Abstract: Background High quality response [very good partial remission (VGPR), complete remission (CR)] is associated with improved long-term outcome in multiple myeloma (MM) therapy. Lenalidomide (Len)/ dexamethasone (Dex) (Rd) is considered a standard 2nd-line regimen. However, after 1st-line MM therapy containing a “novel agent” like thalidomide, only a relatively small fraction (21.3%) of patients (pts) achieved VGPR or better when RD was used in relapsed/refractory MM (RRMM)1. Bendamustine (Ben) is an alkylating agent with superior activity compared to melphalan/prednisone. The combination of Ben, Len and Dex (BRd) in pts with advanced RRMM resulted in dose-limiting hematotoxicity, which restricted its efficacy in extensively pretreated pts2. However, recent phase I experience demonstrated the feasibility of BRd as 2nd- and 3rd-line myeloma therapy3. We therefore evaluated the efficacy and toxicity of the BRd-regimen as 2nd line therapy for RRMM. Patients and methods This multicenter Phase II study was designed to enroll 50 pts with RRMM undergoing 2nd-line MM therapy [including also pts with prior autologous stem cell transplantation (ASCT)]. Pts had to have measurable disease, ECOG performance status 0-2, adequate hematological values and a creatinine clearance 〉 50 ml/min. Study treatment consisted of Ben 75 mg/m2 i.v. day (d) 1 & 2 and Len 25 mg p.o. d 1-21 for a total of six 28-day induction cycles. Dex (40 and 20 mg p.o. for pts 〈 = or 〉 75 years of age, respectively) was given on d 1, 8, 15, and 22. Pegfilgrastim 6 mg s.c. was administered on d 3 in case of severe neutropenia, treatment delay due to neutropenia or febrile neutropenia according to predefined application rules. Induction treatment was followed by 12 cycles (28 d) of maintenance therapy with Rd at the same dose. The primary study endpoint was the CR/VGPR rate after induction therapy, based on standard IMWG criteria. A Simon's two stage design was used to differentiate between 20% (considered uninteresting) vs 40 % (considered promising, power of 80%, p=5%) of high quality responses. At least 13 pts with VGPR or better after induction therapy were required to meet the statistical threshold predefined for promising activity of the BRd regimen in this study. Results 50 pts were enrolled between 04/2012 and 07/2014 (median age 68 years [46-84y], 73% men). 49% pts had ISS stage II/III, 42.5% had undergone prior SCTs, and 13% had known high risk cytogenetic aberrations. 91% of pts had received novel agents (thalidomide, bortezomib) during 1st-line therapy. At the time of abstract submission, data from 38 pts having completed induction treatment were available. Final analysis of the primary study endpoint including all patients will be updated and presented at the meeting. Of the currently 38 evaluable pts, 20 (52.6%, Table 1) achieved a CR/VGPR after a median of 3.3 induction cycles. Only 1 patient experienced disease progression (PD) during induction phase. 77% of pts received pegfilgrastim. Dose reduction during induction therapy was required in 7.7% of pts. 42.5% received 〈 6 scheduled induction cycles (50% due to toxicities, 50% for other reasons). 49% had treatment-related SAEs. Grade 3/ 4 neutropenia and thrombocytopenia occurred in 51%/25.5% and 23.4%/8.5% of pts, respectively. Only 1 patient developed CTC grade 3 febrile neutropenia. Most common grade 3/4 non-hematologic toxicities were infections (14%), rash (9.5%), and diarrhea (9.5%). Anaphylactic reaction grade 4 related to Ben and pulmonary embolism grade 3 occurred in 1 patient each. A cerebral insult grade 4 occurred in a patient non-compliant with the anti-thrombotic prophylaxis required per protocol. One death due to respiratory failure (considered to be unlikely related to study treatment) was reported for an 83 year old male. Conclusion BRd is a safe and efficacious regimen for 2nd line treatment of RRMM patients whose 1st-line therapy included thalidomide or bortezomib. High quality responses ( 〉 = VGPR) can be achieved in a considerable proportion (52.6%) of these pts. Our study suggests that the fraction of patients achieving VGPR or better after BRd treatment may be substantially higher than attainable with Rd alone. References 1 Wang et al. Blood, 2008, 112: 4445-51 2 Lentzsch et al. Blood, 2012, 119: 4608-13 3 Poenisch et al., Br J Haematol, 2013, 162, 202–9 Table 1 Best response after induction CR VGPR PR MR SD total (n=38) 3 17 15 1 2 prior ASCT (n=16) 2 6 7 1 0 no prior ASCT (n=22) 1 11 8 0 2 Disclosures Mey: Mundipharma: Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Use of Bendamustine in relapsed/refractory Multiple Myekoma. To investigate the efficacy and safety of Bendamustine in combination with the standard backbone of Lenalidomide/ Dexamethasone in patients with replaced/refractory MM.. Bargetzi:Celgene: Membership on an entity's Board of Directors or advisory committees. Taverna:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schmid:Celgene: Honoraria. Knauf:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. von Moos:Amgen: Consultancy, Honoraria, Research Funding. Hiendlmeyer:Celgene: Research Funding; Mundipharma: Research Funding; Amgen: Research Funding. Hitz:Celgene: Research Funding. Driessen:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.

Abstract: This survey was conducted to identify factors that influence how patients with neovascular age-related macular degeneration (nAMD) deal with their disease and information that are considered useful from a patient’s point of view. Methods A total of 5035 patients with nAMD living in Germany were interviewed via internet-based cross-sectional survey, where the following information was collected: personal data, disease awareness, and patients’ needs. In addition, a Quality of Life questionnaire (SF-12v2) could be completed. Results Out of the 5035 participants, more males than females participated (55% vs 45%), and most participants were in the age groups 76 to 85 years (37%) and 66 to 75 years (35%). Seventy-three percent of patients rated their understanding of the disease as at least sufficient, and more than two-thirds of the patients (68%) were aware that their disease needs to be controlled on a regular basis and treated on an “as needed” basis. Regarding potential risk factors for AMD, most participants were aware of age (89%), but only 39% of hereditary load and 33% of smoking as evidence-based risk factors, indicating a need for further information. The doctor remains the major source of information (93%), with internet (29%), brochures (14%), opticians (13%), or patient support groups (4%) with only limited contribution. Distance to the treatment center was identified as one of the factors, which had the greatest influence on patients’ compliance. A “treat as needed” regime turned out to be the preferred control and treatment schedule in contrast to a “fixed appointment” every 4 weeks. Conclusion This internet-based survey appears to be representative for nAMD patients. To increase patients’ compliance, proximity to the treatment center and a “treat as needed” regime turned out to be important factors as well as patients’ awareness of their disease. In this regard, the reported desire for more information indicates that patients’ knowledge still needs to be improved. Our results will help to further optimize patient care and patient-oriented information.

Abstract: Colorectal cancer is one of the main cancers in the Western world. About 90% of the deaths arise from formation of distant metastasis. The expression of the newly identified gene metastasis associated in colon cancer 1 (MACC1) is a prognostic indicator for colon cancer metastasis. Here, we analyzed for the first time the impact of single nucleotide polymorphisms (SNPs) in the coding region of MACC1 for clinical outcome of colorectal cancer patients. Additionally, we screened met proto-oncogene (Met), the transcriptional target gene of MACC1, for mutations. Methods We sequenced the coding exons of MACC1 in 154 colorectal tumors (stages I, II and III) and the crucial exons of Met in 60 colorectal tumors (stages I, II and III). We analyzed the association of MACC1 polymorphisms with clinical data, including metachronous metastasis, UICC stages, tumor invasion, lymph node metastasis and patients’ survival (n = 154, stages I, II and III). Furthermore, we performed biological assays in order to evaluate the functional impact of MACC1 SNPs on the motility of colorectal cancer cells. Results We genotyped three MACC1 SNPs in the coding region. Thirteen % of the tumors had the genotype cg (rs4721888, L31V), 48% a ct genotype (rs975263, S515L) and 84% a gc or cc genotype (rs3735615, R804T). We found no association of these SNPs with clinicopathological parameters or with patients’ survival, when analyzing the entire patients’ cohort. An increased risk for a shorter metastasis-free survival of patients with a ct genotype (rs975263) was observed in younger colon cancer patients with stage I or II (P = 0.041, n = 18). In cell culture, MACC1 SNPs did not affect MACC1-induced cell motility and proliferation. Conclusion In summary, the identification of coding MACC1 SNPs in primary colorectal tumors does not improve the prediction for metastasis formation or for patients’ survival compared to MACC1 expression analysis alone. The ct genotype (rs975263) might be associated with a reduced survival for younger colon cancer patients in early stages. However, further studies with larger sample sizes are needed.

Abstract: Glucocorticoids (GCs) are critical regulators of metabolic control in mammals and their aberrant function has been linked to several pathologies. GCs are widely used in human and veterinary clinical practice as potent anti-inflammatory and immune suppressive agents. Dyslipidaemia is a frequently observed consequence of GC treatment, typified by increased lipolysis, lipid mobilization, liponeogenesis, and adipogenesis. Dogs with excess GC show hyperlipidaemia, hypertension, and a higher risk of developing type 2 diabetes mellitus, but the risk of developing atherosclerotic lesions is low as compared to humans. This study aimed to examine alterations in the canine plasma lipidome in a model of experimentally induced short-term and long-term GC excess. Both treatments led to significant plasma lipidome alterations, which were more pronounced after long-term excess steroid exposure. In particular, monohexosylceramides, phosphatidylinositols, ether phosphatidylcholines, acyl phosphatidylcholines, triacylglycerols and sphingosine 1-phosphates showed significant changes. The present study highlights the hitherto unknown effects of GCs on lipid metabolism, which will be important in the further elucidation of the role and function of GCs as drugs and in metabolic and cardiovascular diseases.