A superconducting gravimeter on the island of Heligoland for the high-accuracy determination of regional ocean tide loading signals of the North Sea

The superconducting gravimeter GWR iGrav 047 has been installed on the small offshore island of Heligoland in the North Sea approximately at sea level with the overall aim of high-accuracy determination of regional tidal and non-tidal ocean loading signals. For validation, a second gravimeter (gPhoneX 152) has been setup within a gravity gradiometer approach to observe temporal gravity variations in parallel on the upper land of Heligoland. This study covers the determination of regional ocean tide loading (OTL) parameters based on the two continuous gravimetric time-series after elimination of the height-dependent gravity component by empirical transfer functions between the local sea level from a nearby tide gauge and local attraction effects. After reduction of all gravity recordings to sea level, both gravimeters provide very similar height-independent OTL parameters for the eight major diurnal and semidiurnal waves with estimated amplitudes between 0.3 nm s−2 (Q1) and 11 nm s−2 (M2) and RMSE of 0.1–0.2 nm s−2 for 2 yr of iGrav 047 observations and a factor of 2 worse for 1.5 yr of gPhoneX 152 observations. The mean absolute OTL amplitude differences are 0.3 nm s−2 between iGrav 047 and gPhoneX 152, 0.4 nm s−2 between iGrav 047 and the ocean tide model FES2014b and 0.7 nm s−2 between gPhoneX 152 and FES2014b which is in good agreement with the uncertainty estimations. As by-product of this study, OTL vertical displacements are estimated from the height-independent OTL gravity results from iGrav 047 applying proportionality factors dh/dg for the eight major waves. These height-to-gravity ratios and the corresponding phase shifts are derived from FES2014b. The OTL vertical displacements from iGrav 047 are estimated with amplitudes between 0.4 mm (Q1) and 5.1 mm (M2) and RMSE of 0.1–0.7 mm. These OTL amplitudes agree with FES2014b within 0.0 (M2) and 0.8 mm (K1) with a mean difference of 0.3 mm only. The OTL amplitudes from almost 5 yr of GNSS observations show deviations of up to 6 mm (M2) compared to vertical displacements from both iGrav 047 and FES2014b, which suggests systematic effects included in the estimation of OTL vertical displacements from GNSS. With the demonstrated accuracy, height-independent sensitivity in terms of gravity and vertical displacements along with the high temporal resolution and the even better performance with length of time-series, iGrav 047 delivers the best observational signal for OTL which is representative for a large part of the North Sea

Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG)

To evaluate the effect of first-line and subsequent therapies, the outcome of 1,558 patients with chronic lymphocytic leukemia from five prospective phase II/III trials conducted between 1999 and 2010 was analyzed. The 3-year overall survival rate was higher after first-line treatment with chemoimmunotherapies such as fludarabine/cyclophosphamide/rituximab (87.9%) or bendamustine/rituximab (90.7%) compared to chemotherapies without an antibody (fludarabine/cyclophosphamide: 84.6%; fludarabine: 77.5%; chlorambucil: 77.4%). Furthermore, the median overall survival was longer in patients receiving at least one antibody-containing regimen in any treatment line (94.4 months) compared to the survival in patients who never received an antibody (84.3 months, P 24 months after first-line therapy repeated the first-line regimen. Among 315 patients requiring treatment <= 24 months after first-line therapy, cyclophosphamide/doxorubicin/vincristine/prednisone with or without rituximab as well as alemtuzumab were the most commonly used therapies. In these early relapsing patients, the median overall survival was shorter following therapies containing an anthracycline and/or three or more cytotoxic agents (e.g. cyclophosphamide/doxorubicin/vincristine/prednisone or fludarabine/cyclophosphamide/mitoxantrone, 30.0 months) compared to single agent chemotherapy (e.g. fludarabine; 39.6 months) and standard chemoimmunotherapy (e.g. fludarabine/cyclophosphamide/rituximab: 61.6 months). In conclusion, the analysis confirms the superior efficacy of chemoimmunotherapies in patients with chronic lymphocytic leukemia. Moreover, the use of aggressive chemo(immuno) therapy combinations in patients with an early relapse does not offer any benefit when compared to less intensive therapies

Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia

In addition to clinical staging, a number of biomarkers predicting overall survival (OS) have been identified in chronic lymphocytic leukemia (CLL). The multiplicity of markers, limited information on their independent prognostic value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We therefore performed an analysis of 23 prognostic markers based on prospectively collected data from 1948 CLL patients participating in phase 3 trials of the German CLL Study Group to develop a comprehensive prognostic index. A multivariable Cox regression model identified 8 independent predictors of OS: sex, age, ECOG status, del(17p), del(11q), IGHV mutation status, serum beta(2)-microglobulin, and serum thymidine kinase. Using a weighted grading system, a prognostic index was derived that separated 4 risk categories with 5-year OS ranging from 18.7% to 95.2% and having a C-statistic of 0.75. The index stratified OS within all analyzed subgroups, including all Rai/Binet stages. The validity of the index was externally confirmed in a series of 676 newly diagnosed CLL patients from Mayo Clinic. Using this multistep process including external validation, we developed a comprehensive prognostic index with high discriminatory power and prognostic significance on the individual patient level. The studies were registered as follows: CLL1 trial (NCT00262782, http://clinicaltrials.gov), CLL4 trial (ISRCTN 75653261, http://www.controlled-trials.com), and CLL8 trial (NCT00281918, http://clinicaltrials.gov)

Bendamustine and rituximab in combination with lenalidomide in patients with chronic lymphocytic leukemia

PurposeA phase I/II trial to assess safety and efficacy of the combination bendamustine, rituximab, and lenalidomide (BRL) in patients with chronic lymphocytic leukemia (CLL). Patients and MethodsSeventeen relapsed or refractory (R/R) and five previously untreated (FL) CLL patients were enrolled in the trial. In the R/R cohort, four different dose levels of lenalidomide (maximum 15 mg/d) were used. In the FL cohort, lenalidomide was dose escalated from 5 mg/d to 15 mg/d. Bendamustine was used at doses of 50 or 90 mg/m(2) for R/R or FL treatment, respectively. 375 mg/m(2) Rituximab were used for the first and 500 mg/m(2) for subsequent treatment courses. Treatment consisted of up to six courses of 28 d. ResultsThe maximal tolerable dose of lenalidomide was 5 mg/d. The response rate was 47.1% in R/R and 60% in FL patients. Median progression-free survival was 8.0 months. Median overall survival was 22.9 and 12.3 months, respectively, in R/R and FL patients. Grade 3/4 hematological toxicity was observed in 71.4%, and severe infections in 47.6% of patients. Due to high toxicity and low response rate of BRL, the trial was closed prematurely. ConclusionBRL was associated with a high toxicity rate, a high number of treatment interruptions, and a low remission rate. Therefore, BRL cannot be considered an appropriate treatment option for patients with CLL