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In patients with RAS wild-type metastatic colorectal cancer, depth of response (DpR) has gained importance as a novel end-point in clinical trials. We investigated the overall DpR, as well as the prognostic and predictive impact of DpR to induction therapy (six cycles of 5-fluorouracil, leucovorin [FU/FA], oxaliplatin [FOLFOX] and panitumumab [Pmab]) on consecutive maintenance therapy (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial.Central radiological assessment was performed according to RECIST 1.1. DpR was defined as percentage change in tumour diameter within defined time intervals (induction therapy, maintenance therapy, total course of therapy). For prognostic and predictive analyses, median DpR (/≥) served as threshold.Out of 248 patients receiving maintenance therapy, 211 were evaluable for DpR analyses (FU/FA + Pmab, n = 106; FU/FA alone, n = 105). The overall DpR in all patients was 56.5%. DpR of induction therapy (42.5%) accounted for the largest proportion (75.2%) of the overall DpR. While greater DpR to induction therapy was significantly associated with prolonged PFS (HR 0.70, 95% CI 0.52-0.93, p = 0.013) and OS (HR 0.38, 95% CI 0.28-0.51, p 0.001), there was no significant correlation of DpR and maintenance treatment arm.In the PanaMa trial, the overall DpR was similar to DpR achieved by other epidermal growth factor receptor-based regimens. DpR to induction therapy accounted for three quarters of the total tumour shrinkage potentially suggesting that FOLFOX plus Pmab can be de-escalated following induction without substantially compromising efficacy. DpR to induction therapy was prognostic but not predictive for efficacy of consecutive maintenance therapy.NCT01991873.

51 Background: The PANAMA study demonstrated superior progression-free survival (PFS) with the addition of panitumumab (Pmab) to fluorouracil and folinic acid (FU/FA) as maintenance therapy following first-line induction therapy with FOLFOX/Pmab in patients with RAS wild-type metastatic colorectal cancer. We report health-related quality of life (HRQOL) analyses of the PANAMA study. Methods: HRQOL was assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at every cycle of therapy until disease progression. All patients who received at least one dose of induction therapy and completed at least one HRQOL assessment were included into the analysis. HRQOL outcomes were mean changes in EORTC QLQ-C30 from baseline (prior to cycle 1 of induction therapy) to each cycle of treatment (both induction and maintenance therapy). The trial is registered with ClinicalTrials.gov (NCT01991873). Results: In total, 349/377 (93%) of the induction and 237/248 pts (96%) of the maintenance group completed at least one HRQOL assessment and were included in the HRQOL analysis population. There were no significant differences in any of the EORTC QLQ-C30 items between both treatment arms before induction therapy and at randomization. From baseline to cycle 6 of induction therapy there was significant improvement in mean EORTC QLQ-C30 global health status (GHS)/QOL, functioning (except for cognitive functioning) and symptom (except for nausea and vomiting, dyspnea, appetite loss, constipation, and financial difficulties) scores in the randomized population. During maintenance therapy, no significant differences between FU/FA plus Pmab and FU/FA alone were observed. In both arms of the trial, GHS/QOL scores were maintained or trended to improve from baseline (start of induction therapy) to cycle 10 of maintenance therapy (FU/FA plus Pmab: mean difference 9.48 [95% CI 1.96-17.00]; p=0.014); FU/FA arm (mean difference 6.52 [95% CI –1.9-14.95]; p=0.128). Conclusions: Using the established EORTC QLQ-C30 assessment, the addition of Pmab to FU/FA as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer did not impair the HRQOL endpoints analyzed compared to FU/FA alone. These results, along with previously reported improvement in PFS, may support clinical decision-making concerning maintenance treatments. Clinical trial information: NCT01991873 .

Soils, the thin skin of the earth, a living body, are the basis of all highly developed life and have ensured human existence and culture since millennia. Their functions and ecosystem services are crucial for the survival of humanity. Increasing pressure on soils through overuse and mismanagement has exceeded their capacity to perform, which is considered as soil degradation. To meet the mission of the Sustainable Development Goals of the United Nations, soil degradation must be stopped and reversed. We reviewed framework conditions of soil degradation, scientific concepts of research and status and trends of their operationalization. Soil performance and degradation processes must be understood, monitored, mitigated and combated in the context of different categories and scales such as ecosystems, land and landscapes. Approaches to the assessment and monitoring of soil dynamics, degradation and desertification show inconsistencies and knowledge gaps at several levels. Concepts of soil health and ecosystem services of soil should be backed by “hard data” based on field and landscape indicators and measurements. Participatory approaches to mediate conflicting demands of stakeholders are crucial for a broad understanding of soil and its long-term sustainable use. This requires an advanced field diagnostic system of soil performance based on reliable on-site measurement technology in combination with expert-based knowledge and assessment methodologies. Strengthening field soil science is essential for progress in reducing and reversing soil degradation.

Physical soil degradation is a deterioration of the soil’s structure diminishing its functions and ecosystem services. It is mainly initiated and manifested by physical forces and processes, such as energy impacts of water, wind and mechanical pressure on soils, and it is accelerated by various kinds of anthropogenic pressure. This is a threat to meeting visions of the Sustainable Development Goals of the United Nations. We review the current state of some types of physical soil degradation, such as erosion by water, wind and tillage, soil compaction and soil sealing/land take. Despite some knowledge in research of degradation processes, gaps in knowledge and need for action exist at several levels. There is a need to understand the event-wise, stochastic character of erosion and compaction processes and the complex interaction of mechanical disturbances of soil structure with soil hydrological and biochemical processes. The implications of these processes for soil health and ecosystem functioning must be better quantified, yielding indicators, baseline values and thresholds. Progress is needed to develop simulation models of soil erosion and compaction towards complex modular models that can figure and forecast ecosystem processes. There is a demand to construct manageable decision support systems, which can help to plan and conduct zero-soil degradation projects at a landscape level. Cross-comparisons of models and strengthening the databases in terms of field laboratories and long-term experiments are essential to prevent and monitor soil degradation at different scales.

Doxorubicin represents the standard first-line treatment for metastatic soft-tissue sarcoma. We assessed the efficacy and safety of trofosfamide in elderly patients. In this controlled phase II trial, we randomly (1:2) assigned 120 previously untreated patients with soft-tissue sarcoma, older than 60 years, with an Eastern Cooperative Oncology Group score of 0–2, to receive either doxorubicin for 6 cycles (arm A) or oral trofosfamide (arm B). The primary end-point was a 6-month progression-free rate (PFR) in the experimental arm (clinical trial information: NCT00204568). Between August 2004 and October 2012, forty and 80 patients were randomly assigned to arm A and arm B, respectively, in 16 centres. The median age was 70 years (range, 60–89). The primary study end-point (6-month PFR) was exceeded, with 27.6% in arm B (95% confidence interval [CI], 18.0–39.1) and 35.9% in arm A: (95% CI, 21.2–52.8). Survival data in terms of progression-free survival were 4.3 months (95% CI, 2.2–6.3) and 2.8 months (95% CI, 1.7–3.6) and in terms of overall survival were 9.8 months (95% CI, 6.7–11.6) and 12.3 months (95% CI, 9.6–16.2), respectively. The number of serious adverse event (SAE) was 59% in arm A and 30.3% in arm B (p = 0.005). Trofosfamide caused more often dyspnoea and low-grade fatigue, whereas with doxorubicin, more often leukocytopenia, neutropenia and mucositis were seen. Discontinuation rates for reasons other than disease progression were 15.4% (arm A) vs. 7.9% (arm B). In an elderly population of patients, oral trofosfamide achieved the estimated primary end-point 6-month PFR and was associated with a favourable toxicity profile compared with doxorubicin.

