Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma.

Deciphering the cell-state transitions underlying immune adaptation across time is fundamental for advancing biology. Empirical in vivo genomic technologies that capture cellular dynamics are currently lacking. We present Zman-seq, a single-cell technology recording transcriptomic dynamics across time by introducing time stamps into circulating immune cells, tracking them in tissues for days. Applying Zman-seq resolved cell-state and molecular trajectories of the dysfunctional immune microenvironment in glioblastoma. Within 24 hours of tumor infiltration, cytotoxic natural killer cells transitioned to a dysfunctional program regulated by TGFB1 signaling. Infiltrating monocytes differentiated into immunosuppressive macrophages, characterized by the upregulation of suppressive myeloid checkpoints Trem2, Il18bp, and Arg1, over 36 to 48 hours. Treatment with an antagonistic anti-TREM2 antibody reshaped the tumor microenvironment by redirecting the monocyte trajectory toward pro-inflammatory macrophages. Zman-seq is a broadly applicable technology, enabling empirical measurements of differentiation trajectories, which can enhance the development of more efficacious immunotherapies.

Glioma progression is shaped by genetic evolution and microenvironment interactions.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Identification, Organic Synthesis, and Sensitive Analysis of a cis-Homosalate-Specific Exposure Biomarker.

Homosalate (HMS) is an organic UV filter used in sunscreens and personal care products. Despite its widespread use and detection in environmental matrices, little is known regarding its exposure in humans. HMS is used as a mixture of cis- and trans-isomers, and we recently revealed major differences in human toxicokinetics, indicating the need to consider these isomers separately in exposure and risk assessments. In the course of these previous investigations of human HMS toxicokinetics, we identified two trans-HMS-specific and one cis-HMS-specific biomarker candidates. However, the latter lacks sensitivity due to only low amounts excreted in urine, prompting the search for another cis-HMS-specific biomarker. Our toxicokinetic investigations revealed a total of five isomers of HMS carboxylic acid metabolites (HMS-CA). Of these, only one was specifically formed from cis-HMS (HMS-CA 5), but its full identity in terms of constitution and configuration had, so far, not been elucidated. Here, we describe the synthesis of three HMS-CA isomers, of which the isomer (1R,3S,5S)/(1S,3R,5R)-3-((2-hydroxybenzoyl)oxy)-1,5-dimethylcyclohexane-1-carboxylic acid turned out to be HMS-CA 5. Taken together with two previously synthesized HMS-CA isomers, we were able to identify the constitution and configuration of all five HMS-CA isomers observed in human metabolism. We integrated the newly identified cis-HMS-specific metabolite HMS-CA 5 into our previously published human biomonitoring LC-MS/MS method. Intra- and interday precisions had coefficients of variation below 2% and 5%, respectively, and the mean relative recovery was 96%. The limit of quantification in urine was 0.02 µg L-1, enabling the quantification of HMS-CA 5 in urine samples for at least 96 h after sunscreen application. The extended method thus enables the sensitive and separate monitoring of cis- and trans-HMS in future human biomonitoring studies for exposure and risk assessment.

Toxicokinetics of homosalate in humans after dermal application: applicability of oral-route data for exposure assessment by human biomonitoring.

Homosalate (HMS) is a UV filter used in sunscreens and personal care products as a mixture of cis- and trans-isomers. Systemic absorption after sunscreen use has been demonstrated in humans, and concerns have been raised about possible endocrine activity of HMS, making a general population exposure assessment desirable. In a previous study, it was shown that the oral bioavailability of cis-HMS (cHMS) is lower than that of trans-HMS (tHMS) by a factor of 10, calling for a separate evaluation of both isomers in exposure and risk assessment. The aim of the current study is the investigation of HMS toxicokinetics after dermal exposure. Four volunteers applied a commercial sunscreen containing 10% HMS to their whole body under regular-use conditions (18-40 mg HMS (kg bw)-1). Parent HMS isomers and hydroxylated and carboxylic acid metabolites were quantified using authentic standards and isotope dilution analysis. Further metabolites were investigated semi-quantitatively. Elimination was delayed and slower compared to the oral route, and terminal elimination half-times were around 24 h. After dermal exposure, the bioavailability of cHMS was a factor of 2 lower than that of tHMS. However, metabolite ratios in relation to the respective parent isomer were very similar to the oral route, supporting the applicability of the oral-route urinary excretion fractions for dermal-route exposure assessments. Exemplary calculations of intake doses showed margins of safety between 11 and 92 (depending on the approach) after single whole-body sunscreen application. Human biomonitoring can reliably quantify oral and dermal HMS exposures and support the monitoring of exposure reduction measures.

[Immunotherapy against gliomas]. / Immuntherapie gegen Gliome.

BACKGROUND: Gliomas represent the most frequent malignant primary brain tumors in adults. Despite multimodal treatment concepts involving surgery, irradiation and chemotherapy, the prognosis remains poor and they are incurable. Recent insights into the interactions between the immune system and the central nervous system as well as breakthroughs in the results of other cancer types have led to the fact that various immunotherapeutic approaches against gliomas have also been investigated and in some cases specifically developed. OBJECTIVE: This article provides an overview of the current status of different immunotherapeutic concepts against gliomas, highlighting the advantages, disadvantages, and challenges. Additionally, it provides an overview of currently ongoing immunotherapeutic clinical trials in Germany and neighboring countries. RESULTS: Previous randomized studies on antibodies against programmed cell death protein 1 (anti-PD1) immune checkpoint inhibition, viral treatment and peptide vaccination targeting the variant III of the epidermal growth factor receptor (EGFRvIII) in glioblastomas were negative with respect to survival benefits. Conversely, other immunotherapeutic approaches, such as multivalent or driver mutation-based vaccinations, cytokine-based therapy and cell therapy, demonstrated a robust scientific foundation, with at least early studies showing promising safety and pharmacodynamic effects on the tumors. DISCUSSION: Currently, immunotherapies against gliomas should only be applied within the framework of well-designed clinical studies. There are still many knowledge gaps regarding the mechanisms of action and resistance of various immunotherapies. Accompanying translational research is essential to address these gaps and develop more effective therapies.

A T-cell antigen atlas for meningioma: novel options for immunotherapy.

Meningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood-brain barrier, they might be an accessible target for immunotherapy. However, the landscape of naturally presented tumor antigens in meningioma is unknown. We here provide a T-cell antigen atlas for meningioma by in-depth profiling of the naturally presented immunopeptidome using LC-MS/MS. Candidate target antigens were selected based on a comparative approach using an extensive immunopeptidome data set of normal tissues. Meningioma-exclusive antigens for HLA class I and II are described here for the first time. Top-ranking targets were further functionally characterized by showing their immunogenicity through in vitro T-cell priming assays. Thus, we provide an atlas of meningioma T-cell antigens which will be publicly available for further research. In addition, we have identified novel actionable targets that warrant further investigation as an immunotherapy option for meningioma.

An engineered 4-1BBL fusion protein with "activity on demand".

Engineered cytokines are gaining importance in cancer therapy, but these products are often limited by toxicity, especially at early time points after intravenous administration. 4-1BB is a member of the tumor necrosis factor receptor superfamily, which has been considered as a target for therapeutic strategies with agonistic antibodies or using its cognate cytokine ligand, 4-1BBL. Here we describe the engineering of an antibody fusion protein, termed F8-4-1BBL, that does not exhibit cytokine activity in solution but regains biological activity on antigen binding. F8-4-1BBL bound specifically to its cognate antigen, the alternatively spliced EDA domain of fibronectin, and selectively localized to tumors in vivo, as evidenced by quantitative biodistribution experiments. The product promoted a potent antitumor activity in various mouse models of cancer without apparent toxicity at the doses used. F8-4-1BBL represents a prototype for antibody-cytokine fusion proteins, which conditionally display "activity on demand" properties at the site of disease on antigen binding and reduce toxicity to normal tissues.

The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers.

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.

Smoking intensity and urinary nicotine metabolites by socioeconomic status in the Heinz Nixdorf Recall study.

BACKGROUND: Smoking intensity, which is generally based on self-reported average cigarettes per day (CPD), is a major behavioural risk factor and strongly related to socioeconomic status (SES). To assess the validity of the CPD measure, correlations with objective markers of tobacco smoke exposure - such as urinary nicotine metabolites - were examined. Yet, it remains unclear, whether this correlation is affected by SES, which may indicate imprecise or biased self-reports of smoking intensity. METHODS: We investigated the role of SES in the association between CPD and nicotine metabolites in current smokers among the participants of the population-based, prospective Heinz Nixdorf Recall Study. We determined urinary cotinine and additionally trans-3'-hydroxy-cotinine. SES was assessed by the International Socio-Economic Index of occupational status, and education. We calculated correlations (Pearson's r) between logarithmised CPD and cotinine in subgroups of SES and analysed SES and further predictors of cotinine in multiple linear regression models separately by gender. RESULTS: Median reported smoking intensity was 20 CPD in male and 19 CPD in female smokers. Men showed higher cotinine concentrations (median 3652 µg/L, interquartile range (IQR) 2279-5422 µg/L) than women (3127 µg/L, IQR 1692-4920 µg/L). Logarithmised CPD correlated moderately with cotinine in both, men and women (Pearson's r 0.4), but correlations were weaker in smokers with lower SES: Pearson's r for low, intermediate, and high occupational SES was 0.35, 0.39, and 0.48 in men, and 0.28, 0.43, and 0.47 in women, respectively. Logarithmised CPD and urinary creatinine were main predictors of cotinine in multiple regression models, whereas SES showed a weak negative association in women. Results were similar for trans-3'-hydroxy-cotinine. CONCLUSIONS: Decreasing precision of self-reported CPD was indicated for low SES in men and women. We found no strong evidence for biased self-reports of smoking intensity by SES.

Effectiveness of a specialised breathlessness service for patients with advanced disease in Germany: a pragmatic fast-track randomised controlled trial (BreathEase).

BACKGROUND: The effectiveness of the Munich Breathlessness Service (MBS), integrating palliative care, respiratory medicine and physiotherapy, was tested in the BreathEase trial in patients with chronic breathlessness in advanced disease and their carers. METHODS: BreathEase was a single-blinded randomised controlled fast-track trial. The MBS was attended for 5-6 weeks; the control group started the MBS after 8 weeks of standard care. Randomisation was stratified by cancer and the presence of a carer. Primary outcomes were patients' mastery of breathlessness (Chronic Respiratory Disease Questionnaire (CRQ) Mastery), quality of life (CRQ QoL), symptom burden (Integrated Palliative care Outcome Scale (IPOS)) and carer burden (Zarit Burden Interview (ZBI)). Intention-to-treat (ITT) analyses were conducted with hierarchical testing. Effectiveness was investigated by linear regression on change scores, adjusting for baseline scores and stratification variables. Missing values were handled with multiple imputation. RESULTS: 92 patients were randomised to the intervention group and 91 patients were randomised to the control group. Before the follow-up assessment after 8 weeks (T1), 17 and five patients dropped out from the intervention and control groups, respectively. Significant improvements in CRQ Mastery of 0.367 (95% CI 0.065-0.669) and CRQ QoL of 0.226 (95% CI 0.012-0.440) score units at T1 in favour of the intervention group were seen in the ITT analyses (n=183), but not in IPOS. Exploratory testing showed nonsignificant improvements in ZBI. CONCLUSIONS: These findings demonstrate positive effects of the MBS in reducing burden caused by chronic breathlessness in advanced illness across a wide range of patients. Further evaluation in subgroups of patients and with a longitudinal perspective is needed.

Endoglin and TGF-ß signaling in glioblastoma.

Microvascular proliferation is a key feature of glioblastoma and neovascularization has been implicated in tumor progression. Glioblastomas use pro-angiogenic factors such as vascular endothelial growth factor (VEGF) for new blood vessel formation. Yet, anti-VEGF therapy does not prolong overall survival so that alternative angiogenic pathways may need to be explored as drug targets. Both glioma cells and glioma-associated endothelial cells produce TGF-ß superfamily ligands which bind TGF-ß receptors (TGF-ßR). The TGF-ßR type III endoglin (CD105), is a marker of proliferating endothelium that has already been studied as a potential therapeutic target. We studied endoglin expression in glioblastoma tissue and in glioma-associated endothelial cells in a cohort of 52 newly diagnosed and 10 recurrent glioblastoma patients by immunohistochemistry and by ex vivo single-cell gene expression profiling of 6 tumors. Endoglin protein levels were similar in tumor stroma and endothelium and correlated within tumors. Similarly, endoglin mRNA determined by ex vivo single-cell gene expression profiling was expressed in both compartments. There was positive correlation between endoglin and proteins of TGF-ß superfamily signaling. No prognostic role of endoglin expression in either compartment was identified. Endoglin gene silencing in T98G glioma cells and in human cerebral microvascular endothelial cells (hCMEC) did not affect constitutive or exogenous TGF-ß superfamily ligand-dependent signaling, except for a minor facilitation of pSmad1/5 signaling in hCMEC. These observations challenge the notion that endoglin might become a promising therapeutic target in glioblastoma.

Human Metabolism and Urinary Excretion Kinetics of Nonylphenol in Three Volunteers after a Single Oral Dose.

Nonylphenol (NP) is an endocrine-disrupting anthropogenic chemical that is ubiquitous in the environment. Human biomonitoring data and knowledge on internal NP exposure are still sparse, and its human metabolism is largely unknown. Therefore, in this study, we investigated human metabolism and urinary excretion of NP. Three male volunteers received a single oral dose of 1 mg 13C6-labeled NP (10.6-11.7 µg/kg body weight). Consecutive full urine voids were collected for 48 h. A metabolite screening identified nine ring- and/or side chain-oxidized metabolites. We chose the most promising hits, the alkyl chain-oxidized metabolites hydroxy-NP (OH-NP) and oxo-NP, for quantitative investigation next to the parent NP. For this purpose, we newly synthesized specific n - 1-oxidized monoisomeric analytical standards. Quantification of the polyisomeric metabolites was performed via online-solid phase extraction-LC-MS/MS with stable isotope dilution using a previously published consensus method. Alkyl chain hydroxylation (OH-NP) constituted the major metabolism pathway representing 43.7 or 62.2% (depending on the mass transition used for quantification) of the NP dose excreted in urine. The urinary excretion fraction (FUE) for oxo-NP was 6.0 or 9.3%. The parent NP, quantified via an analogous isomeric 13C6-NP standard, represented 6.6%. All target analytes were excreted predominately as glucuronic acid conjugates. Excretion was rather quick, with concentration maxima in urine 2.3-3.4 h after dosing and biphasic elimination kinetics (elimination half-times first phase: 1.0-1.5 h and second phase: 5.2-6.8 h). Due to its high FUE and insusceptibility to external contamination (contrary to parent NP), OH-NP represents a robust and sensitive novel exposure biomarker for NP. The novel FUEs enable to robustly back-calculate the overall NP intakes from urinary metabolite levels in population samples for a well-informed cumulative exposure and risk assessment.

A tumor-promoting role for soluble TßRIII in glioblastoma.

PURPOSE: Members of the transforming growth factor (TGF)-ß superfamily play a key role in the regulation of the malignant phenotype of glioblastoma by promoting invasiveness, angiogenesis, immunosuppression, and maintaining stem cell-like properties. Betaglycan, a TGF-ß coreceptor also known as TGF-ß receptor III (TßRIII), interacts with members of the TGF-ß superfamily and acts as membrane-associated or shed molecule. Shed, soluble TßRIII (sTßRIII) is produced upon ectodomain cleavage of the membrane-bound form. Elucidating the role of TßRIII may improve our understanding of TGF-ß pathway activity in glioblastoma METHODS: Protein levels of TßRIII were determined by immunohistochemical analyses and ex vivo single-cell gene expression profiling of glioblastoma tissue respectively. In vitro, TßRIII levels were assessed investigating long-term glioma cell lines (LTCs), cultured human brain-derived microvascular endothelial cells (hCMECs), glioblastoma-derived microvascular endothelial cells, and glioma-initiating cell lines (GICs). The impact of TßRIII on TGF-ß signaling was investigated, and results were validated in a xenograft mouse glioma model RESULTS: Immunohistochemistry and ex vivo single-cell gene expression profiling of glioblastoma tissue showed that TßRIII was expressed in the tumor tissue, predominantly in the vascular compartment. We confirmed this pattern of TßRIII expression in vitro. Specifically, we detected sTßRIII in glioblastoma-derived microvascular endothelial cells. STßRIII facilitated TGF-ß-induced Smad2 phosphorylation in vitro and overexpression of sTßRIII in a xenograft mouse glioma model led to increased levels of Smad2 phosphorylation, increased tumor volume, and decreased survival CONCLUSIONS: These data shed light on the potential tumor-promoting role of extracellular shed TßRIII which may be released by glioblastoma endothelium with high sTßRIII levels.

Quantification of systemic o-toluidine after intrathecal administration of hyperbaric prilocaine in humans: a prospective cohort study.

Hyperbaric 2% prilocaine is increasingly used for spinal anesthesia. It is the only local anesthetic metabolized to o-toluidine, a human bladder carcinogen. Increase of o-toluidine hemoglobin adducts, a marker of o-toluidine ability to modify the DNA structure, was described following subcutaneous injection. In this prospective cohort study we aimed to assess and quantify o-toluidine hemoglobin adducts and urinary o-toluidine after a single intrathecal dose of hyperbaric prilocaine.10 patients undergoing surgery received 50 mg of hyperbaric prilocaine intrathecally. Blood and urine samples were collected before injection and up to 24 h later (Hospital Braine l'Alleud-Waterloo, Braine l'Alleud, Belgium). Urinary o-toluidine and o-toluidine hemoglobin adducts were measured by tandem mass-spectrometry after gas-chromatographic separation (Institute of the Ruhr-Universität, Bochum Germany). The trial was registered to ClinicalTrials.gov (NCT03642301; 22-08-2018)Intrathecal administration of 50 mg of hyperbaric prilocaine leads to a significant increase of o-toluidine hemoglobin adducts (0.1 ± 0.02-11.9 ± 1.9 ng/g Hb after 24 h, p = 0.001). Peak of urinary o-toluidine was observed after 8 h (0.1 ± 0.1-460.5 ± 352.8 µg/L, p = 0.001) and declined to 98 ± 66.8 µg/L after 24 h (mean ± SD)Single intrathecal administration of hyperbaric prilocaine leads to a systemic burden with o-toluidine and o-toluidine hemoglobin adducts. O-toluidine-induced modifications of DNA should be examined and intrathecal hyperbaric prilocaine should not be proposed to patients chronically exposed to o-toluidine.Clinical trial number and registry URL NCT03642301.

Naphthalene: irritative and inflammatory effects on the airways.

OBJECTIVE: This cross-sectional study determined whether acute sensory irritative or (sub)chronic inflammatory effects of the eyes, nose or respiratory tract are observed in employees who are exposed to naphthalene at the workplace. METHODS: Thirtynine healthy and non-smoking male employees with either moderate (n = 22) or high (n = 17) exposure to naphthalene were compared to 22 male employees from the same plants with no or only rare exposure to naphthalene. (Sub)clinical endpoint measures included nasal endoscopy, smell sensitivity, self-reported work-related complaints and the intensity of naphthalene odor and irritation. In addition, cellular and soluble mediators in blood, nasal lavage fluid (NALF) and induced sputum (IS) were analysed. All measurements were carried out pre-shift on Monday and post-shift on Thursday. Personal air monitoring revealed naphthalene shift concentrations up to 11.6 mg/m3 with short-term peak concentrations up to 145.8 mg/m3 and 1- and 2-naphthol levels (sum) in post-shift urine up to 10.1 mg/L. RESULTS: Acute sensory irritating effects at the eyes and upper airways were reported to occur when directly handling naphthalene (e.g., sieving pure naphthalene). Generally, naphthalene odor was described as intense and unpleasant. Habituation effects or olfactory fatigue were not observed. Endoscopic examination revealed mild inflammatory effects at the nasal mucosa of exposed employees in terms of reddening and swelling and abnormal mucus production. No consistent pattern of cellular and soluble mediators in blood, NALF or IS was observed which would indicate a chronic or acute inflammatory effect of naphthalene in exposed workers. CONCLUSIONS: The results suggest that exposure to naphthalene induces acute sensory irritative effects in exposed workers. No (sub)chronic inflammatory effects on the nasal epithelium or the respiratory tract could be observed under the study conditions described here.

Spatially Resolved Analysis of Urban Thermal Environments Based on a Three-Dimensional Sampling Algorithm and UAV-Based Radiometric Measurements.

A new method and workflow to assess outdoor thermal comfort and thermal stress in urban areas is developed. The new methodology is applied to a case of an urban quarter in the city of Graz. The method recognises the significance of detailed and accurate spatially resolved determination of mean radiant temperatures taking into account all relevant radiative components, comprising thermal radiation, as well as global radiation. The method relies on radiometric imaging data that are mapped onto a three-dimensional model. The image data are acquired by means of drones (UAVs) equipped with multispectral and thermographic cameras to capture short- and long-wave radiation. Pre-existing city models and a Monte Carlo raytracing algorithm to perform anisotropic sampling based on a 3D model with human topology are used to determine local radiation temperatures with high spatial resolution. Along with spot measurements carried out on the ground simultaneously, the spatially resolved and three-dimensionally determined mean radiation temperatures are used to calculate thermal comfort indicator maps using UTCI and PMV calculation. Additional ground measurements are further used to validate the detection, as well as the entire evaluation process.

Perioperative imaging in patients treated with resection of brain metastases: a survey by the European Association of Neuro-Oncology (EANO) Youngsters committee.

BACKGROUND: Neurosurgical resection represents an important treatment option in the modern, multimodal therapy approach of brain metastases (BM). Guidelines for perioperative imaging exist for primary brain tumors to guide postsurgical treatment. Optimal perioperative imaging of BM patients is so far a matter of debate as no structured guidelines exist. METHODS: A comprehensive questionnaire about perioperative imaging was designed by the European Association of Neuro-Oncology (EANO) Youngsters Committee. The survey was distributed to physicians via the EANO network to perform a descriptive overview on the current habits and their variability on perioperative imaging. Chi square test was used for dichotomous variables. RESULTS: One hundred twenty physicians worldwide responded to the survey. MRI was the preferred preoperative imaging method (93.3%). Overall 106/120 (88.3%) physicians performed postsurgical imaging routinely including MRI alone (62/120 [51.7%]), postoperative CT (29/120 [24.2%]) and MRI + CT (15/120 [12.5%]). No correlation of postsurgical MRI utilization in academic vs. non-academic hospitals (58/89 [65.2%] vs. 19/31 [61.3%], p = 0.698) was found. Early postoperative MRI within ≤72 h after resection is obtained by 60.8% of the participants. The most frequent reason for postsurgical imaging was to evaluate the extent of tumor resection (73/120 [60.8%]). In case of residual tumor, 32/120 (26.7%) participants indicated to adjust radiotherapy, 34/120 (28.3%) to consider re-surgery to achieve complete resection and 8/120 (6.7%) to evaluate both. CONCLUSIONS: MRI was the preferred imaging method in the preoperative setting. In the postoperative course, imaging modalities and timing showed high variability. International guidelines for perioperative imaging with special focus on postoperative MRI to assess residual tumor are warranted to optimize standardized management and adjuvant treatment decisions for BM patients.

