Single organ metastatic sites in non-small cell lung cancer: Patient characteristics, treatment patterns and outcomes from a large retrospective Canadian cohort.

BACKGROUND: There is a paucity of information about the characteristics, treatment patterns, and outcomes of non-small cell lung cancer (NSCLC) patients with single organ metastasis (SOM). METHODS: This retrospective cohort study includes all patients with a diagnosis of stage IV NSCLC diagnosed from 2014 to 2016 and treated at Princess Margaret Cancer Centre. We compared baseline characteristics and patterns of metastatic sites between patients with SOM versus multiple (M)OM. Additionally, we identified treatment modalities and outcomes for patients with SOM. Cox multivariable models (MVA) were utilized to evaluate differences in overall survival (OS) between the SOM and MOM cohorts. RESULTS: Of 893 pts analyzed, 457 (51 %) had SOM, while 436 (49 %) had MOM at initial diagnosis. Demographics were comparable between the two groups. Brain was the most common site of metastasis for SOM patients. When compared to the MOM group, the SOM group had lower percentages of liver and adrenal metastases. Amongst SOM patients, 54 % received single modality treatment, and 20 % did not receive any treatment for their SOM. In MVA, patients with liver (HR 2.4), bone (HR 1.8), and pleural (HR 1.7) metastasis as their SOM site had the worst outcomes, with median OS of 6.8 months, 12.1 months, and 13.0 months respectively. Patients with SOM had a significantly improved median OS compared to those with MOM (15.9 months vs. 10.6 months; HR 0.56, 95 % CI 0.47-0.66, p < 0.001). CONCLUSION: In NSCLC patients who presented with SOM, survival correlated with the initial organ involved and was better overall compared to patients with MOM. SOM NSCLC may benefit from specific management strategies and SOM patients could be considered as a specific subgroup for survival analyses in observational and non-randomized interventional studies. In clinical trials, SOM can be considered as a stratification factor in the future.

Urban abiotic stressors drive changes in the foraging activity and colony growth of the black garden ant Lasius niger.

Changes in habitat characteristics are known to have profound effects on biotic communities and their functional traits. In the context of an urban-rural gradient, urbanisation drastically alters abiotic characteristics, e.g., by increasing environmental temperatures and through light pollution. These abiotic changes significantly impact the functional traits of organisms, particularly insects. Furthermore, changes in habitat characteristics also drive changes in the behavioural traits of animals, allowing them to adapt and thrive in new environments. In our study, we focused on the synanthropic ant species Lasius niger as a model organism. We conducted nocturnal field observations and complemented them with laboratory experiments to investigate the influence of night warming (NW) associated with Urban Heat Islands (UHI), light pollution (ALAN), and habitat type on ant foraging behaviour. In addition, we investigated the influence of elevated temperatures on brood development and worker mortality. Our findings revealed that urban populations of L. niger were generally more active during the night compared to their rural counterparts, although the magnitude of this difference varied with specific city characteristics. In laboratory settings, higher temperatures and continuous illumination were associated with increased activity level in ants, again differing between urban and rural populations. Rural ants exhibited more locomotion compared to their urban counterparts when maintained under identical conditions, which might enable them to forage more effectively in a potentially more challenging environment. High temperatures decreased the developmental time of brood from both habitat types and increased worker mortality, although rural colonies were more strongly affected. Overall, our study provides novel insights into the influence of urban environmental stressors on the foraging activity pattern and colony development of ants. Such stressors can be important for the establishment and spread of synanthropic ant species, including invasive ones, and the biotic homogenization of anthropogenic ecosystems.

The value of sonographic microvascular imaging in the diagnosis of lipedema.

BACKGROUND: Lipedema is a chronic disease marked by symmetric enlargement of painful nodular and fibrotic adipose tissue, predominantly affecting the limbs. Since there is no specific test or biomarker for this condition, years often pass before the diagnosis of lipedema is established for the first time, thereby causing psychosocial distress, including depression, eating disorders, and social isolation. Over the last few years several advanced Doppler-based technologies have been developed to visualize slow flow blood vessels and superficial microvascular architecture undetectable by traditional color Doppler flow imaging (CDFI). OBJECTIVE: The aim of this study was to evaluate the superficial microvascular anatomy in lipedema patients compared to healthy controls and investigate the clinical significance of the Ultra Micro Angiography (UMA) technology in the diagnosis of lipedema. This new technique may contribute to reduce the diagnostic delay and, eventually, establish and guide treatment strategies toward a better therapeutic outcome in lipedema patients. METHODS: 25 patients with lipedema and ten healthy controls with no history of lipedema were included in this study. All ultrasound examinations were performed on a novel high-performance ultrasound system (Resona R9/Mindray) using CDFI and the UMA technique. RESULTS: In all of the patients, Ultra Micro Angiography achieved the excellent visualization of microvascular structures, revealing that most lipedema patients showed grade 3 (n = 13) or grade 2 (n = 8) flow. UMA was superior to CDFI for depicting the microvascular structures. CONCLUSIONS: Here we show that UMA imaging characterizes the subcutaneous microvasculature with an unprecedented accuracy. The method has the advantage of being sensitive to small, slow-flowing vessels. This allows for the assessment of the course of vessels and vascular pathologies in great detail. Thus, UMA as a non-invasive diagnostic method can improve diagnostic accuracy in lipedema.

Patterns of progression on first line osimertinib in patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC): A Swiss cohort study.

AIM: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for patients with EGFR mutated non-small cell lung cancer as first-line treatment. However, treatment resistance inevitably emerges and may present as oligo-progressive disease (OPD) or systemic progressive disease (SPD). The incidence of OPD on first-line osimertinib is unknown. METHODS: We retrospectively analyzed patients who received first-line osimertinib at 13 Swiss centers. The rate of OPD (PD in ≤ 5 lesions) and treatment outcomes were analyzed. RESULTS: The median age of the 148 patients was 68.2 years (range. 38.0-93.3). There were 62 % females, 83 % with a PS ≤ 1, 59 % never smokers, 57 % of patients with an EGFR exon 19 deletion and 37 % with EGFR p.L858R exon 21. 77 % experienced OPD. Median overall survival (OS) was 51.6 months (95 % CI, 38.4-65.0). Median progression-free survival (PFS) was 19.2 (95 % CI, 14.3-23.5) and 8.7 (95 % CI, 2.8-15.6) months for patients with common and uncommon EGFR mutations. Patients with OPD compared to SPD had a significantly longer time to treatment failure and longer OS of (22.9 vs. 10.8 months, p < 0.001 and 51.6 vs. 26.4 months, p = 0.004, respectively). The most common organ sites of PD were lung (62 %), brain (30 %), lymph nodes (30 %), bone (27 %) and pleura (27 %). Twenty-six patients (45 %) with OPD received local ablative treatment (LAT). The OS of OPD patients with LAT was 60.0 (95 % CI, 51.6-NA) vs. 51.4 (95 % CI 38.4-65.3) months (p = 0.43) without LAT. CONCLUSION: The rate of OPD of patients receiving first line osimertinib was 77 %. Patients with OPD had a significantly better OS compared to patients with SPD (51.6 vs. 26.4 months). Patients with OPD receiving LAT had the longest median OS (60.0 months).

Neoadjuvant treatment does not influence PD-L1 expression in stage III non-small-cell lung cancer: a retrospective analysis of tumor samples from the trials SAKK 16/96, 16/00, 16/01, and 16/14.

BACKGROUND: The inclusion of immune checkpoint inhibitors (ICIs) in the treatment of operable stage III non-small-cell lung cancer is becoming a new standard. Programmed death-ligand 1 (PD-L1) protein expression on tumor cells has emerged as the most important biomarker for sensitivity to ICIs targeting the programmed cell death protein 1 (PD-1)-PD-L1 axis. Little is known about the impact of neoadjuvant treatment on PD-L1 expression. PATIENTS AND METHODS: We assessed PD-L1 expression by immunohistochemistry (Ventana SP263 assay) on tumor cells in treatment-naive diagnostic tumor samples and matched lung resections from patients with stage III non-small-cell lung cancer included in the Swiss Group for Clinical Cancer Research (SAKK) trials 16/96, 16/00, 16/01, and 16/14. All patients received neoadjuvant chemotherapy (CT) with cisplatin/docetaxel, either as single modality (CT), with sequential radiotherapy [chemoradiation therapy (CRT)] or with the PD-L1 inhibitor durvalumab (CT + ICI). RESULTS: Overall, 132 paired tumor samples were analyzed from patients with neoadjuvant CT (n = 69), CRT (n = 33) and CT + ICI (n = 30). For CT and CRT, PD-L1 expression before and after neoadjuvant treatment did not differ significantly (Wilcoxon test, P = 0.94). Likewise, no statistically significant difference was observed between CT and CRT for PD-L1 expression after neoadjuvant treatment (P = 0.97). For CT + ICI, PD-L1 expression before and after neoadjuvant treatment also did not differ significantly (Wilcoxon test, P > 0.99). Event-free survival and overall survival for patients with downregulation or upregulation of PD-L1 expression after neoadjuvant treatment were similar. CONCLUSIONS: In our cohort of patients neoadjuvant treatment did not influence PD-L1 expression, irrespective of the specific neoadjuvant treatment protocol. Dynamic change of PD-L1 expression did not correlate with event-free survival or overall survival.

[Value of immunotherapy in the perioperative treatment of localized muscle invasive bladder cancer]. / Stellenwert der Immuntherapie in der perioperativen Behandlung des lokalisierten muskelinvasiven Harnblasenkarzinoms.

Immune checkpoint inhibitors are standard of care in the treatment of metastatic and locally advanced urothelial cancer. Their use in perioperative treatment is currently under investigation as monotherapy as well as in combination with chemotherapy or radiation regimens. This article provides an overview of recent trials, current data as well as an outlook on future developments in the perioperative management of urothelial cancer.

["Surgery only" is not enough: potential of multimodal therapy in urothelial bladder carcinoma]. / "Surgery only" reicht nicht aus: Potenziale einer multimodalen Therapie beim Urothelkarzinom der Harnblase.

Radical cystectomy is the standard treatment for muscle invasive bladder cancer. Using perioperative cisplatin-based chemotherapy, 5­year overall survival rates are 5% higher with neoadjuvant chemotherapy compared to local therapy alone. New multimodal concepts have been developed to improve oncologic efficacy and to reduce treatment-related morbidity. Perioperative use of checkpoint inhibitors aims at improving efficacy, while bladder-preserving concepts try to avoid cystectomy in good responders. This article reviews new developments in radioimmunotherapy and perioperative combination therapies as well as bladder-preserving concepts like trimodal bladder therapy.

How to read a next-generation sequencing report-what oncologists need to know.

Next-generation sequencing (NGS) of tumor cell-derived DNA/RNA to screen for targetable genomic alterations is now widely available and has become part of routine practice in oncology. NGS testing strategies depend on cancer type, disease stage and the impact of results on treatment selection. The European Society for Medical Oncology (ESMO) has recently published recommendations for the use of NGS in patients with advanced cancer. We complement the ESMO recommendations with a practical review of how oncologists should read and interpret NGS reports. A concise and straightforward NGS report contains details of the tumor sample, the technology used and highlights not only the most important and potentially actionable results, but also other pathogenic alterations detected. Variants of unknown significance should also be listed. Interpretation of NGS reports should be a joint effort between molecular pathologists, tumor biologists and clinicians. Rather than relying and acting on the information provided by the NGS report, oncologists need to obtain a basic level of understanding to read and interpret NGS results. Comprehensive annotated databases are available for clinicians to review the information detailed in the NGS report. Molecular tumor boards do not only stimulate debate and exchange, but may also help to interpret challenging reports and to ensure continuing medical education.

Trends, events and potential sources of Xe-detections in the German radioxenon network.

The measurement of radioxenons (133Xe, 131mXe, 133mXe, 135Xe) in the atmosphere is a keystone for the verification of the Comprehensive Nuclear-Test-Ban Treaty (CTBT). At the German Federal Office for Radiation Protection (Bundesamt für Strahlenschutz, BfS) activity concentrations of radioactive noble gases at several sites in Germany have been measured for more than 5 decades, initially to monitor nuclear facilities and since the mid-1990s also to support the development of measurement and monitoring systems and procedures for verification of the CTBT. Average 133Xe activity concentration in air measured daily at station RN33 of the International Monitoring System (IMS) of the CTBTO on Mt Schauinsland has decreased since 2008. Due to the decreasing radioxenon background in the atmosphere, laboratory measurements with less sensitive proportional counters developed in-house are increasingly replaced by an isotope specific ß-γ laboratory system for radioxenon analyses. Six years of radioxenon activity concentrations measured with the ß-γ laboratory system in weekly samples from monitoring sites in Germany are presented. Activity concentrations of 133Xe in southern Germany are now typically below 1 mBq m-3 and have decreased by an order of magnitude in the past 25 years. Magnitude and variability of 133Xe activity concentrations are generally larger in northern and western Germany compared to the south, most likely due to the prevailing wind directions in the region. Selected, but typical, periods of elevated radioxenon levels at the stations are investigated and the value of stack emission data is demonstrated.

[Potential effect of the stimulus threshold level of the nociceptive flexion reflex (NFRT) on mortality and delirium incidence in the critically ill patient: a retrospective cohort analysis]. / Potenzieller Einfluss der Reizschwellenhöhe des nozizeptiven Flexorenreflex (NFRT) auf die Mortalitäts- und Delirinzidenz beim kritisch kranken Patienten: eine retrospektive Kohortenanalyse.

BACKGROUND: Mortality and delirium in critically ill patients are affected by the provided analgesics and sedatives. The deeper the sedation and the higher the dose of analgesics applied, the more difficult it is to assess pain and the depth of sedation. Therefore, instrumental measurement methods, such as the measurement of the stimulus threshold of the nociceptive flexion reflex (NFRT), are becoming increasingly more important. OBJECTIVE: The aim of the present study is to investigate a potential association between the level of the nociceptive flexion reflex, mortality, and the occurrence of delirium. MATERIAL AND METHODS: By retrospectively analyzing a pilot data set of 57 ICU patients from the interdisciplinary surgical ICU of Ulm University Hospital surveyed between 11/2018 and 03/2020, a possible association between the NFRT, mortality, and the occurrence of delirium was calculated in an adjusted logistic regression model. Depending on the cut-off value, the stimulus threshold corridors result in the following comparison pairs: < 20 mA vs. 20-40 mA/20-50 mA/20-60 mA, > 40 mA vs. 20-40 mA, > 50 mA vs. 20-50 mA and > 60 mA vs. 20-60 mA. Results are presented as odds ratios (OR) adjusted for age, sex, height, TISS-28, SAPS II, RASS, BPS, and applied analgesics. Pain assessment was performed, in addition to the Behavioral Pain scale, ≥ 3 times daily by measuring NFRT. RESULTS: A statistically nonsignificant tendency for an increase in mortality incidence occurred with an NFRT > 50 mA, versus a stimulus threshold corridor of 20-50 mA (OR 3.3, CI: 0.89-12.43, p = 0.07). A trend toward a reduction in delirium incidence occurred at an NFRT < 20 mA, versus a stimulus threshold corridor of 20-40 mA (OR 0.40, CI: 0.18-0.92, p = 0.03). CONCLUSION: Based on the level of the NFRT, no recommendation can be made at this point to adjust the analgesic regimen of critically ill patients, who are unable to communicate. The observation of a tendency towards an increase in mortality at high stimulus thresholds or a reduction in the occurrence of delirium at low stimulus thresholds of the NFRT must be verified in standardized studies.

Multimodal ultrasound imaging with conventional B-mode, elastography, and parametric analysis of contrast-enhanced ultrasound (CEUS): A novel approach to assess small bowel manifestation in severe COVID-19 disease.

The aim was to describe the small bowel morphology with conventional B-mode and elastography and additionally to evaluate dynamic effects of COVID-19 associated small bowel microvascularization using CEUS with color coded perfusion parameters.Thirteen patients with severe COVID-19 acute respiratory distress syndrome (ARDS) were investigated. 13 patients required intensive care treatment with mechanical ventilation. Five patients required extracorporeal membrane oxygenation (ECMO). Contrast-enhanced ultrasound (CEUS) was performed by an experienced investigator as a bolus injection of up to 2.4 ml sulfur hexafluoride microbubbles via a central venous catheter. In the parametric analysis of CEUS, the flare of microbubbles over time is visualized with colors. This is the first work using parametric analysis of CEUS to detect perfusion differences in the small bowel.Parametric analysis of CEUS in the intestinal phase was carried out, using DICOM loops for 20 seconds. In 5 patients, parametric analysis revealed intraindividual differences in contrast agent behavior in the small bowel region. Analogous to the computed tomography (CT) images parametric analysis showed regions of simultaneous hyper- and hypoperfusion of the small intestine in a subgroup of patients. In 5 patients, the parametric image of transmural global contrast enhancement was visualized.Our results using CEUS to investigate small bowel affection in COVID-19 suggest that in severe COVID-19 ARDS systemic inflammation and concomitant micro embolisms may lead to disruption of the epithelial barrier of the small intestine.This is the first study using parametric analysis of CEUS to evaluate the extent of small bowel involvement in severe COVID-19 disease and to detect microemboli. In summary, we show that in COVID-19 the small bowel may also be an important interaction site. This is in line with the fact that enterocytes have been shown to a plenitude of angiotensin converting enzyme (ACE)-2 receptors as entry sites of the virus.

Long-term benefit of lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma (MPM): final efficacy and translational data of the SAKK 17/16 study.

BACKGROUND: The SAKK 17/16 study showed promising efficacy data with lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma. Here, we evaluated long-term outcome and analyzed the impact of lurbinectedin monotherapy on the tumor microenvironment at the cellular and molecular level to predict outcomes. MATERIAL AND METHODS: Forty-two patients were treated with lurbinectedin in this single-arm study. Twenty-nine samples were available at baseline, and seven additional matched samples at day one of cycle two of treatment. Survival curves and rates between groups were compared using the log-rank test and Kaplan-Meier method. Statistical significance was set at P value <0.05. RESULTS: Updated median overall survival (OS) was slightly increased to 11.5 months [95% confidence interval (CI) 8.8-13.8 months]. Thirty-six patients (85%) had died. The OS rate at 12 and 18 months was 47% (95% CI 32.1% to 61.6%) and 31% (95% CI 17.8% to 45.0%), respectively. Median progression-free survival was 4.1 months (95% CI 2.6-5.5 months). No new safety signals were observed. Patients with lower frequencies of regulatory T cells, as well as lower tumor-associated macrophages (TAMs) at baseline, had a better OS. Comparing matched biopsies, a decrease of M2 macrophages was observed in five out of seven patients after exposure to lurbinectedin, and two out of four patients showed increased CD8+ T-cell infiltrates in tumor. DISCUSSION: Lurbinectedin continues to be active in patients with progressing malignant pleural mesothelioma. According to our very small sample size, we hypothesize that baseline TAMs and regulatory T cells are associated with survival. Lurbinectedin seems to inhibit conversion of TAMs to M2 phenotype in humans.

Contrast enhanced ultrasonography (CEUS) a novel tool to detect intestinal epithelial barrier dysfunction in severe COVID-19 disease.

Ten patients with confirmed COVID-19 disease were studied. Nine patients required intensive care treatment, among them four needed extracorporeal membrane oxygenation (ECMO). Contrast enhanced ultrasonography (CEUS) was performed by one experienced investigator as a bolus injection of up to 2.4 ml of sulphur hexafluoride microbubbles via a central venous catheter. B-Mode evaluation and strain elastography showed mural edema of the small bowel with a thickness of up to 10 mm in all patients. We applied color coded Doppler sonography (CCDS) and power mode with flow-adapted parameters and early, dynamic capillary arterial contrast enhancement of bowel wall structures <10 s to assess perfusion of the small bowel. In all patients, reactive hyperemia was seen in the entire small bowel. In a subgroup of seven patients microbubbles translocated into the intestinal lumen. Thus, high-grade intestinal barrier disruption secondary to SARSCoV-2 infection can be postulated in these patients.This is the first description of perfusion changes and a disruption of the small bowel epithelial barrier in COVID-19 Patients using contrast ultrasonography and elastography.

Germanium nanowire microbolometer.

Near-infrared detection is widely used for nondestructive and non-contact inspections in various areas, including thermography, environmental and chemical analysis as well as food and medical diagnoses. Common room temperature bolometer-type infrared sensors are based on architectures in theµm range, limiting miniaturization for future highly integrated 'More than Moore' concepts. In this work, we present a first principle study on a highly scalable and CMOS compatible bolometer-type detector utilizing Ge nanowires as the thermal sensitive element. For this approach, we implemented the Ge nanowires on top of a low thermal conducting and highly absorptive membrane as a near infrared (IR) sensor element. We adopted a freestanding membrane coated with an impedance matched platinum absorber demonstrating wavelength independent absorptivity of 50% in the near to mid IR regime. The electrical characteristics of the device were measured depending on temperature and biasing conditions. A strong dependence of the resistance on the temperature was shown with a maximum temperature coefficient of resistance of -0.07 K-1atT = 100 K. Heat transport simulations using COMSOL were used to optimize the responsivity and temporal response, which are in good agreement with the experimental results. Further, lock-in measurements were used to benchmark the bolometer device at room temperature with respect to detectivity and noise equivalent power. Finally, we demonstrated that by operating the bolometer with a network of parallel nanowires, both detectivity and noise equivalent power can be effectively improved.

[Geriatric patients in the intensive care unit]. / Der geriatrische Patient auf der Intensivstation.

The percentage of geriatric patients treated in intensive care units continues to increase, comprising up to 30%. Age per se is not of great relevance for the outcome of intensive care treatment. Functional status and geriatric syndromes are crucial for prognosis. Frailty and delirium are very important and should be screened using the Clinical Frailty Scale (CFS) and Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), respectively. Furthermore, age-physiological organ changes as well as multimorbidity and associated polypharmacy play an important role. The latter should be assessed at the time of admission. Another goal of intensive care treatment of geriatric patients is to maintain and improve the nutritional status, which can be assessed with the help of an established tool (e.g. NRS 2002). In the treatment of critically ill geriatric patients with coronavirus disease 2019 (COVID-19), frailty is also crucial. It is particularly important in the intensive medical treatment of critically ill geriatric patients to clarify the question whether the patient benefits from each intensive care therapy, e.g., whether a desired therapeutic goal can be achieved, whether intensive care is in the (presumed) patient's will and whether the burdens during treatment are justified by the perspective of life. Furthermore, interdepartmental cooperation plays an important role in the intensive medical care of geriatric patients.

Sparing the hippocampus and the hypothalamic- pituitary region during whole brain radiotherapy: a volumetric modulated arc therapy planning study.

BACKGROUND: Feasibility testing of a simultaneous sparing approach of hippocampus, hypothalamus and pituitary gland in patients undergoing whole-brain radiotherapy (WBRT) with and without a concomitant boost to metastatic sites. INTRODUCTION: Cognitive impairment and hormonal dysfunction are common side effects of cranial radiotherapy. A reduced dose application to the patho-physiologically involved functional brain areas, i.e. hippocampus, hypothalamus and pituitary gland, could reduce these common side effects. While hippocampal sparing is already a common practice to improve cognitive outcome, technical experience of additional combined sparing of the hypothalamus/pituitary gland (HT-P) is insufficient. METHODS: Twenty patients were included in the planning study. In 11 patients, a total dose of 36 Gy of WBRT (2 Gy per fraction) plus a simultaneous integrated boost (SIB) of 9 Gy (0.5 Gy per fraction, total dose: 45 Gy) to the brain metastases was applied. In 9 patients, prophylactic cranial irradiation (PCI) was simulated with a total dose of 30 Gy (2 Gy per fraction). In both patient cohorts, a sparing approach of the hippocampus and the HT-P area was simulated during WBRT. For all treatment plans, volumetric modulated arc therapy (VMAT) was used. Quality assurance included assessment of homogeneity, conformality and target coverage. RESULTS: The mean dose to the hippocampus and HT-P region was limited to less than 50% of the prescribed dose to the planning target volume (PTV) in all treatment plans. Dose homogeneity (HI) of the target volume was satisfying (median HI = 0.16 for WBRT+SIB and 0.1 for PCI) and target coverage (conformation number, CN) was not compromised (median CN = 0.82 for SIB and 0.86 for PCI). CONCLUSION: Simultaneous dose reduction to the hippocampus and the HT-P area did not compromise the PTV coverage in patients undergoing WBRT+SIB or PCI using VMAT. While the feasibility of the presented approach is promising, prospective neurologic, endocrine outcome and safety studies are required.

[Gastroenteropancreatic neuroendocrine neoplasms-Heterogeneity, management and perspectives of treatment and research]. / Gastroenteropankreatische neuroendokrine Neoplasien ­ Heterogenität, Management und Perspektiven der Versorgung und Forschung.

The term neuroendocrine neoplasms (NEN) encompasses a molecularly and biologically very heterogeneous group of tumors, which have in common their origin in neuroendocrine cells. The also very heterogeneous subgroup of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is the best classified and investigated group. This article provides a systematic review of the current classification, diagnostics and treatment options of GEP-NEN. In order to achieve a better overview, it was consciously decided not to use an approach based on the primary localization. Instead, a thematic organization according to classification, clinical phenotype, diagnostics and treatment was chosen.

Detection of antibodies against tick-borne encephalitis flaviviruses in breeding and sport horses from Spain.

Tick-borne encephalitis virus (TBEV) and louping-ill virus (LIV) are two closely related zoonotic flaviviruses leading to neurological diseases and belonging to the tick-borne encephalitis (TBE) serocomplex. Both viruses are transmitted by the same ixodid tick vector, Ixodes ricinus. Due to global warming affecting vector biology and pathogen transmission, the viruses pose an emerging threat for public health in Europe and Asia. These flaviviruses share some hosts, like sheep, goats and humans, although the main hosts for LIV and TBEV are sheep and small rodents, respectively. Whereas LIV has been detected in Spanish sheep and goat herds, circulating antibodies against TBEV have only been reported in dogs and horses from particular regions in this country. The limited available information about the prevalence of these viruses in Spain led us to investigate the serological evidence of TBE flaviviruses in horses from Spain. Serum neutralization tests (SNT) were performed using sera from 495 breeding and sport horses collected during two periods (2011-2013 and 2015-2016). A seroprevalence of 3.1 % (95 % CI 1.5-4.6) was found and cross-reactivity with West Nile virus was excluded in the positive samples. Sport horses showed a significantly higher TBE serocomplex seropositivity compared to breeding horses. An increased seroprevalence was observed in the second sampling period (2015-2016). Our results demonstrate for the first time the presence of antibodies against TBE flaviviruses in horses residing in mainland Spain; further epidemiological surveys are necessary in order to understand and monitor the active transmission of TBE flaviviruses in this country and rule out the presence of other flaviviruses co-circulating in Spain.

Circadian regulation of hedonic appetite in mice by clocks in dopaminergic neurons of the VTA.

Unlimited access to calorie-dense, palatable food is a hallmark of Western societies and substantially contributes to the worldwide rise of metabolic disorders. In addition to promoting overconsumption, palatable diets dampen daily intake patterns, further augmenting metabolic disruption. We developed a paradigm to reveal differential timing in the regulation of food intake behavior in mice. While homeostatic intake peaks in the active phase, conditioned place preference and choice experiments show an increased sensitivity to overeating on palatable food during the rest phase. This hedonic appetite rhythm is driven by endogenous circadian clocks in dopaminergic neurons of the ventral tegmental area (VTA). Mice with disrupted clock function in the VTA lose their hedonic overconsumption rhythms without affecting homeostatic intake. These findings assign a functional role of VTA clocks in modulating palatable feeding behaviors and identify a potential therapeutic route to counteract hyperphagy in an obesogenic environment.

[Immuno-oncological approaches in the perioperative therapy of muscle invasive bladder cancer]. / Immunonkologische Ansätze in der perioperativen Therapie des muskelinvasiven Urothelkarzinoms.

Perioperative chemotherapy has become a standard treatment for muscle invasive bladder cancer and is recommended by national and international guidelines. The treatment of metastatic urothelial cancer evolved by the use of immune-modulating therapies like checkpoint inhibitors. Many clinical trials have been initiated which try to evaluate the role of immune checkpoint inhibition in the neoadjuvant and adjuvant setting. These trials focus not only on monotherapy, but also on the combination of checkpoint inhibitors with classical chemotherapy or with local radiation therapy (radioimmunotherapy). In neoadjuvant radioimmunotherapy, the radiation is supposed to act as a sensitizer for the systemic effects of checkpoint inhibition, in addition to the local effects. This review presents and discusses current trials and published results for perioperative immunomodulating treatment-alone or in combination-in muscle invasive bladder cancer.