3616 Background: MSI due to mismatch repair defects accounts for 15-20% of all CC, has high prognostic and predictive value and is broadly utilized in treatment decisions. Artificial intelligence (AI) integrated, label-free quantum cascade laser (QCL) based infrared (IR) imaging resolves spatial and molecular alterations such as MSI in unstained cancer tissue sections. We aimed to evaluate the method for microsatellite instability/stability (MSI/MSS) classification in samples from the prospective multicenter AIO CPP registry trial. Methods: Paraffin-embedded unstained cancer tissue slides from patients (pts.) participating in CPP were measured (avg. 30 min/slide) and analyzed. The cohort was split into training (train), test (test), and validation (vali) sets. Cancer regions were first preselected based on a self-developed convolutional neural network (CNN) CompSegNet (Schuhmacher, medrxiv 2021). A VGG-16 CNN then classified MSI/MSS in these regions. Endpoints were area under receiver operating characteristic (AUROC) and area under precision recall curve (AUPRC). Results: 547 pts. (train n=331, test n=69, vali n=147) were analyzed. The baseline characteristics for the sub-cohorts are illustrated in the table. Mutation (MT) status: RAS MT: train 30% / test 30% / vali 37%; BRAF MT: train 27% / test 23% / vali 14%. The preselection of cancer regions reached a validation AUROC of 1.0. The subsequent MSI/MSS classifier reached a validation AUROC of 0.9 and AUPRC of 0.74 (sensitivity 85%, specificity 84%). Conclusions: Our multicenter approach using AI integrated label-free IR imaging provides an automated, fast, and reliable classification for MSI/MSS with an AUROC of 0.9 (sensitivity 85%, specificity 84%) almost comparable to the present gold standard immunohistochemistry. The method described here requires less samples for training when compared to other AI approaches which could facilitate the development of prognostic/predictive classifiers in the setting of randomized controlled trials. This novel technique may support further understanding of the increasingly important MSI CC cohort and support treatment decisions e.g. in specific subgroups such as targetable fusions. We expect our approach to be a broadly applicable diagnostic tool in the future.[Table: see text]

Sustainable intensification (SI) is a concept for increasing agricultural production under sustainable conditions to meet the needs of the worldwide growing population. We reviewed the status and trends of SI on the basis of latest scientific publications. Some progress was found in evolving the concept of SI for meeting the Sustainable Development Goals of the United Nations. However, gaps in knowledge and quantitative data are largely missing. To achieve progress in understanding and evolving SI, knowledge about soils is of paramount importance. Soil data are suitable indicators for sustainable land-use practices. We used data of soil resilience and productivity for assessing land potentials for SI. Six intrinsic land and soil characteristics (organic C content, clay + silt, pH, CEC, soil depth and slope) were selected as indictors for defining the resilience and performance of land in Europe. These six indicators comprise the main biochemical and physical soil properties. To analyze the potential of SI in EU-25, the above described approach was based on LUCAS 2009 topsoil data, using the dataset of the arable land in the Corine Land Use Cover 2006 as well as to the European Soil Database (ESDB). The results show that due to a low natural resilience and productivity of soils, almost half (44%) of the investigated arable land cannot be recommended for SI. More than 3% of this area should be de-intensified in order to reduce environmental harm. 16% of the arable land can be recommended for SI with restrictions, whereas 40% of arable land has the potential for SI without impacting the delivery of goods and services provided by soils. As Europe is a region of suitable bio-climatic and societal conditions for sustainable land management, serious limitations for SI must be expected in other parts of the globe. Interdisciplinary studies should clarify this problem.

Agricultural landscapes (rural landscapes, agrolandscapes) are territories shaped by agricultural production. They have enabled the development of human civilizations and are a cultural achievement. Peasants, farmers and agricultural enterprises feed society. They have created agricultural landscapes for their business and habitats for their life. To understand transformation processes in agricultural landscapes, we analyse the history of agriculture with a special focus on Europe and Eurasia. Current agricultural landscapes in a crowded, globalized world are multifunctional, highly complex systems. They not only serve to produce food commodities and energy for the increasing and expanding urban population but also provide diverse ecosystem services and need to cater for the demands of the rural population. Current agriculture is highly productive in wealthy countries, but due to high inputs it is also responsible for environmental problems such as water pollution and loss of biodiversity. Industrial-style agriculture in large fields has resulted in increased productivity but simplified the structure of landscapes and eliminated elements of nature and rural culture. Major problems that urgently need to be addressed include trends towards disrupting natural cycles in agricultural production, soil and water degradation, ageing populations in villages and the breakdown of rural infrastructure. Agricultural landscape research provides analyses to understand these processes and helps elaborate sustainable scientific, technical and cultural solutions.

Fil: Mueller, Lothar. Leibniz Centre for Agricultural Landscape Research. Alemania. Fil: Eulenstein, Frank. Leibniz Centre for Agricultural Landscape Research. Alemania. Fil: Mirschel, Wilfried. Leibniz Centre for Agricultural Landscape Research. Alemania. Fil: Schindler, Uwe. Kuban State Agrarian University. Rusia. Fil: Sychev, Viktor G. Pryanishnikov-Institute for Agrochemistry. Rusia. Fil: Rukhovich, Olga V. Pryanishnikov-Institute for Agrochemistry. Rusia. Fil: Sheudzhen, Askhad K. Kuban State Agrarian University. Rusia. Fil: Romanenkov, Vladimir. Moscow Lomonosov State University. Rusia. Fil: Lukin, Sergey M. All Russian Research Institute for Organic Fertiliser and Peat. Rusia. Fil: McKenzie, Blair M. University of Dundee. Escocia. Fil: Jones, Michael. Norwegian University of Science and Technology. Noruega. Fil: Dannowski, Ralf. Leibniz Centre for Agricultural Landscape Research. Alemania. Fil: Blum, Winfried E. H. University of Natural Resources and Life Sciences. Austria. Fil: Salnjikov, Elmira. Soil Science Institute. Serbia. Fil: Saparov, Abdulla. Kazakh Research Institute of Soil Science and Agrochemistry. Kazajistán. Fil: Pachikin, Konstantin. Kazakh Research Institute of Soil Science and Agrochemistry. Kazajistán. Fil: Hennings, Volker. Büro Für Bodenfunktionsbewertung. Alemania. Fil: Scherber, Christoph. Zoological Research Museum Alexander Koenig. Alemania. Fil: Hoffmann, Jörg. Institute for Strategies and Technology Assessment, Sustainable Agriculture and Biodiversity. Alemania. Fil: Antrop, Marc. Ghent University. Bélgica. Fil: Garibaldi, Lucas A. Universidad Nacional de Río Negro. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural. Río Negro, Argentina. Fil: Garibaldi, Lucas A. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural. Río Negro, Argentina. Fil: Gómez Carella, Dulce S. Universidad Nacional de Río Negro. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural. Río Negro, Argentina. Fil: Gómez Carella, Dulce S. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural. Río Negro, Argentina. Fil: Augstburger, Horacio. University of Bern. Suiza. Fil: Schwilch, Gudrun. University of Bern. Suiza. Fil: Angelstam, Per. Swedish University of Agricultural Sciences. Suecia. Fil: Manton, Michael. Vytautas Magnus University. Lituania. Fil: Dronin, Nikolai M. Moscow Lomonosov State University. Rusia.

Most vegetated land on earth has been used for agriculture for hundreds of years, shaping the land’s features and functions. Agricultural (rural) landscapes are the basis for feeding the global population and meeting their many other demands. In the globalised world of the twenty-first century, agriculture is facing some crucial challenges: feeding more people whilst maintaining natural resources, biodiversity and landscape heritage, and mitigating climate change. This requires new knowledge, innovations and decision tools for taking responsible action. Research on agricultural landscapes provides analyses to help understand landscape processes and elaborates sustainable scientific, technical and cultural solutions. We report on recent progress in some topics of measuring, modelling and monitoring processes, and on organismic diversity in agricultural landscapes, focusing on developments in Western Europe. Information is also given about long-term experimental agricultural research in Russia and neighbouring countries. Results indicate that there has been considerable progress in understanding landscape processes based on experimental and modelling research on different scales. A number of landscape-related research methods and tools have been developed in recent years. These include high-tech measurement systems, models and decision aids, and tools for monitoring and optimising agricultural systems and for agri-environmental monitoring. Many of them also have potential for successfully tackling existing problems with the sustainability of agricultural systems in other landscapes and regions. Transdisciplinary international research projects are required to make innovations operable.

Colorectal cancer is one of the leading malignancies and still accounts for almost 25 000 deaths in Germany each year. Although there is accumulating data on the molecular basis, treatment and clinical outcome of patients within clinical trials evidence from the real-world setting is mostly lacking. We started the molecular registry trial Colopredict Plus in 2013 to collect clinical and molecular data from a real-world cohort of patients with early colon cancer stage II and III in 70 German colon cancer centers focusing on the prognostic impact of high microsatellite instability. In this interim report, we characterize a clinical cohort of 2615 patients, of whom 1787 tissue probes were analyzed. Microsatellite status was assessed using immunhistochemistry and fragment length analysis, with a concordance of 91.4 %. These established histopathological methods are sensitive and cost-effective. The median age was 72 years, significantly higher compared to clinical trial populations, with a median Charlson Comorbidity Index of 3. The stage-dependent incidence of microsatellite instability was 23.7 % and was associated with female gender, BRAF-mutation, UICC stage II and localization in the right colon. Survival calculated in disease free, relapse free and overall survival significantly differed between MSI-H and MSS, in favor of MSI-H patients. Multivariate age-adjusted analyses of relapse-free survival, disease-free survival, and overall survival highlighted microsatellite instability as a robust and positive prognostic marker for early colon cancer independent of age.Das kolorektale Karzinom ist weiterhin eine der häufigsten Tumorerkrankungen mit einer Mortalität von fast 25 000 pro Jahr in Deutschland. Obwohl wir mehr und mehr Daten zur molekularen Basis, zu neuen Behandlungsmethoden und Verläufen von Patienten im Rahmen klinischer Studien generieren, gibt es nur wenige Informationen aus der klinischen Versorgungsrealität. Wir starteten die molekulare Registerstudie Colopredict Plus im Jahre 2013, um klinische sowie molekulare Daten von einer „Real-World“-Kohorte von Patienten mit Kolonkarzinomen im UICC-Stadium II und III aus 70 deutschen Darmkrebszentren zu dokumentieren. Der Fokus liegt hier auf dem prognostischen Wert einer hochgradigen Mikrosatelliteninstabilität. In dieser Interimsanalyse charakterisieren wir das klinische Kollektiv von 2615 Patienten, von denen 1787 Tumorproben analysiert wurden. Der Mikrosatellitenstatus wurde via Immunhistochemie und Fragmentlängenanalyse mit einer Konkordanz von 91,4 % durchgeführt, was eine kosteneffektive histopathologische Nachweismethodik darstellt. Das mediane Alter lag bei 72 Jahren und damit deutlich höher als üblicherweise in klinischen Studien, der mediane Charlson Comorbidity Index lag bei 3. Die stadienabhängige Mikrosatelliteninstabilität-Inzidenz lag bei 23,7 % und war assoziiert mit dem weiblichen Geschlecht, BRAF-Mutationen, UICC-Stadium II und der Primärtumorlokalisation im rechten Kolon. Das Überleben berechnet in krankheitsfreiem, rezidivfreiem sowie Gesamtüberleben unterschied sich signifikant zugunsten der MSI-H-Patienten. Multivariate altersadjustierte Analysen des rezidivfreien und krankheitsfreien Überlebens sowie des Gesamtüberlebens bestätigten eine hochgradige Mikrosatelliteninstabilität als robusten und positiven prognostischer Marker für frühe Kolonkarzinome unabhängig vom Alter.

An agricultural landscape is a section of a region shaped by its natural landscape features primarily involving agricultural land use and land management. Intensive anthropogenic activities have left a permanent mark on agricultural landscapes, which have been developed over hundreds of years. Agricultural landscapes constitute a spatiotemporal structure. Hence they represent a complex system in which a large number of processes occur continuously that, due to their temporal dynamics, lead to constant changes in the state of the system. Traditional experiments are inappropriate for the impact assessment of anthropogenic and naturally occurring changes in agricultural landscapes. The only option here is to conduct virtual landscape experiments at the computer level. To this end, a relevant set of spatial, quantifiable landscape indicators is defined that can be used to map the landscape on the computer. Building on the extensive expertise in agricultural landscape research, indicators can be mapped using validated and robust models and their dynamics described involving temporal aspects. Various model types can be used in this process. Special simulation environments involving the use of spatial data and accounting for possible land use and global changes enable forward-looking scenario simulations to provide answers to the question of the sustainability of agricultural land use systems. Decision support systems (DSS) that exploit the latest possibilities offered by information technology, statistics and artificial intelligence provide the framework for integrating models, spatial data concerning the state of the landscape and scenario data, simulation techniques as well as tools for interpreting and visualising results. Such DSS are also the basis for quantifying the complex impact of site conditions, changes in land use or management, and of potential climate change on individual landscape parameters or landscape indicators. A number of examples show how indicator-based models of different types can be used to assess the impact and sustainability of land use systems on a landscape scale. As a prerequisite for the development and validation of integrated dynamic landscape models, more long-term ecological studies and monitoring systems are required. This also means that more resources are necessary to support these activities. The use of models and virtual simulation experiments within a DSS framework at the computer is a very promising way of finding suitable site-specific complex measures for the adaptation of agriculture to climate change.

Background Palliative chemotherapy of advanced oesophageal squamous cell cancer (ESCC) consists of cisplatin/5-fluorouracil (CF) to target epidermal growth factor receptor (EGFR) with panitumumab (P); chemotherapy enhanced overall survival (OS) in advanced colorectal or squamous cell head and neck cancers. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in advanced ESCC. Patients and methods Eligible patients with confirmed ESCC that was not curatively resectable or did not qualify for definitive radiochemotherapy, were randomised 1 : 1 to receive CF [cisplatin (C) 100 mg/m2 i.v., day 1; 5-fluorouracil (F) 1000 mg/m2 i.v., days 1–4] or CF plus P (9 mg/kg, i.v., day 1, each q3-week cycle) until progressive disease or unacceptable toxicity. Safety was reviewed by the Data Safety Monitoring Board after 40, 70 and 100 patients who completed at least one cycle. After 53 enrolled patients, cisplatin was reduced from 100 mg/m2 to 80 mg/m2. Results The trial was stopped early based on interim efficacy results triggered by the third safety analysis: median OS (mOS) favoured CF over CFP, regardless of cisplatin dose [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.06–2.98; P = 0.028]. In the final analysis, mOS was 10.2 versus 9.4 months for CF versus CFP, respectively (HR 1.17, 95% CI 0.79–1.75; P = 0.43). One hundred (70.4%) of 142 patients in the safety population died, 51 (51.0%) with CFP. Most deaths were related to disease progression [44/49 (90%) deaths in CF versus 34/51 (67%) deaths in CFP]; objective responses [27/73 (37.0%)] were identical. The most common serious adverse events were kidney injury [3 (4.3%) versus 7 (9.7%)], general health deterioration [5 (7.1%) versus 5 (6.9%)] and dysphagia [4 (5.7%) versus 4 (5.6%)] in CF versus CFP, respectively. There were three (4.3%) and 17 (23.6%) common terminology criteria for adverse events (CTCAE) grade 5 events in CF versus CFP, respectively. Low soluble (s)EGFR levels were associated with better progression-free survival; sEGFR was induced under CFP. Conclusion EGFR inhibition added to CF did not improve survival in unselected advanced ESCC patients. The results support further liquid biopsy studies. Trial registration ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15).

10–20% of patients with gastric cancer (GC) have HER2+ tumors. Addition of trastuzumab (T) to cisplatin/fluoropyrimidine-based chemotherapy (CT) improved survival in metastatic, HER2+ GC. When pertuzumab (P) was added to neoadjuvant T and CT, a significant increase in histopathological complete response rate was observed in HER2+ breast cancer. This study aims to investigate the added benefit of using both HER2 targeting drugs (T alone or the combination of T + P), in combination with perioperative CT for localized HER2+ GC. This is a prospective, randomized, open-label, phase II trial. HER2 status from patients with resectable GC (UICC TNM7 tumor stage Ib-III) will be centrally determined. Two hundred and-fifteen patients from 52 sites in 14 countries will be centrally randomized (1:2:2 ratio) to one of the following treatment arms: 1. Standard: CT alone. CT regimens will be FLOT (5-FU, leucovorin, oxaliplatin, taxotere) CapOx (capecitabine, oxaliplatin) or FOLFOX (5-FU, leucovorin, oxaliplatin) according to investigator’s choice in Europe, and cisplatin/capecitabine in Asia. 2. Experimental arm 1: CT as in control group, plus T (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) at day 1, independent of CT chosen for 3 cycles of 3 weeks before and after surgery. 3. Experimental arm 2: CT plus T as in experimental arm 1, plus P (840 mg every 3 weeks) on day 1. Standard: CT alone. CT regimens will be FLOT (5-FU, leucovorin, oxaliplatin, taxotere) CapOx (capecitabine, oxaliplatin) or FOLFOX (5-FU, leucovorin, oxaliplatin) according to investigator’s choice in Europe, and cisplatin/capecitabine in Asia. Experimental arm 1: CT as in control group, plus T (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) at day 1, independent of CT chosen for 3 cycles of 3 weeks before and after surgery. Experimental arm 2: CT plus T as in experimental arm 1, plus P (840 mg every 3 weeks) on day 1. Adjuvant treatment with T or T + P will continue for 17 cycles in total. Stratification factors are: histology (intestinal/non-intestinal); region (Asia vs Europe); location (GEJ vs non-GEJ); HER2 immunohistochemistry score (IHC 3+ vs IHC 2+/FISH+) and chemotherapy regimen. Primary objective is to detect an increase in the major pathological response rate from 25 to 45% either with CT plus T alone, or with CT plus the combination of T and P. Depending on the results of the INNOVATION trial, the addition of HER2 targeted treatment with either T or T and P to CT may inform future study designs or become a standard in the perioperative management HER2+ GC. This article reports a health care intervention on human participants and was registered on July 10, 2014 under ClinicalTrials.gov identifier: NCT02205047 ; EudraCT: 2014–000722-38.

Studies have demonstrated that body surface area-based dosing of chemotherapy drugs leads to significant individual exposure variability, with a substantial risk of under- or overdosing. The present study was initiated to validate the use of therapeutic drug management (TDM) to personalize 5-fluorouracil (5-FU) dosing in patients with metastatic colorectal cancer treated in routine clinical practice.A total of 75 patients with metastatic colorectal cancer from 8 German medical centers received ≤ 6 administrations of infusional 5-FU according to the AIO (folinate, 5-FU; n = 16), FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin; n = 26), or FUFOX (oxaliplatin plus 5-FU/folinic acid; n = 33) regimen. Initial infusional 5-FU dosing for all patients was determined by the BSA. Individual 5-FU exposure (area under the curve [AUC]) was measured using an immunoassay of a blood sample taken during each infusion. To achieve a target AUC of 20 to 30 mg × h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle's 5-FU AUC. The primary objective was to confirm that TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the fourth versus the first administration. The secondary objective was to determine whether 5-FU TDM reduced the treatment-related toxicities compared with the historical data.The average 5-FU AUC at the first administration was 18 ± 6 mg × h/L, with 64%, 33%, and 3% of the patients below, within, or above the target AUC range, respectively. By the fourth administration, the average 5-FU AUC was 25 ± 7 mg × h/L (P .001), with 54% of patients within the target 5-FU AUC range (P = .0294). The incidence of 5-FU-related grade 3 and 4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%), and mucositis (0.2%) was reduced compared with the historical data, despite 55% of the patients receiving increased doses.Personalization of 5-FU dosing using TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested a lower incidence of 5-FU-related toxicities.

BACKGROUND Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

264 Background: The novel drug EDO-S7.1 (CAP7.1) is converted to active etoposide by CES allowing administration of higher doses, reducing resistance, and permitting treatment of advanced tumors. Methods: The primary objective was to compare disease control rate (DCR) in 22 pts with unresectable BTC randomized 1:1 to 3-week cycles of EDO-S7.1 (200 or 150mg/m2; iv) given on days (d) 1–5, or best supportive care (BSC) until progression (assessed every 4 weeks). Secondary objectives were progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. BSC pts could crossover to EDO-S7.1 upon progression. Results: DCR favored EDO-S7.1 (55.6% [CI 21.2, 86.3] vs BSC (20.0% [2.5, 55.6]; treatment difference –12.80, 72.39). More EDO-S7.1 treated pts achieved sustainable stable disease (SD) or partial response (PR) vs BSC. Progressive disease occurred in 40% EDO-S7.1 vs 70% BSC pts. Three pts (30%) who progressed on BSC achieved SD following crossover to EDO-S7.1, and one pt (10%) PR (total: 40.0% [12.2, 73.8]) vs two pts with SD following BSC (20.0% [2.5, 55.6]; treatment difference –0.17, 0.57; p=0.0786). Median PFS was 103d with EDO-S7.1 vs 39d with BSC (p=0.006), and median TTF 92d vs 39d, respectively (p=0.006). Median OS was 227d with EDO-S7.1 vs 162d with BSC (p=0.088), and estimated 1-year OS 44% vs 11.3%, respectively. EDO-S7.1 had significant efficacy in pts with metastatic disease (p=0.029) or without prior surgery (p=0.032). Seven pts were eligible for exploratory analysis of tumor CES via immunohistochemistry. 4/7 pts had CES+ tumors and longer median PFS (195d [163, 233]) and OS (302d [214, 838]) vs pts with CES– tumors (46d [46, 83] and 83d [43, 319], respectively). The most common drug-related adverse events (G3–4) (%) were leukopenia 65 (26.1), neutropenia 78.3 (56.5), thrombocytopenia 56.5 (17.4), anemia 52.2 (17.4), alopecia 34.4 (0), fatigue 26.1 (0), and abdominal pain 30.4 (0). Conclusions: EDO-S7.1 demonstrated efficacy in pts with advanced BTC and may provide a new biomarker-guided therapeutic option with stratification by intra-tumor CES assessment. These findings will be explored in a larger patient cohort. Clinical trial information: NCT02094560.

Background: Advanced unresectable esophageal squamous cell cancer (ESCC) is treated with palliative chemotherapy of cisplatin and 5-fluorouracil (CF). Targeting epidermal growth factor receptor (EGFR) with antibodies panitumumab (P) or cetuximab with chemotherapy enhanced overall survival (OS) in metastatic colorectal cancer or squamous cell cancer of head and neck. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in confirmed advanced ESCC. Methods: 146 patients, not curatively resectable and not qualified for definitive radio-chemotherapy were randomised 1:1 to CF (cisplatin [100 mg/m² i.v., day 1] and 5-fluorouracil [1000 mg/m²/day i.v., days 1-4]), versus CF plus P [9 mg/kg, i.v., day 1], each q3-week cycle) until progressive disease or inacceptable toxicity. Safety was reviewed by a pre-planned Monitoring Board after 40, 70 and 100 patients completing at least one cycle. After 53 patients enrolled, cisplatin was amended from 100 to 80 mg/m². Findings: The academic phase 3 trial was terminated early for futility on an interim efficacy analysis: median OS favoured CF over CFP, regardless of cisplatin dose (HR 1·77, 95%CI 1·06-2·98; p=0·028). In the final analysis, median OS was 10·2 vs 9·4 months for CF vs CFP, respectively (HR 1·17, 95%CI 0·79-1·75; p=0·43). Most deaths were related to disease progression, 44 (56·4%) in CF and 34 (43·6%) in CFP. Objective responses (27/73 [37·0%]) were identical in both arms. Most common severe adverse events were kidney injury (3 [4·3%] vs 7 [9·7%]), general deterioration (5 [7·1%] vs 5 [6·9%]), and dysphagia (4 [5·7%] vs 4 [5·6%]) in CF vs CFP, respectively. High levels of soluble (s)EGFR were associated with worse PFS. sEGFR was induced under CFP. Interpretation: Cisplatin/5-fluorouracil is an established palliative regimen in unselected advanced or metastatic ESCC patients. EGFR inhibition added to CF did not improve survival. Biomarker results support further liquid biomarker studies. Trial Registration Number: The study is registered with ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15). Funding: The trial was funded by AIO-Studien-gGmbH. Partial financial support and panitumumab were provided by Amgen Inc. Declaration of Interest: MM has travel support and advisory role for Amgen. FL reports personal fees from Amgen. All other authors declare that they have no conflicts of interest during the conduct of the study. Ethical Approval: The clinical study protocol was reviewed and approved by the responsible ethics committees of all participating sites. The trial was conducted in accordance with the principles of the International Conference on Harmonisation on Good Clinical Practice. All patients gave written informed consent before enrolment and any trial-specific procedures.

A new geological epoch has begun—the Anthropocene. Huge anthropogenic transformations of terrestrial landscapes over the past five decades have forced its declaration. Exploring of interaction of humans with nature in general, and with landscapes in particular, can be characterised properly by the terms ‘landscape research’ and ‘landscape science’. Landscape science has been a traditional scientific discipline of geography. This is the case in Russia, whilst the terms geo-ecology and landscape ecology have become established in the English-speaking scientific community. As landscapes are multifunctional, highly complex systems, landscape research is a platform for disciplinary, interdisciplinary and transdisciplinary research. Landscape research in the Anthropocene must aim to combine landscape sustainability with high quality and productivity. This mission is in accord with the Sustainable Development Goals of the United Nations and the provisions of the Landscape Convention of the European Council. It includes halting landscape degradation, developing cultural landscapes and maintaining semi-natural landscapes. Clean water and air, fertile and healthy soils for food and other ecosystem services and a green and biodiverse environment are attributes of landscapes for the survival and well-being of humans in coexistence with nature. Landscape research must generate knowledge, innovations and responsible decision rules for achieving these aims. Big data gathering and scenario modelling are important for knowledge generation in a globalised world. International long-term experiments, observatories and monitoring systems will deliver data for comprehensive ecosystem models and decision support systems. Technical innovations must be imbedded in cultural solutions for the evolvement of landscapes. Springer International’s new book series ‘Innovations in Landscape Research’ aims to support better understanding, monitoring and managing landscapes. It contains a multitude of approaches and data. Some focus is on technical innovations for agri-environmental monitoring, on land and water management and its implications for landscape sustainability. Authors present novel tools for ecosystem modelling and forecasting of landscape processes, and on creating knowledge, rules and approaches for handling the multifunctionality of landscapes. The coming book series may serve as a knowledge, data and communication basis for informed decisions regarding the development of landscapes. It will enlarge our horizon and field of action by building bridges between scientific communities, scientific disciplines, and researchers and citizens.

Background Antiangiogenic agents such as bevacizumab (bev) are widely used in combination with chemotherapy to treat metastatic colorectal cancer (mCRC). Predictive markers indicating resistance to antiangiogenic agents are elusive. Cytokines and angiogenic factors (CAF) may enable such a prediction. The PERMAD trial has two phases: Phase I, reported here, aims to establish a CAF marker combination (CAFmC) that enables early prediction of treatment resistance in treatment naive patients with mCRC receiving bev plus mFOLFOX6. Phase II will prospectively evaluate this CAFmC and randomize between an early replacement of bev by aflibercept or continuation of bev when the CAFmC indicates imminent progress. Methods In phase I 41 out of 50 patients recruited in 15 centers in Germany and Austria with treatment naive mCRC under FOLFOX plus bev treatment were evaluable for CAF analysis. 102 different, preselected CAFs were prospectively collected and centrally analyzed in plasma samples (n = 647) obtained prior to treatment and biweekly until radiologic progress determined by CT scan every 2 months. The values of various CAFs were affected by both, chemotherapeutic treatment itself as well as progress. These CAF were excluded from the bioinformatic analysis. Using the remaining CAF we employed a machine learning approach to define a combination of 5 CAF whose change in values/pattern correlated with later progress at least 2 months prior to radiologic progress as determined by CT. Out of various classifiers examined, a random forest classifier provided a CAF set with the highest accuracy. Results Using the samples described above and a random forest algorithm we established a CAFmC comprising 5 CAF whose specific change in value/pattern over time indicated treatment resistance 3 months prior to radiologic progress with an accuracy of 83%. The CAFmC was established and cross-validated in two cohorts of 26 and 15 patients, respectively. Conclusions Using advanced bioinformatics we identified a CAFmC that points out treatment resistance to FOLFOX plus Bev in patients with mCRC 3 months prior to radiological progress. A decision process using this marker combination will be evaluated in the randomized phase II of the trial. Clinical trial identification NCT02331927, 2012-005657-24. Legal entity responsible for the study Ulm University Hospital. Funding Sanofi-Aventis. Disclosure T. Seufferlein: Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Celgene; Advisory / Consultancy: Lilly; Advisory / Consultancy: Boeringer Ingelheim; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche. T.J. Ettrich: Advisory / Consultancy: Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi-Aventis; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Lilly; Speaker Bureau / Expert testimony: Celgene; Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Servier. A. Konig: Travel / Accommodation / Expenses: Ipsen. L. Perkhofer: Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.

A comprehensive study of interactive processes between soil, water, plant, animal and atmosphere to protect the natural resources requires knowledge of parameters and processes in different scales. Soil hydrological studies in North-East Germany were carried out in different scales, starting with laboratory, lysimeter measurements and in the field. The measurements of soil hydrological properties were executed with the Extended Evaporation Method (EEM) and the HYPROP device. A method for quantifying deep seepage and solute leaching under field conditions was developed, tested and applied at more than 40 soil hydrological field plots in NE Germany. The hypothesis was confirmed that arable land constitutes the main source of deep drainage and groundwater recharge in Northeast Germany. Deep seepage was strongly reduced under forest. For decision support on landscape renovation and land rededication by afforestation in NE Germany the seepage reduction under forest is to be taken into consideration, especially with respect to the conservation or restoration of wetlands in regions with negative climatic water balance. The EEM and the soil hydrological field method so called “virtual lysimeter” have the potential for the improvement of soil hydrological studies in Asia as a whole.

11507Background: DOX is still the standard in metastatic STS. We assessed the efficacy and safety of oral TRO. Methods: This is a randomized phase 2 trial at 15 german and 1 french centers. We incl...

IF 6.029; International audience; BackgroundThe prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use.Patients and methodsAccording to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data.ResultsAmong the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients.ConclusionAlthough this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.

Background For patients (pts) with advanced or metastatic renal cell carcinoma (mRCC), approval of novel therapies led to continuous changes in treatment options. The Tumour Registry Renal Cell Carcinoma (TNK) analysed treatment and outcome of pts treated in Germany from 2007-2017. CARAT is the successor registry, which continues to assess longitudinal real world clinical outcome, incl. patient-reported outcomes (PROs) and decentralized biobanking. Today, we introduce CARAT and report on current changes of the treatment landscape in mRCC in Germany. Methods Since Dec 2017 150 pts have been enrolled in CARAT, expanding the previous TNK (2007-17, 1500 pts). CARAT is an observational, prospective, open, multicentre clinical research platform aiming to enrol 1000 pts by 150 sites. Pts with mRCC who start systemic 1stline treatment are eligible. Treatment characteristics, clinical outcome and physician-reported factors on treatment decision making are collected. Overall survival (OS) is assessed by the KM-method. Changes of the treatment landscape are shown descriptively. Results By April 2019 >1650 pts with mRCC have been recruited. Median age is 68 years. 60% had intermediate risk (MSKCC) at start of 1st-line. Median OS for pts with start of 1st-line 2007-17 is 19 months (>60% events). If selected by trial eligibility criteria, the median OS is 27 months. Pts who started treatment in 2018 mostly received pazopanib or sunitinib (38%/34%). Since the approval (May 2018) 18% are treated with cabozantinib. Preferred 2nd-line treatment changed from sorafenib/temsirolimus (35%/21%, 2007-09), everolimus (33% 2010-12), everolimus/axitinib/sunitinib (29%/19%/18%, 2013-15) to nivolumab (>60% since 2016). The impact of new treatment options on OS will be analysed. Conclusions Pts in routine care in Germany are older and have inferior prognosis than trial-eligible pts. CARAT complements results of RCTs with prospective data on clinical and PROs for pts with mRCC in routine care. CARAT will show changes in the choice of treatment due to new approvals, applied sequences and investigate the effectiveness in a “real world” setting. For the first time, these data will be combined with PROs and a decentralized biobank for translational research. Legal entity responsible for the study IOMEDICO. Funding Ipsen. Disclosure P.J. Goebell: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self): IOMEDICO. M. Bogemann: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Astellas; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ipsen; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Eusa Pharma; Honoraria (self), Advisory / Consultancy: ABX; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Amgen. S. Dorfel: Shareholder / Stockholder / Stock options: IOMEDICO. N.W. Marschner: Advisory / Consultancy, Leadership role, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: IOMEDICO; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ipsen. M. Staehler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): GSK; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche. V. Grunwald: Honoraria (self), Research grant / Funding (self), Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: MSD; Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self), Shareholder / Stockholder / Stock options: AstraZeneca; Honoraria (self), Research grant / Funding (self), Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: BMS; Honoraria (self), Non-remunerated activity/ies: Merck Serono; Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Lilly; Honoraria (self), Non-remunerated activity/ies: PharmaMar; Honoraria (self): Nanobiotix; Honoraria (self): Janssen. All other authors have declared no conflicts of interest.

Background Etoposide toniribate (also known as EDO-S7.1, and previously known as CAP7.1), a novel topoisomerase II inhibitor, is activated in the presence of carboxylesterases. In specific tumor cell lines, it was found to be more active than etoposide, with in vivo activity demonstrated in several drug-resistant tumor models. Anti-tumor activity was confirmed in a Phase II randomized study in patients (pts) with relapsed BTC. Methods Pts with BTC and disease progression after ≥1 line of chemotherapy were randomized 1:1 to 3-week cycles of etoposide toniribate (200 or 150mg/m2; iv on days 1–5), or best supportive care (BSC). Pts who progressed on BSC crossed over to receive etoposide toniribate. Efficacy data collected after crossover were evaluated separately as part of this post-hoc exploratory analysis. Results The per protocol analysis set included 19 pts: 10 pts were randomized to BSC, and crossed over to etoposide toniribate after disease progression, 9 pts were randomized directly to the etoposide toniribate treatment arm. Treatment after crossover from BSC to etoposide toniribate was associated with a trend for improved disease control: n/N (%; 95% CI) 4/10 (40%; 12.2, 73.8) vs 2/10 (20%; 2.5, 55.6), with tumor control achieved in 4/10 patients (1 pt partial response, 3 pts stable disease). Risk of disease progression was 2.33 times higher during BSC treatment vs after crossover to etoposide toniribate. Crossover from BSC to etoposide toniribate was associated with a trend for prolonged median PFS (39 vs 50 days). Median OS for pooled etoposide toniribate and crossover pts was 145 (59, 243) days, estimated 1-year OS 14.1%. Median (95% CI) OS for etoposide toniribate vs crossover pts was 180 (43, 468) vs 83 (11, 243) days, HR 0.39 (0.13, 1.18), estimated 1-year OS 29.6% (5.2%, 60.7%) vs 0%. Conclusions This post-hoc analysis provides further evidence for the efficacy of etoposide toniribate and suggests that early initiation in pts with advanced BTC may offer a potential survival benefit. The efficacy of etoposide toniribate will be further investigated in a planned phase III study. Funding: CellAct Pharm GmbH and Mundipharma EDO GmbH. Clinical trial identification NCT02094560. Editorial acknowledgement Sarah Birch, PhD, at Makara Health Communications Ltd, UK, funded by Mundibiopharma Ltd. Legal entity responsible for the study CellAct Pharma GmbH. Funding CellAct Pharma GmbH, Mundipharma EDO GmbH. Disclosure U. Pape: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Shire; Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ipsen. S. Kasper: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: MSD; Research grant / Funding (self): Celgene; Research grant / Funding (self), Travel / Accommodation / Expenses: Lilly. J. Meiler: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Sanofi/Aventis. M. Sinn: Honoraria (self): Amgen; Honoraria (self), Research grant / Funding (self): Leo Pharma; Honoraria (self), Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Incyte; Research grant / Funding (self): Merck Sharp and Dohme; Research grant / Funding (self): Servier; Research grant / Funding (self): Taiho Pharmaceutical. H. Jansen: Advisory / Consultancy: CellAct Pharma. T. Mehrling: Leadership role, Full / Part-time employment: Mundipharma EDO. K. Hilgier: Advisory / Consultancy: Mundipharma EDO. I. Wagner: Full / Part-time employment: Mundipharma EDO. N. Utku: Honoraria (self), Advisory / Consultancy, Leadership role, Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: CellAct Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Mundipharma EDO; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

This paper provides information about a novel approach of rating agricultural soil quality (SQ) and crop yield potentials consistently over a range of spatial scales. The Muencheberg Soil Quality Rating is an indicator-based straightforward overall assessment method of agricultural SQ. It is a framework covering aspects of soil texture, structure, topography and climate which is based on 8 basic indicators and more than 12 hazard indicators. Ratings are performed by visual methods of soil evaluation. A field manual is then used to provide ratings from tables based on indicator thresholds. Finally, overall rating scores are given, ranging from 0 (worst) to 100 (best) to characterise crop yield potentials. The current approach is valid for grassland and cropland. Field tests in several countries confirmed the practicability and reliability of the method. At field scale, soil structure is a crucial, management induced criterion of agricultural SQ. At the global scale, climate controlled hazard indicators of ...

Knowledge of the soil hydraulic functions is required for various hydrological studies and for the simulation of water and solute fluxes in unsaturated soils. Sand/kaolin boxes are frequently used to determine these properties in the low-tension range. For higher tensions the pressure plate extractor is mainly applied. The extended evaporation method allows a more efficient determination of the water-retention curve in an adequate range. Besides this method enables to quantify simultaneously the unsaturated hydraulic-conductivity function. The objective of this study was to compare the water-retention curves obtained from the standard methods (STM) with those determined with the extended evaporation method (EEM). A set of 90 natural soil samples of different texture and origin was analyzed, and the agreement between the methods was statistically evaluated. The average water-content deviation (AWCD) of all samples was 1.83 vol.%, and the root mean square error (RMSE) 2.08 vol.%. The deviation of soil water-storage capacity in the pore-size classes 0–6, 6–30, 30–500, 500–1500 kPa varied between minimum –0.17 and 0.25 vol.% and maximum –2.89 and 2.36 vol.%, and confirmed the good comparability among the adopted methods. Systematic deviations between the methods were not found.

Knowledge of hydraulic functions is required for various hydrological and plant-physiologicalstudies. The evaporation method is frequently used for the simultaneous determination ofhydraulic functions of unsaturated soil samples, i.e. , the water-retention curve and hydraulic-conductivity function. All methodic variants of the evaporation method suffer from the limitationthat the hydraulic functions can only be determined to a mean tension of ≈ 60 kPa. This iscaused by the limited measurement range of the tensiometers of typically 80 kPa on the dryend. We present a new, cost- and time-saving approach which overcomes this restriction. Usingthe air-entry pressure of the tensiometer’s porous ceramic cup as additional defined tensionvalue allows the quantification of hydraulic functions up to close to the wilting point. The proce-dure is described, uncertainties are discussed, and measured as well as simulated test resultsare presented for soil samples of various origins, different textures (sand, loam, silt, clay, andpeat) and variable dry bulk density. The experimental setup followed the system HYPROP whichis a commercial device with vertically aligned tensiometers that is optimized to perform evapora-tion measurements. During the experiment leaked water from the tensiometer interior wets thesurrounding soil of the tensiometer cup and can lead to a tension retardation as shown by simu-lation results. This effect is negligible when the tensiometers are embedded vertically. For coar-sely textured soils and horizontal tensiometer alignment, however, the retardation must be con-sidered for data evaluation.

The aim of the paper was to utilize methods of visual structure assessments in conjunction with soil physical measurements for the analysis of the impact of tillage, rotation and traffic on topsoil structure. The study was conducted in long-term-experiments on the Elora rotation (ER) and Elora Landscape (EL) sites in Canada, the Luancheng (LS) site in China and the Dedelow (DT) site in Germany. Texture of soils ranged from loamy sand (DT) to sandy loam (EL, ER) to silt loam (LS), climate ranged from clearly subhumid (LS), slightly sub-humid (DT) to humid (EL, ER). Two common variants of tillage were compared on all sites: (1) Moldboard Ploughing (MP) and (2) No-Till (NT). Within the plots, wheeltracks were analysed separately on ER and DT sites. On ER site, different rotation variants were sampled. On EL site, large alfalfa and corn plots and the driveway in between were sampled at different slope positions. Methods of visual structure analysis of Peerlkamp, Diez and Shepherd were tested along with measurements of dry bulk density (DBD), initial infiltration rates and soil penetrometer and shear resistance. Both visual structure assessment and measurements indicated significant differences between variants of tillage and traffic on DT and ER sites. Differences between alfalfa (good structure) and corn rotation (less favourable structure) were also significant on EL and ER sites. Soils in Germany and Canada were partly compacted, under wheeltracks in particular. Most favourable topsoil structure conditions were found under MP plots, most unfavourable structure was detected under wheeeltracks and NT plots. On LS site in China (loess soil, lower weights of machinery) visual structure was overall favourable and no significant differences between tillage variants were found. However, MP plots indicated the beginning of subsoil compaction. Crop yields confirmed differences between tillage variants. Yields of cereals were significantly higher (350–800 kg ha � 1 ) under MP as compared with NT on ER and DT sites due to a better air capacity. It may be concluded that (i) results of visual assessments were coincident with those of soil physical measurements and can complement them, (ii) under intensively mechanised soil management in subhumid to humid regions, NT can lead to sub-optimum topsoil structure states, (iii) subsoil compaction is a risk of MP on all soils, and (iv) controlled traffic and the inclusion of perennials into the rotation may be advantageous for soil structure.

Starting in 1993, interactions between land use and precipitation have been investigated in three research areas of northeast Germany. The research based on continuous measurements of soil water tension and water content down to a depth of 5 m at 36 plots situated at diverse soils under different land use (arable land, forest, grass fallow). At arable sites, the main period of deep seepage occurred between February and April during the study period. With 175 mm a−1, the mean annual deep seepage rate under arable land was highest at sandy soils. At loamy soils, the mean seepage rate amounting to 122 mm a−1 appeared significantly less. Smallest seepage rates, however, were determined for forested plots (pine 15 mm a−1, beech 18 mm a−1). Differences were significant as compared to arable land at sandy and loamy soils and grass fallow. It is concluded that deep seepage and groundwater recharge under forest will tend to wane at annual precipitation rates of

8051 Background: Variability of chemotherapy exposure may cause severe toxicity or lack of efficacy. Paclitaxel (PTX) exposure (time above a plasma concentration of 0.05mM, Tc > 0.05) has been show...

The aim of the study was to analyse aspects of fen soil quality for grassland use with regard to the different topsoil structure and their status of earthification/moorshification (degradation). Fifty fens of different origin, structural status and land use intensity were sampled, analysed and scored by different methods: Visual Soil Assessment, Peerlkamp test and Muencheberg Soil Quality Rating. Suitable soil structure scores were found at different land use intensities with the exception of stock tracks on pastures. These had lower water and air permeability and lower soil strength. Highest visual scores of macrostructure were found where the water table was deeper; while highest overall soil quality scores occurred where the water table was optimum. The accelerated status of moorshification had no effect on the soil quality scores and on the crop yield. At lower levels of soil development (earthification) the crop yield was slightly lower due to higher proportions of inedible plants. It may be...

The objective of the paper was to analyse the implications of the origin of peat (muck) soil substrate, the current type of land use and the state of anthropogenic soil development for the topsoil properties of fens. Chemical and biological properties of peat soils of the Rhin-Havelluch lowland and the Uckermark rural landscape were analyzed. The unit water content according to Ohde and the ash content were utilized to characterize the anthropogenic development status of peat topsoils. Several chemical properties were significantly influenced by soil substrate, in particular by the proportion and kind of the mineral component. The substrate was associated with the hydrological type of mire and the soil development state. TOC/N ratio and microbial activity were increased in cases of high lime spring mires and moorshified low ash peat. The proportion of easily soluble organic carbon increased, whereas the sulphur content decreased with the soil development state. The nitrogen content and the propor...

The aim of the study was to investigate the effects of peat soil substrate governed by the hydrological type of mire, land use and state of anthropogenic changes on the fen soil structure in terms of the water retention curve, soil aggregates and topsoil strength. Our hypothesis was that morphological parameters of the peat soil landscape, like peat thickness and water table, are correlated with functional parameters of internal soil structure like water retention or cone resistance. These parameters were measured along several transects in fens of the Rhin-Havelluch and the Uckermark region. Results confirmed our hypothesis. The peat thickness was cross-correlated with the state of anthropogenic soil changes and soil structure. The type of land use (grassland, forest) had significant implications for the moisture status and structure in terms of density, strength, pore size distribution and aggregate sizes of topsoils.

The influence of regional soil distribution and land use on discharge formation in the “Stettiner Haff” catchment (8,456 km2) was investigated. The model ABIMO was used to calculate mean discharge for a long period (1961 – 1990) in consideration of regional differences in hydrological site conditions and soil heterogeneity. The highest discharge was found on settlement areas (276 mm a−1), on devastated plots (319 mm a−1) and on the non-hydromorphic agriculturally used sandy soils (214 mm a−1). Due to their small size these sub-areas were found to influence regional discharge for a limited extent only. On loam and clay soils only about 100 mm a−1 of discharge was formed. However, this share proved to be most important for the height of regional discharge because of the high area proportion in the region. Mineral soils of comparable parent material produce lower discharge under hydromorphic conditions than under non-hydromorphic conditions. With increasing clay content of the soils these difference...

Monitoring and protecting the natural resources of soil and water, and their ecosystems, is intended to ensure the long-term conservation of their functions. To understand the reasons for resource degradation or ecosystem alterations and interactions, knowledge is required of processes and parameters on different scales of landscapes. Soil hydrological studies are an essential part of ecosystem and landscape research. The aim of our study was to develop new research methods and technical equipment to understand and monitor soil hydrological processes. The investigations were carried out on different scales, starting with laboratory and lysimeter measurements, followed by investigations in the field. To measure soil hydrological properties, we developed the Extended Evaporation Method (EEM) and the HYPROP device. In this chapter we report on some innovations in this field. Using new cavitation tensiometers and applying the air-entry pressure of the tensiometer’s porous ceramic cup as the final tension value allowed us to quantify both hydraulic functions close to the wilting point. Additionally, both soil shrinkage dynamics and soil water hysteresis can now be quantified easily and reliably. The experimental setup followed the HYPROP system, which is a commercial device with vertically aligned tensiometers that is optimized to perform evaporation measurements. Depending on the soil and the evaporation rate, the measurement time varied between 2 and at most 10 days. The simultaneous measurement of multiple soil samples was possible with only one balance. Pedotransfer functions (PDFs) were created on the basis of various measured soil water retention and hydraulic conductivity functions. In the next step, a method for quantifying deep seepage and solute leaching under field conditions was developed, tested and applied at more than 40 soil hydrological field plots in Germany. The method is based on tension and soil water content measurements down to a depth of 3 m at arable and grassland sites and a depth of 5 m at forest sites. These data were used to construct a field water retention curve. This pF curve was fitted, the relative hydraulic conductivity function K(θ) was derived and relative deep seepage rates were calculated based on DARCY’s law. To obtain reliable discharge rates, the K function was matched to the water balance. Lysimeter experiments confirmed the validity and reliability of this soil hydrological field method. It works like a virtual lysimeter on sandy to loamy soils which have a deep water table and a zero flux plane above the measurement depth The EEM and the soil hydrological field method have the potential to improve soil hydrological studies, and water and solute transport monitoring systems could be installed in Eurasia.