Exposure to welding fumes suppresses the activity of T-helper cells.

Welders have an increased susceptibility to airway infections with non-typeable Haemophilus influenzae (NTHi), which implicates immune defects and might promote pneumonia and chronic obstructive pulmonary disease (COPD). We hypothesized that welding-fume exposure suppresses Th1-lymphocyte activity. Non-effector CD4+ T-cells from blood of 45 welders (n = 23 gas metal arc welders, GMAW; n = 16 tungsten inert gas welders, TIG; n = 6 others) and 25 non-welders were ex vivo activated towards Th1 via polyclonal T-cell receptor stimulation and IL-12 (first activation step) and then stimulated with NTHi extract or lipopolysaccharide (LPS) (second activation step). IFNγ and IL-2 were measured by ELISA. In the first activation step, IFNγ was reduced in welders compared to non-welders and in the GMAW welders with higher concentrations of respirable particles compared to the lower exposed TIG welders. IFNγ was not influenced by tobacco smoking and correlated negatively with welding-fume exposure, respirable manganese, and iron. In the second activation step, NTHi and LPS induced additional IFNγ, which was reduced in current smokers compared to never smokers in welders as well as in non-welders. Analyzing both activation steps together, IFNγ production was lowest in smoking welders and highest in never smoking non-welders. IL-2 was not associated with any of these parameters. Welding-fume exposure might suppress Th1-based immune responses due to effects of particulate matter, which mainly consists of iron and manganese. For responses to NTHi this is strongest in smoking welders because welding fume suppresses T-cell activation towards Th1 and cigarette smoke suppresses the subsequent Th1-response to NTHi via LPS. Both effects are independent from IL-2-regulated T-cell proliferation. This might explain the increased susceptibility to infections and might promote COPD development.

Correction to: Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24-h urine samples of the German Environmental Specimen Bank from 1991 to 2014.

The article Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24-h urine samples of the German Environmental Specimen Bank from 1991 to 2014.

Dependency of the blood oxygen level dependent-response to hyperoxic challenges on the order of gas administration in intracranial malignancies.

PURPOSE: Literature reports contradicting results on the response of brain tumors to vascular stimuli measured in T2*-weighted MRI. Here, we analyzed the potential dependency of the MRI-response to (hypercapnic) hyperoxia on the order of the gas administration. METHODS: T2* values were quantified at 3 Tesla in eight consenting patients at rest and during inhalation of hyperoxic/hypercapnic gas mixtures. Patients were randomly divided into two groups undergoing different gas administration protocols (group A: medical air-pure oxygen-carbogen; group B: medical air-carbogen-pure oxygen). Mann-Whitney U test and Wilcoxon signed rank test have been used to proof differences in T2* regarding respiratory challenge or different groups, respectively. RESULTS: T2* values at rest for gray and white matter were 50.3 ± 2.6 ms and 46.1 ± 2.0 ms, respectively, and slightly increased during challenge. In tumor areas, T2* at rest were: necrosis = 74.1 ± 10.1 ms; edema = 60.3 ± 17.6 ms; contrast-enhancing lesions = 48.6 ± 20.7 ms; and solid T2-hyperintense lesions = 45.0 ± 3.0 ms. Contrast-enhancing lesions strongly responded to oxygen (+ 20.7%) regardless on the gas protocol (p = 0.482). However, the response to carbogen significantly depended on the order of gas administration (group A, + 18.6%; group B, - 6.4%, p = 0.042). In edemas, a different trend between group was found when breathing oxygen (group A, - 9.9%; group B, + 19.5%, p = 0.057). CONCLUSION: Preliminary results show a dependency of the T2* response of contrast-enhancing brain tumor lesions on the order of the gas administration. The gas administration protocol is an important factor in the interpretation of the T2*-response in areas of abnormal vascular growth.