zinc, or copper, or copper and zinc for 6 h. Plasma samples were collected before, 6 and 24 h after start of exposure and biomarkers therein were measured by electrochemiluminescent assay. For each exposure, systemic concentrations of systemic SAA, but not VCAM-1, increased significantly at 24 h after exposure start compared with baseline ("copper only": P=0.0005, "zinc only": P=0.027, "copper and zinc": P=0.001). SAA showed a wider range of concentrations than did CRP and its levels increased up to 19-fold after welding fume exposure. The recognition of copper as a potential harmful component in welding fumes, also independent from zinc, deserves further consideration. SAA might represent a new sensitive biomarker for potential subclinical sterile inflammation after inhalation of copper- and/or zinc-containing welding fumes. As elevations of CRP and SAA protein have both been linked to a higher risk for cardiovascular disease, these findings might particularly be important for long-term welders.

Human nasal mucosal C-reactive protein responses after inhalation of ultrafine welding fume particles: positive correlation to systemic C-reactive protein responses.

Exposures to occupationally relevant ultrafine, zinc- and copper-containing welding fumes cause inflammatory responses involving systemic IL-6, C-reactive protein (CRP) and serum amyloid A (SAA), all associated with elevated risk of cardiovascular events. We investigated whether the systemic response is preceded by nasal inflammatory reactions. Fifteen nonsmoking male subjects were exposed for 6 h under controlled conditions to zinc-/copper-containing welding fumes (at 2.5 mg/m3) or ambient air control in a randomized order. Nasal secretions were collected before and at 1, 3, 6, 10, and 29 h after exposure. Nasal levels of selected biomarkers were determined by electrochemiluminescent assays and related to their systemic levels. Nasal interferon-γ (IFN-γ) peaked significantly 1 h after start of exposure compared to baseline. Nasal CRP as well as SAA increased significantly at 10 and 29 h compared to baseline. Receiver operating characteristic (ROC) curve analysis for differentiating welding fume from control exposure was performed: The highest area under ROC curve (AUC) values were found for the CRP increases (10, 29 h versus 0 h): AUC = 0.83, and for IFN-γ increases (1 h versus 0 h): AUC = 0.92. Nasal and systemic changes of CRP at 29 h revealed a strong correlation (Spearman rank test: increases compared to baseline: r = 0.815, p = 0.0022; absolute levels: r = 0.9, p = 0.0002). In conclusion, short-term exposure to a zinc- and copper-containing welding fume causes significant increases of inflammatory mediators in nasal mucosal lining fluid. Therefore, measurement of nasal inflammatory mediators may provide a useful means for occupational surveillance of workers exposed to ultrafine metal fume particles.

Videocapsule endoscopy is useful for the diagnosis of intestinal lymphangiectasia.

We study two authentic cases of protein-losing enteropathy, the diagnosis of which was facilitated using Given M2A videocapsule endoscopy. The first case corresponded to a primary intestinal lymphangiectasia confirmed by jejunum biopsies and the second one to a protein-losing enteropathy with lymphatic abnormalities secondary to a chronic constrictive pericarditis. In the first case, the mucosa of jejunum presented with a diffuse oedematous aspect, whitish villi, white curved lines probably related to submucosal dilated lymphatics and lacteal juice. In the second case, capsule endoscopy showed oedematous aspect of jejunum mucosa associated with white curved lines similar to those observed in the first case. Videocapsule endoscopy is useful in cases of protein-losing enteropathy to identify presence of intestinal lymphangiectasia and to specify their localisation after ruling out other disorders liable to induce protein-losing gastrointestinal syndrome.

Estradiol regulation of the human retinoic acid receptor alpha gene in human breast carcinoma cells is mediated via an imperfect half-palindromic estrogen response element and Sp1 motifs.

Estrogen receptor (ER)-positive human breast carcinoma (HBC) cell lines express significantly higher levels of retinoic acid receptor alpha (RAR alpha) (isoform 1) mRNA than ER-negative HBCs. Estradiol enhances RAR alpha mRNA expression in different ER-positive HBCs by 2-3-fold, which in turn results in increased sensitivity of ER-positive HBCs to the growth inhibitory effects of retinoic acid. To investigate the regulatory mechanisms of estradiol-mediated enhancement of RAR alpha mRNA expression, the functional promoter for the human RAR alpha isoform 1 was cloned and used to assess estradiol-mediated promoter-dependent enhancement of firefly luciferase reporter gene activity in transiently transfected ER-positive (MCF-7 and T47D) and ER-negative (MDA-MB-231) HBCs. Deletional promoter constructs were obtained to further delineate the promoter region responsible for estradiol-mediated enhancement of promoter activity. Here, we present evidence that approximately 130 bp of the promoter fragment preceding the transcriptional start site are responsible for estradiol-mediated enhancement of hRAR alpha gene expression. The estradiol-mediated enhancement is dependent on ER binding. Further deletional analysis showed that a promoter sequence of 42 base pairs, located approximately 100 bases upstream of the transcriptional start site, contains elements for estradiol-mediated enhancement. Specific deletion of either the Sp1 motif or mutations in the imperfect half-palindromic estrogen response element motif of this fragment abolish its estradiol responsiveness in transient transfections.

Regulation of the human retinoic acid receptor alpha gene in the estrogen receptor negative human breast carcinoma cell lines SKBR-3 and MDA-MB-435.

Estradiol-mediated enhancement of retinoic acid receptor alpha (RARalpha) expression in the estrogen receptor (ER)-positive human breast carcinoma (HBC) cells results in their sensitivity to RA-mediated growth inhibition (A. K. Rishi et al., Cancer Res., 55: 4999-5006, 1995). Most ER-negative HBCs are known to express lower levels of RARalpha and are resistant to RA-mediated inhibition of growth. We show that ER-negative SKBR-3 and MDA-MB-435 HBCs express approximately 2-fold higher levels of RARalpha isoform 1 mRNA when compared to the ER-negative MDA-MB-231 and MDA-MB-468 HBCs. SKBR-3 cells are sensitive to growth inhibition by RA, and by using RARalpha-selective synthetic retinoids, we demonstrate that the antiproliferative effects of RA in the SKBR-3 cell line are accomplished, in part, via activation of RARalpha. Both MDA-MB-231 and MDA-MB-468 HBCs are not growth inhibited by RA or any of the retinoids tested. Transient transfection experiments using a 5.0-kb RARalpha promoter fragment fused to the luciferase reporter gene showed 2-3-fold higher transcriptional activation in SKBR-3 cells when compared to MDA-MB-468 cells. We report identification of a 72-bp fragment of RARalpha promoter that contains unique cis elements responsible for mediating an estradiol-independent 2.5-fold enhancement of RARalpha gene expression in SKBR-3 and MDA-MB-435 cells.

Reversal of mitomycin C resistance by overexpression of bioreductive enzymes in Chinese hamster ovary cells.

The clinical utility of antineoplastic agents is limited by the development of drug resistance by tumors. Mitomycin C (MC) is a bacterial product that must be enzymatically reduced to exert anticancer activity. We have demonstrated that expression of the bacterial MC resistance-associated (MCRA) protein in Chinese hamster ovary (CHO) cells confers profound resistance to this antibiotic under aerobic conditions, but not under hypoxia. MCRA produces resistance to MC by redox cycling of the activated hydroquinone intermediate back to the prodrug form. A CHO cell line developed by stepwise exposure to increasing concentrations of MC likewise expressed high level resistance to MC in air, but not under hypoxia. The overexpression of DT-diaphorase and NADPH:cytochrome c (P-450) reductase, two enzymes known to activate MC, restored sensitivity to MC in both MCRA-transfected and drug-selected cell lines. The level of sensitization was proportional to the quantity of enzyme activity expressed, supporting the concept that the levels of these two activating enzymes are important for sensitivity to MC. The findings of resistance to MC in air but not under hypoxic conditions and of restoration of sensitivity to MC by increasing levels of DT-diaphorase activity, properties not adequately explained by other resistance mechanisms (i.e., decreases in MC activation, repair of DNA lesions, and/or drug efflux), support the hypothesis that a functional mammalian homologue of MCRA may be involved in producing resistance to MC.