Abstract: Topography and relief variability play a key role in ecosystem functioning and structuring. However, the most commonly used concept to relate pattern to process in landscape ecology, the so-called patch-corridor-matrix model, perceives the landscape as a planimetric surface. As a consequence, landscape metrics, used as numerical descriptors of the spatial arrangement of landscape mosaics, generally do not allow for the examination of terrain characteristics and may even produce erroneous results, especially in mountainous areas. This brief methodological study provides basic approaches to include relief properties into large-scale landscape analyses, including the calculation of standard landscape metrics on the basis of "true" surface geometries and the application of roughness parameters derived from surface metrology. The methods are tested for their explanatory power using neutral landscapes and simulated elevation models. The results reveal that area and distance metrics possess a high sensitivity to terrain complexity, while the values of shape metrics change only slightly when surface geometries are considered for their calculation. In summary, the proposed methods prove to be a valuable extension of the existing set of metrics mainly in "rough" landscape sections, allowing for a more realistic assessment of the spatial structure.

Abstract: We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time 〈 12 months, serum thymidine kinase 〉 10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W & W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0–99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W & W patients (median not reached vs. 18.5 months, p   〈  0.001). There was no significant overall survival benefit for high-risk patients receiving early FCR therapy (5-year OS 82.9% in Hi-FCR vs. 79.9% in Hi-W & W, p  = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care “watch and wait” for these patients.

Abstract: Introduction Chronic lymphocytic leukemia (CLL) is a disease of the elderly patient with a median age of 72 years at diagnosis. In addition to a generally increased obesity prevalence, higher age is also associated with increased body fat contents, and currently 22.5% of men and 31.8% of women above 65 years in Germany qualify as obese (body mass index [BMI] ≥30 kg/m²). While high BMI values are regarded as a risk factor for certain cancers, the impact of obesity on treatment outcomes is controversial and differs between genders. In aggressive B-cell lymphoma the prognosis of obese elderly women was worse following R-CHOP chemoimmunotherapy (CIT). With this meta-analysis the question whether obesity has an impact in CLL was addressed. Methods We analyzed pooled data from three prospective phase III trials (CLL4, CLL8, CLL10) of the German CLL study group (GCLLSG). With the aim to assess the effect of rituximab, patients treated with fludarabine monotherapy (F) or bendamustine and rituximab (BR) were excluded from this analysis. Underweighted patients (BMI 〈 18.5 kg/m², n=10) were excluded as well. Finally, the total analysis cohort comprised 1237 previously untreated patients receiving fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). We analyzed progression-free survival (PFS) and overall survival (OS) according to baseline BMI (normal weight (NW) 18.5-24.9 kg/m²; overweight (OW) 25-29.9 kg/m²; obese (OB) ≥ 30 kg/m²), gender and treatment regimen. Kaplan-Meier curves were plotted and compared by non-stratified log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression modelling. Results In this combined cohort 560 (45.3%) patients received FC and 677 (54.7%) received FCR. 319 (25.8%) patients were female, 918 (74.2%) were male, median age was 60 years (range 30-81). The cohort comprised 497 (40.2%) NW patients, 521 (42.1%) OW patients and 219 (17.7%) OB patients. Median BMI was 25.1 kg/m² (range 18.6-45.0) in the female and 26.0 kg/m² (range 18.7-45.2) in the male study population. Clinical characteristics, in particular CLL-IPI risk groups and other prognostic factors, were equally distributed between BMI subgroups. Median observation time was 68.4 (range 0.4-151.3) months. OB patients received lower CIT doses compared to NW patients with regard to planned doses based on body surface area (Table 1). Medians of given dose intensities were for fludarabine: NW 95.1% (range 10.8-124.7) vs. OB 84.0% (range 9.2-121.0), for cyclophosphamide: NW 93.5% (range 11.1-105.7) vs. OB 84.0% (range 9.2-102.3), and for rituximab: NW 98.2% (range 0.1-108.7) vs. OB 88.9% (range 26.8-101.3). This difference was observed in male and female patients. We found significantly increased creatinine clearance rates in OB patients of both genders calculated by three different methods including the Salazar/Corcoran method that adjusts for obesity. PFS and OS according to the three BMI groups were not different in the entire cohort comprising both genders or males only. However, obese females had significantly worse outcomes following FCR treatment compared to NW females: median PFS was 44.6 in OB vs. 73.0 months in NW females (HR 1.743 [1.022-2.973]; p=0.041) and the median OS was 83.7 months compared to not reached in the female NW group (HR 3.013 [1.345-6.752] ; p=0.007) (Figure 1). These survival differences could not be detected in FC treated females (Figure 2). Conclusions Our data suggest that obesity is associated with significantly shorter PFS and OS in female CLL patients undergoing FCR chemoimmunotherapy but not conventional FC chemotherapy without rituximab. Therefore we assume that lower relative chemotherapy dose exposition that OB females received was not the major contributing factor to this survival difference. In contrast, we assume lower rituximab exposure in OB females treated with FCR due to obesity-associated increased clearance rates as described before. The significantly increased creatinine clearance rates in OB female patients might have additionally contributed to this effect, however the detailed mechanisms remain to be characterized. Our results are in line with recently published data on obesity as a survival risk factor in female patients with aggressive B-cell lymphoma undergoing R-CHOP CIT. Taken together, this warrants closer metabolic and anthropometric status evaluation in future immunotherapeutic studies. Disclosures Hopfinger: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria; Janssen: Honoraria; Gilead: Honoraria, Research Funding. Fink:Celgene: Consultancy, Research Funding; AbbVie: Consultancy, Other: travel geants; Roche: Other: travel grants; Mundipharma: Other: travel grants. Al-Sawaf:Roche: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Langerbeins:Sunesis: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Mundipharma: Consultancy, Other: Travel grants; Roche: Consultancy, Other: Travel grants, Research Funding. Cramer:Mundipharma: Other: Travel grants; Roche: Honoraria, Other: Travel grants, Research Funding; Acerta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Gilead: Other: Travel grants, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grants, Research Funding; AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel grants, Research Funding. Von Tresckow:Celgene: Consultancy, Other: Travel grants; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; Janssen-Cliag: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria. Kutsch:Janssen: Other: Travel support; AbbVie: Other: Travel support; Mundipharma: Other: Travel support; Gilead: Research Funding. Hoechstetter:Hexal: Other: Travel Grants; Abbvie: Other: Travel Grants; Gilead Sciences: Consultancy, Other: Travel Grants. Dreyling:Gilead: Consultancy, Honoraria; Mundipharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Acerta: Consultancy; Sandoz: Consultancy. Kneba:AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Stilgenbauer:Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding. Döhner:AbbVie: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding. Hensel:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jaeger:Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria. Wendtner:Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding. Goede:Janssen: Honoraria, Other: Travel grants; Abbvie: Consultancy; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel grants. Fischer:Roche: Other: Travel support. Hallek:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding.