Clinical Development of Experimental Therapies for Malignant Glioma

Advances in medical and surgical treatments in the last two to three decades have resulted in quantum leaps in the overall survival of patients with many types of non-central nervous system (CNS) malignant disease, while survival of patients with malignant gliomas (WHO grades 3 and 4) has only moderately improved. Surgical resection, external fractionated radiotherapy and oral chemotherapy, during and after irradiation, remain the pillars of malignant glioma therapy and have shown significant benefits. However, numerous clinical trials with adjuvant agents, most of them administered systemically and causing serious complications and side effects, have not achieved a noteworthy extension of survival, or only with considerable deterioration in patients’ quality of life. Significant attention was focussed in the last decades on the cell biology and molecular genetics of gliomas. Improved understanding of the fundamental features of tumour cells has resulted in the introduction and increasing clinical use of local therapies, which employ spatially defined delivery methods and tumour-selective agents specifically designed to be used in the environment of a glioma-invaded brain. This review summarises the key findings of some of the most recent and important clinical studies of locally administered novel treatments for malignant glioma. Several such therapies have shown considerable anti-tumour activity and a favourable profile of local and systemic side effects. These include biodegradable polymers for interstitial chemotherapy, targeted toxins administered by convection enhanced delivery, and intra- and peritumourally injected genetically modified viruses conferring glioma-selective toxicity. Areas of possible improvement of these therapies and essential future developments are also outlined.

European-wide forest monitoring substantiate the neccessity for a joint conservation strategy to rescue European ash species (Fraxinus spp.)

European ash (Fraxinus excelsior) and narrow-leafed ash (F. angustifolia) are keystone forest tree species with a broad ecological amplitude and significant economic importance. Besides global warming both species are currently under significant threat by an invasive fungal pathogen that has been spreading progressively throughout the continent for almost three decades. Ash dieback caused by the ascomycete Hymenoscyphus fraxineus is capable of damaging ash trees of all age classes and often ultimately leads to the death of a tree after years of progressively developing crown defoliation. While studies at national and regional level already suggested rapid decline of ash populations as a result of ash dieback, a comprehensive survey at European level with harmonized crown assessment data across countries could shed more light into the population decline from a pan-European perspective and could also pave the way for a new conservation strategy beyond national boarders. Here we present data from the ICP Forests Level I crown condition monitoring from 27 countries resulting in > 36,000 observations. We found a substantial increase in defoliation and mortality over time indicating that crown defoliation has almost doubled during the last three decades. Hotspots of mortality are currently situated in southern Scandinavia and north-eastern Europe. Overall survival probability after nearly 30 years of infection has already reached a critical value of 0.51, but with large differences among regions (0.20–0.86). Both a Cox proportional hazard model as well as an Aalen additive regression model strongly suggest that survival of ash is significantly lower in locations with excessive water regime and which experienced more extreme precipitation events during the last two decades. Our results underpin the necessity for fast governmental action and joint rescue efforts beyond national borders since overall mean defoliation will likely reach 50% as early as 2030 as suggested by time series forecasting.European-wide forest monitoring substantiate the neccessity for a joint conservation strategy to rescue European ash species (Fraxinus spp.)publishedVersio

Activation of T Lymphocytes in Response to Persistent Bacterial Infection: Induction of CD11b and of Toll-Like Receptors on T Cells

T cell activation is invariably associated with virus infections, but activation of T cells is also noted, for example, in patients with persistent bacterial infections with intracellular pathogens or localised bacterial biofilms. The latter is characterised by a destructive inflammatory process. Massive infiltration of leukocytes, predominantly of polymorphonuclear neutrophils (PMNs) and of T lymphocytes, is seen. While PMN influx into sites of bacterial infection is in line with their role as “first-line defence” a role of T cells in bacterial infection has not yet been delineated. We now found evidence for activation and expansion of peripheral blood T cells and an upregulation of Toll-like receptors 1, 2, and 4 on small portions of T cells. T cells recovered from the infected site were terminally differentiated and produced interferon gamma, a cytokine known to enhance functions of phagocytic cells, leading to the conclusion that infiltrated T cells support the local immuner defence

CLRM-14. OPEN-LABEL, MULTINATIONAL, MULTICENTER, PHASE 3B/4 STUDY OF TRASTUZUMAB DERUXTECAN (T-DXD) IN PATIENTS WITH OR WITHOUT BASELINE BRAIN METASTASIS (BM) WITH PREVIOUSLY TREATED ADVANCED/METASTATIC HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2–POSITIVE BREAST CANCER (HER2+ BC): DESTINY-BREAST12

Abstract BACKGROUND Despite treatment advances, up to 50% of patients with advanced HER2+ BC develop BM (Zimmer. Cancer Rep. 2020). Patients with HER2+ BC with BM have a worse prognosis than patients without BM. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a subgroup with stable BM, with a confirmed objective response rate (ORR) of 61.4% and an extracranial confirmed ORR by independent central review (ICR) of 58.3%, median progression-free survival (PFS) of 19.4 and 18.1 mo, and median duration of response (DOR) of 20.8 and 16.9 mo (Modi. Cancer Res. 2021; Jerusalem. Ann Oncol. 2020). Here we describe a trial evaluating T-DXd in patients with previously treated advanced/metastatic HER2+ BC ±BM. DESIGN DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (86 sites in the US, Europe, Australia, and Japan), phase 3b/4 study assessing T-DXd 5.4 mg/kg q3w efficacy and safety in patients with previously treated advanced/metastatic HER2+ BC ±BM that progressed with ≥1 prior anti-HER2–based regimen and received ≤2 lines of therapy in the metastatic setting (excluding patients with prior tucatinib). Patients (n=250/cohort) will be enrolled in cohort 1 (−BM at baseline) or 2 (+BM at baseline). BM must be untreated and not needing immediate local therapy or previously treated and stable or progressing. Primary endpoints are ORR (cohort 1) and PFS (cohort 2) (both by RECIST version 1.1 per ICR). Secondary endpoints are OS, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and QOL in both cohorts; incidence of new symptomatic CNS metastasis (CNSM) in cohort 1; and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNSM in cohort 2. This is an encore; the original presentation will be at The European Society for Medical Oncology 2021

Serum concentrations of cortisol, interleukin 6, leptin and adiponectin predict stress induced insulin resistance in acute inflammatory reactions

Introduction Inflammatory stimuli are causative for insulin resistance in obesity as well as in acute inflammatory reactions. Ongoing research has identified a variety of secreted proteins that are released from immune cells and adipocytes as mediators of insulin resistance; however, knowledge about their relevance for acute inflammatory insulin resistance remains limited. In this study we aimed for a clarification of the relevance of different insulin resistance mediating factors in an acute inflammatory situation. Methods Insulin resistance was measured in a cohort of 37 nondiabetic patients undergoing cardiac surgery by assessment of insulin requirement to maintain euglycaemia and repeated measurements of an insulin glycaemic index. The kinetics of cortisol, interleukin 6 (IL6), tumour necrosis factor alpha (TNF alpha), resistin, leptin and adiponectin were assessed by repeated measurements in a period of 48 h. Results Insulin resistance increased during the observation period and peaked 22 h after the beginning of the operation. IL6 and TNF alpha displayed an early increase with peak concentrations at the 4-h time point. Serum levels of cortisol, resistin and leptin increased more slowly and peaked at the 22-h time point, while adiponectin declined, reaching a base at the 22-h time point. Model assessment identified cortisol as the best predictor of insulin resistance, followed by IL6, leptin and adiponectin. No additional information was gained by modelling for TNF alpha, resistin, catecholamine infusion rate, sex, age, body mass index (BMI), operation time or medication. Conclusions Serum cortisol levels are the best predictor for inflammatory insulin resistance followed by IL6, leptin and adiponectin. TNF alpha, and resistin have minor relevance as predictors of stress dependent insulin resistance

Das Naturschutzgebiet Aland-Elbe-Niederung – Ausweisung eines NSG zur Umsetzung der Ziele von NATURA 2000

Die EU verabschiedete am 21. Mai 1992 die Richtlinie zur Erhaltung der natürlichen Lebensräume sowie der wildlebenden Tiere und Pflanzen, die sogenannte Fauna-Flora-Habitat-Richtlinie (FFH-Richtlinie). Die Mitgliedsstaaten sind seitdem verpflichtet, ein europaweites Netz von besonderen Schutzgebieten zur Erhaltung der biologischen Vielfalt und zur Förderung einer nachhaltigen Entwicklung aufzubauen. In dieses Natura 2000 genannte Netz sind auch die auf der Grundlage der seit 1979 geltenden EU-Vogelschutzrichtlinie gemeldeten Europäischen Vogelschutzgebiete (EU SPA) integriert. Die reichhaltige Naturausstattung Sachsen-Anhalts ermöglichte die Auswahl von 265 FFH-Gebieten und 32 Vogelschutzgebieten (EU SPA). Die Gebiete wurden als „Gebiete von gemeinschaftlicher Bedeutung der kontinentalen und der atlantischen biogeographischen Region“ im Amtsblatt der EU vom 15.01.2008 veröffentlicht. Nach den Vorgaben der FFH- und Vogelschutzrichtlinie sind die Natura 2000-Gebiete nun als besondere Schutzgebiete national zu sichern. Darüber hinaus sind in den besonderen Schutzgebieten geeignete Maßnahmen zu treffen, um die Verschlechterung der natürlichen Lebensräume und der Habitate der Arten, für die die Gebiete ausgewiesen worden sind, zu vermeiden (vgl. Art. 6, Abs. 2 FFH Richtlinie). Alle erforderlichen Maßnahmen sind an den Ansprüchen der in den jeweiligen Gebieten vorkommenden Lebensraumtypen und Arten auszurichten. Mit dem vorliegenden Sonderheft wird beispielhaft der Verfahrensweg der Ausweisung des Naturschutzgebietes Aland-Elbe-Niederung zur Umsetzung von Natura 2000 im Land Sachsen-Anhalt dokumentiert. Neben der Darstellung der naturräumlichen Situation des Gebietes und seiner naturschutzfachlichen Bedeutung werden insbes. Inhalt und Ablauf des Verwaltungsverfahrens sowie die Lösung der vielfältigen Nutzungskonflikte dargestellt. Dem Heft liegt eine beidseitig bedruckte Schutzgebietskarte des Landes Sachsen-Anhalt im Maßstab 1:250.000 bei. Auf einer Seite sind Schutzgebiete nach internationalem Recht dargestellt. Die zweite Seite der Karte liefert eine aktuelle Zusammenstellung (Stand 31.12.2009) der nach Landesnaturschutzrecht geschützten Gebiete und Objekte. Ein Beiheft mit Namen, Bezeichnung und Größe aller Gebiete komplettiert die Ausgabe

EH-myomesin splice isoform is a novel marker for dilated cardiomyopathy

The M-band is the prominent cytoskeletal structure that cross-links the myosin and titin filaments in the middle of the sarcomere. To investigate M-band alterations in heart disease, we analyzed the expression of its main components, proteins of the myomesin family, in mouse and human cardiomyopathy. Cardiac function was assessed by echocardiography and compared to the expression pattern of myomesins evaluated with RT-PCR, Western blot, and immunofluorescent analysis. Disease progression in transgenic mouse models for dilated cardiomyopathy (DCM) was accompanied by specific M-band alterations. The dominant splice isoform in the embryonic heart, EH-myomesin, was strongly up-regulated in the failing heart and correlated with a decrease in cardiac function (R = −0.86). In addition, we have analyzed the expressions of myomesins in human myocardial biopsies (N = 40) obtained from DCM patients, DCM patients supported by a left ventricular assist device (LVAD), hypertrophic cardiomyopathy (HCM) patients and controls. Quantitative RT-PCR revealed that the EH-myomesin isoform was up-regulated 41-fold (P < 0.001) in the DCM patients compared to control patients. In DCM hearts supported by a LVAD and HCM hearts, the EH-myomesin expression was comparable to controls. Immunofluorescent analyses indicate that EH-myomesin was enhanced in a cell-specific manner, leading to a higher heterogeneity of the myocytes’ cytoskeleton through the myocardial wall. We suggest that the up-regulation of EH-myomesin denotes an adaptive remodeling of the sarcomere cytoskeleton in the dilated heart and might serve as a marker for DCM in mouse and human myocardium

Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers

Introduction: We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy. Methods: Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years. Results: In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results. Conclusions: Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy