Einfluss eines neuartigen aromatischen Kohlenwasserstoff-Amphiphils auf Tumorgenese und Metastasierung des Osteosarkoms im murinen Modell

Auf der tumorzellgerichteten Therapie neoplastischer Erkrankungen ruhen große Hoffnungen der Wissenschaft. Bevor diese jedoch Einzug in die Klinik halten kann, bedarf es aufwändiger Untersuchungen in vitro sowie in vivo. Pires et al. konnten bereits äußerst vielversprechende Ergebnisse während ihrer in vitro-Versuche bezüglich der Wirksamkeit des therapeutischen Agens aKA in Kombination mit einer Osteosarkomzelllinie erzielen. Darauf aufbauend sollte in dieser Arbeit eine erste in vivo-Anwendung des aKA im murinen Modell durchgeführt werden. Zunächst wurde in Vorbereitung dazu die verwendete Osteosarkomzelllinie K7M2 in vitro mit verschiedenen Dosen des aKA getestet. Anschließend sollte das aKA in vivo hinsichtlich seines Einflusses auf Tumorprogredienz, Effizienz und systemische Nebeneffekte evaluiert werden. Zusätzlich sollten aufgrund der bisher geringen Datenlage intraosseäre Sauerstoffdaten generiert werden. Zunächst wurde im Rahmen der in vitro-Versuche der Einfluss verschiedener Dosen des aKA auf die metabolische Aktivität der K7M2-Zellen mittels Viabilitäts-Assay, DNA-Quantifizierung, Mikroskopie und Sauerstoffmessungen untersucht. Im nächsten Schritt erfolgte dann die orthotope Implantation der K7M2-Zellen in die proximale Tibia männlicher C57BL/6J-Mäuse. Nach einer Tumorwachstumsphase von 20 Tagen wurde dann über 14 Tage täglich mit verschiedenen Dosen des aKA behandelt. Von Tag 35 bis zum Versuchsende an Tag 50 erfolgte die Beobachtung der Tiere. Zu den Zeitpunkten Tag 0, 20, 21, 35 und 50 wurden Verlaufskontrollen mittels μCT, Blutentnahme, Histologie der tumortragenden Tibia und Sauerstoffmessung der gesunden Tibia durchgeführt. Analog zu den Versuchen von Pires et al. (Pires et al., 2015) konnte die metabolisch supprimierende Wirksamkeit des aKA auf K7M2-Osteosarkomzellen mit nachgewiesen werden. Der Unterschied war bereits nach 7 Stunden signifikant. Zusätzlich war es möglich eine dosisabhängige Oxygenierung 48 Stunden nach aKA-Exposition nachzuweisen. Im präklinischen murinen Tiermodell konnte eine dosisabhängige Verringerung des totalen Knochenvolumens im Vergleich zur unbehandelten nur Tumorzellen-Gruppe am Tag 50 beobachtet werden. Die Wirkung trat dabei zeitverzögert zum Therapieende ein. Zudem bewirkte die Behandlung mit aKA eine dosisabhängige Erhöhung der Knochenmineraldichte. Histologisch konnten zwischen den mit aKA behandelten Gruppen qualitative Unterschiede hinsichtlich Nekrotisierung und Verkalkung ausgemacht werden, die mit steigender Dosis vermehrt auftraten. Es lagen keine Hinweise auf systemische inflammatorische oder toxische Nebeneffekte vor, lediglich eine reizlose postaurikuläre Alopezie war bei drei Mäusen zu beobachten. Mit aKA behandelte Tiere wiesen höhere VEGF-Plasmalevel auf als unbehandelte Tiere, was auf längere Sicht eine verbesserte Tumorvaskularisierung und damit eine gesteigerte Empfindlichkeit gegenüber hämatogen verabreichten Therapien, wie der Chemotherapie, bedeuten könnte. Intratibiale Sauerstoffmessungen des gesunden kontralateralen Beines zeigten physiologische Werte ohne signifikante Unterschiede zwischen den Versuchsgruppen. Das aKA gehört damit zu den in vitro und in vivo erfolgreich angewendeten Mitgliedern der EISA (enyzme-induced self assembly)-Familie, in die in den letzten Jahren große Hoffnungen der Präzisionsnanomedizin gesetzt wird. Nach Optimierung und Etablierung des erweiterten murinen Modells könnte der nächste Schritt die Übertragung ins kanine Großtiermodell sein, um die klinische Vergleichbarkeit zum Menschen zu verbessern. Zusätzlich könnten derartige Studien der kaninen Osteosarkomtherapie neue Türen öffnen. Diese Strategie könnte Wegbereiter für eine langersehnte tumorzellgerichtete und schonendere Therapie sein, die Lebensqualität und Überlebenszeiten humaner und kaniner Patienten steigert.Great hopes of science rest on the tumor cell-directed therapy of neoplastic diseases. However, elaborate investigations in vitro and in vivo are required before it can be applied clinically. Pires’ group has already achieved very promising results during their in vitro experiments on the efficacy of the therapeutic agent ACA in combination with an osteosarcoma cell line. Based on this, a first in vivo application of ACA in the murine model was carried out in this work. Initially, the used osteosarcoma cell line K7M2 was tested in vitro with various doses of ACA. Subsequently, ACA was aimed to be evaluated in vivo for its influence on tumor progression, efficiency and systemic side effects. In addition, we planned to generate data on intraosseous oxygen due to the insufficient data situation. First, within the in vitro experiments, the influence of different doses of ACA on the metabolic activity of K7M2 cells was investigated using viability assay, DNA quantification, microscopy and oxygen measurements. The next step involved orthotopic implantation of K7M2 cells into the proximal tibia of male C57BL/6J mice. After a tumor growth phase of 20 days, the mice were daily treated with different doses of ACA for 14 days. From day 35 until the end of the experiment on day 50, the animals were under observation. At day 0, 20, 21, 35 and 50, followup monitoring was performed using μCT, blood collection, histology of tumorbearing tibia and oxygen measurement of healthy tibia. Analogous to the experiments of Pires et al. (Pires et al., 2015), the metabolic suppressing effect of ACA could be demonstrated on K7M2 osteosarcoma cells. The difference was already significant after 7 hours. In addition, it was possible to detect dose-dependent oxygenation 48 hours after ACA exposure. In the preclinical murine model, a dose-dependent reduction in total bone volume compared to the untreated tumor-only group was observed on day 50. The effect occurred with a time delay after the end of therapy. In addition, treatment with ACA caused a dose-dependent increase in bone mineral density. Histologically, qualitative differences in necrosis and calcification could be identified between groups treated with ACA, which increased with higher dose. There was no evidence of systemic inflammatory or toxic side effects, with only mild postauricular alopecia diagnosed in three mice. Animals treated with ACA had higher VEGF plasma levels than untreated animals which could cause improved tumor vascularization in the longer term and thus increased sensitivity to hematogenous therapies such as chemotherapy. Intratibial oxygen measurements of the healthy contralateral leg showed no significant differences between the experimental groups. ACA is one of the members of the EISA (enzyme-induced self-assembly) family that has been successfully applied in vitro and in vivo, in which high hopes of precision nanomedicine have been placed in recent years. After optimization and establishment of the extended murine model, the next step could be the transfer to a canine large animal model to improve clinical comparability to humans. In addition, such studies of canine osteosarcoma therapy could open new doors. This strategy could pave the way for a long-desired tumor cell-directed and more gentle therapy that enhances the quality of life and survival of human and canine patients

Patient-reported Outcomes and Quality of Life After Treatment of Choroidal Melanoma: A Comparison of Enucleation Versus Radiotherapy in 1596 Patients

Purpose: To test the hypothesis that patients treated with radiotherapy for choroidal melanoma enjoy better quality of life (QoL) than patients who have undergone enucleation. Methods: In this nonrandomized study, patients with choroidal melanoma treated at the Royal Liverpool University Hospital, Liverpool, UK, were invited to complete QoL questionnaires approximately 6 months postoperatively and then on each anniversary of their primary treatment. These instruments consisted of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-OPT30 questionnaire, Hospital Anxiety and Depression Scale, and the Functional Assessment of Cancer Treatment questionnaire. Patient-reported outcomes were correlated with demographics, ocular treatment, social factors, presenting tumor and ocular status, self-reported general health, marital status, and employment status. Results: The 1596 patients were treated with radiotherapy (72.3%) or enucleation (27.7%). Enucleation was associated with male sex (χ2, P = .004), older age (t test, P Conclusions: Patient-reported outcomes and QoL were worse in patients who had undergone primary enucleation for choroidal melanoma. These outcomes may partly have been caused by factors predisposing to enucleation rather than enucleation itself, because enucleated patients tended to be older, with more advanced disease at presentation, and a worse prognosis for survival. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.</p

Prediction of all-cause mortality from 24 month trajectories in patient-reported psychological, clinical and quality of life outcomes in uveal melanoma patients

AbstractA number of patient-reported outcomes (PROs) predict increased mortality after primary cancer treatment. Studies, though, are sometimes affected by methodological limitations. They often use control variables that poorly predict life expectancy, examine only one or two PROs thus not controlling potential confounding by unmeasured PROs, and observe PROs at only a single point in time. To predict all-cause mortality, this study used control variables affording good estimates of life expectancy, conducted multivariate analyses of multiple PROs to identify independent predictors, and monitored PROs two years after diagnosis. We recruited a consecutive sample of 824 patients with uveal melanoma between April 2008 and December 2014. PROs were variables shown to predict mortality in previous studies; anxiety, depression, visual and ocular symptoms, visual function impairment, worry about cancer recurrence, and physical, emotional, social and functional quality of life (QoL), measured 6, 12 and 24 months after diagnosis. We conducted Cox regression analyses with a census date of December 2018. Covariates were age, gender, marital and employment status, self-reported co-morbidities, tumor diameter and thickness, treatment modality and chromosome 3 mutation status, the latter a genetic mutation strongly associated with mortality. Single predictor analyses (with covariates), showed 6-month depression and poorer functional QoL predicting mortality, as did 6–12 month increases in anxiety and 6–12 month decreases in physical and functional QoL. Multivariate analyses using all PROs showed independent prediction by 6-month depression and decreasing QoL over 6–12 months and 12–24 months. Elevated depression scores six months post-diagnosis constituted an increased mortality risk. Early intervention for depressive symptoms may reduce mortality.</jats:p

Prevalence, temporal course and risk factors for phantom eye symptoms in uveal melanoma

BACKGROUND: Phantom eye symptoms (PES), particularly phantom visual sensations (PVS) and phantom eye pain (PEP), are common in enucleated patients and can lead to psychological distress. Current cross-sectional studies cannot examine the temporal course of symptoms, nor can they identify dynamic risk factors or consequences of PES.METHODS: Cohort study of 105 enucleated uveal melanoma patients returning self-report questionnaires, within 4 weeks of diagnosis and 6-, 12- and 24-months post-treatment. Questionnaires measuring PVS and PEP symptoms in the week prior to completion, pain severity, Hospital Anxiety and Depression Scale scores and the Functional Assessment of Cancer Therapy scale (FACT-G) measuring quality of life.RESULTS: PVS and PEP emerged after 6 months, were relatively stable over the study and did not remit. PVS showed 6-, 12- and 24-month prevalence rates of 44.6%, 48.2% and 30.2%, and PEP 16.1%, 18.4% and 17.5% respectively. PVS were generally elementary, with only 10–15% of the total cohort experiencing complex sensations. PEP was generally neither prolonged nor intense, except in a small proportion. PVS and PEP were showed moderate associations but did not predict each other prospectively. Anxiety within 4 weeks of diagnosis was a risk factor for the initiation of PEP. Neither PVS nor PEP prospectively predicted anxiety, depression or quality of life.CONCLUSIONS: PES were prevalent and non-remitting, beginning within 6 months of enucleation. PVS and PEP may not represent symptoms of a coherent syndrome. We discuss fndings with reference to theories of phantom sensations, and directions for clinical practise and research

Narrative Delikatessen : kulturelle Dimensionen von Ernährung

Die im ersten Band der neuen "Schriftenreihe für Kulturökologie und Literaturdidaktik" versammelten "Narrativen Delikatessen" eröffnen ein breites Spektrum kultureller Dimensionen von Ernährung und stecken damit ein neues Forschungsgebiet ab, das im Zuge globaler Ernährungskrisen von immer größerer Relevanz ist. Die Beiträge untersuchen literarische, mediale und künstlerische Darstellungen von Ernährung in diachroner und synchroner Perspektive und legen komplexe Wechselwirkungen zwischen gesellschaftlichen und ästhetisch transformierten Diskursen offen. Dezidierte Mikroanalysen einzelner Texte stehen dabei neben überblicksartigen Untersuchungen zu spezifischen Motiven oder kulturellen Konstanten in der Inszenierung von Essen. Durch interdisziplinäre Verschränkungen gehen die Betrachtungen über den literaturwissenschaftlichen Tellerrand hinaus und erweitern die Forschungsperspektiven zum Themenkomplex Ernährung auf vielfältige Weise

Associations between empirically proportionate and disproportionate fears of cancer recurrence and anxiety and depression in uveal melanoma survivors: Five-year prospective study.

ObjectiveFear of cancer recurrence (FCR) may develop into elevated anxiety or depression symptoms, but few risk factors for this development are known. Objective recurrence risk estimation is possible in some cancers. Using theories of risk communication and phobias, we examined whether the proportionality of FCR to known objective recurrence risk influences the development of anxiety and depression symptoms.MethodUveal melanoma (UM) patients can opt for reliable prognostic testing. Patients experience either a 'good' or 'poor' prognostic outcome, whereby 10-year mortality due to metastatic disease is, respectively, low or high. In a five-year prospective study of a consecutive sample of 589 UM survivors, we used random intercept cross lagged panel analyses to examine whether proportionality differentially influences whether FCR progresses to anxiety and depression.ResultsPositive cross paths predicting anxiety from FCR were stronger in the poor prognosis group than the good prognosis and not tested groups. Prognostic group differences were not evident for depression.ConclusionsFCR was more likely to progress to elevated anxiety symptoms when proportionate to the known objective recurrence risk. Objective evidence may play a prominent role in the development and structure of fear because it assumes a high epistemic weight that activates a wide range of emotional and cognitive responses. Interventions that assist survivors to tolerate FCR in the presence of higher recurrence risks may be important in reducing anxiety symptoms

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO