Abstract: The annual incidence of new cancer cases has been increasing worldwide for many years, and is likely to continue to rise. In Germany, the number of new cancer cases is expected to increase by 20% until 2030. Half of all cancer patients experience significant emotional and psychosocial distress along the continuum of their disease, treatment, and aftercare, and also as long-term survivors. Consequently, in many countries, psycho-oncological programs have been developed to address this added burden at both the individual and population level. These programs promote the active engagement of patients in their cancer therapy, aftercare and survivorship planning and aim to improve the patients' quality of life. In Germany, the “new form of care isPO” (“nFC-isPO”; integrated, cross-sectoral psycho-oncology/ i ntegrierte, s ektorenübergreifende Psycho-Onkologie) is currently being developed, implemented and evaluated. This approach strives to accomplish the goals devised in the National Cancer Plan by providing psycho-oncological care to all cancer patients according to their individual healthcare needs. The term “new form of care" is defined by the Innovation Fund (IF) of Germany's Federal Joint Committee as “a structured and legally binding cooperation between different professional groups and/or institutions in medical and non-medical care” . The nFC-isPO is part of the isPO project funded by the IF. It is implemented in four local cancer centres and is currently undergoing a continuous quality improvement process. As part of the isPO project the nFC-isPO is being evaluated by an independent institution: the Institute for Medical Sociology, Health Services Research, and Rehabilitation Science (IMVR), University of Cologne, Germany. The four-year isPO project was selected by the IF to be eligible for funding because it meets the requirements of the federal government's National Cancer Plan (NCP), in particular, the “further development of the oncological care structures and quality assurance" in the psycho-oncological domain. An independent evaluation is required by the IF to verify if the new form of care leads to an improvement in cross-sectoral care and to explore its potential for permanent integration into the German health care system. Methods The nFC-isPO consists of six components: a concept of care (C1), care pathways (C2), a psycho-oncological care network (C3), a care process organization plan (C4), an IT-supported documentation and assistance system (C5) and a quality management system (C6). The two components concept of care (C1) and care pathways (C2) represent the isPO clinical care program, according to which the individual cancer patients are offered psycho-oncological services within a period of 12 months after program enrolment following the diagnosis of cancer. The remaining components (C3-C6) represent the formal-administrative aspects of the nFC-isPO that are intended to meet the legally binding requirements of patient care in the German health care system. With the aim of systematic development of the nFC-isPO while at the same time enabling the external evaluators to examine its quality, effectiveness and efficiency under conditions of routine care, the project partners took into consideration approaches from translational psycho-oncology, practice-based health care research and program theory. In order to develop a structured, population-based isPO care program, reference was made to a specific program theory, to the stepped-care approach, and also to evidence-based guideline recommendations. Results The basic version, nFC-isPO, was created over the first year after the start of the isPO project in October 2017, and has since been subject to a continuous quality improvement process. In 2019, the nFC-isPO was implemented at four local psycho-oncological care networks in the federal state North Rhine-Westphalia, in Germany. The legal basis of the implementation is a contract for "special care" with the German statutory health insurance funds according to state law (§ 140a SCB V; Social Code Book V for the statutory health insurance funds). Besides the accompanying external evaluation by the IMVR, the nFC-isPO is subjected to quarterly internal and cross-network quality assurance and improvement measures (internal evaluation) in order to ensure continuous quality improvement process. These quality management measures are developed and tested in the isPO project and are to be retained in order to ensure the sustainability of the quality of nFC-isPO for later dissemination into the German health care system. Discussion Demands on quality, effectiveness and cost-effectiveness of in the German health care system are increasing, whereas financial resources are declining, especially for psychosocial services. At the same time, knowledge about evidence-based screening, assessment and intervention in cancer patients and about the provision of psychosocial oncological services is growing continuously. Due to the legal framework of the statutory health insurance in Germany, it has taken years to put sound psycho-oncological findings from research into practice. Ensuring the adequate and sustainable financing of a needs-oriented, psycho-oncological care approach for all newly diagnosed cancer patients, as required by the NCP, may still require many additional years. The aim of the isPO project is to develop a new form of psycho-oncological care for the individual and the population suffering from cancer, and to provide those responsible for German health policy with a sound basis for decision-making on the timely dissemination of psycho-oncological services in the German health care system. Trial registration The study was pre-registered at the German Clinical Trials Register (https://www.drks.de/DRKS00015326) under the following trial registration number: DRKS00015326 ; Date of registration: October 30, 2018.

Abstract: Background:Immune thrombocytopenia (ITP) is an acquired autoimmune disorder, characterized by increased platelet destruction and impaired platelet production. Therefore, affected patients present with bleeding complications of various severity. However, another frequent complication of ITP is fatigue, which is often underestimated. In Europe the oral thrombopoietin receptor agonist Eltrombopag (EPAG) is licensed for the treatment of patients with persistent and chronic ITP who are refractory to previous treatments. EPAG has previously been shown to elevate platelet count and reduce bleeding complications in ITP patients, but the therapeutic effect on fatigue is unclear. Here we present data from the scheduled 3rd interim analysis of the RISA study. Methods:RISA is an ongoing, single-cohort, non-interventional, multicenter observational study. The individual follow-up period is approximately 24 months. Dosage of EPAG and treatment of patients follows the Summary of Product Characteristic (SmPC) or the routine of treating physicians. Fatigue is assessed at baseline and during the study using the FACIT-Fatigue Scale (Version 4). Annual interim analyses are performed to assess treatment effectiveness and safety. For this interim analysis, an evaluation of patients with prior application of Rituximab is planned. Results:210 patients received at least one dose of EPAG and completed one post baseline assessment. Mean±SD age was 63.1±17.4 years, median (range) duration of ITP was 5.6 (0.0- 44.9) years, 10% were splenectomized, 52.4% were female, median platelet count (range) at baseline was 33.5x109/L (0.0-270.0), 37.6% reported bleeding complications (any grade) within 12 months prior baseline (WHO °I 30% , °II 4.8% , °III 1.9% , °IV 0% , 1% grade missing), 85.2% received prior ITP therapy, and 81.4% had at least one concomitant disease. At least one pre-treatment was given to 179 patients. More than half received prednisolone (46.2%) or prednisone (9%) and 24.3% dexamethasone or immuno globulins (20%). Rituximab as pre-treatment was given to 2.9% of the patients but further analysis is not possible due to the small number. Mean±SD daily dose of EPAG was 45.1±14.4 mg. Treatment with EPAG increased median (range) platelet count to 90x109/L (2.0-617.0) within one month. After two years of treatment median (range) platelet count was 122 (9.0-335.0) (Fig. 1). After one month, 75% of the patients showed treatment response, after 24 months 89 % of the patients exhibited platelet counts above 50x109/L. At baseline mean±SD FACIT-Fatigue Score was 36.3±11.1 and remained unchanged during the two-year observation period (38.0±13.3) (Fig. 1). In a first subgroup analysis, 55 (31%) of 175 patients with an evaluable questionnaire at baseline suffered from severe fatigue (score & lt;=30) with a mean±SD FACIT-Fatigue Score of 22.4±5.7. Due to the small number of evaluable questionnaires, especially at 12 and 24 months (n=11 and n=4), no reliable results could be provided at this time. A total of 166 patients (79%) reported any adverse events (AEs) (n=656), 57 patients (27.1%) experienced 126 serious AEs (SAEs) incl. 9 patients (4.3%) with 12 drug related SAEs. A total of 15 patients (7.1%) were reported to have experienced 27 events with fatal outcome. None of the fatal events was assessed causally related to EPAG. Within the first month of treatment 11 of 202 patients (5.4%) reported bleeding complications (any grade) and after two years 2 of 51 (3.9%). Eleven severe thromboembolic events were observed and 2 mild ones (4 severe and one mild related to EPAG). Discussion:In this 3rd interim analysis it was shown that therapy with EPAG increased the platelet count and reduced bleeding events. No new safety risks were reported despite many concomitant diseases and therapies in these patients. The analysis of the fatigue questionnaire revealed that ITP patients suffer from fatigue, similar to cancer patients and 31% of the patients suffered already from a severe fatigue at baseline. To date, the RISA study could not demonstrate that therapy with EPAG leads to a clinically significant improvement in fatigue. In Germany, ITP patients rarely receive Rituximab prior to EPAG despite their older age and comorbidities. This restrained use of Rituximab is in accordance with the current clinical guidance in Germany. The results in this non-interventional trial are in alignment with the outcomes of other clinical trials with EPAG. Figure Disclosures Meyer: Amgen GmbH:Honoraria;Novartis Pharma GmbH:Honoraria;Grifols Germany:Consultancy, Honoraria.Reiser:Celgene:Consultancy, Honoraria;Roche:Consultancy, Honoraria;BMS:Honoraria;CSL Behring:Honoraria.Plath:Novartis Pharma GmbH:Honoraria.Ballerstädt:Novartis Pharma GmbH:Current Employment.Stark-Lorenzen:Novartis Pharma GmbH:Current Employment.Matzdorff:Novartis Oncology:Consultancy, Other: Honoraria paid to institution;Amgen GmbH:Consultancy, Other: Honoraria paid to institution;Grifols Deutschland GmbH:Consultancy, Other: Honoraria paid to institution;Swedish Orphan Biovitrium GmbH:Consultancy, Other: Honoraria paid to institution;UCB Biopharma SRL:Consultancy, Other: Honoraria paid to institution;Roche Pharma AG:Other: Family stockownership. OffLabel Disclosure: Rituximab has not been licensed for the treatment of ITP and rituximab is not being, and is not intended to be, used to treat patients in this trial. However, some patients have been pretreated with rituximab outside this trial.

Abstract: Gemcitabine/erlotinib treatment offers limited benefit in unselected patients with pancreatic ductal adenocarcinoma (PDAC). Development of skin rash has been associated with favorable outcomes in patients treated with gemcitabine/erlotinib. This study aimed to extend knowledge on the effectiveness of gemcitabine/erlotinib in metastatic PDAC in the context of clinical practice and with focus on skin rash. Methods This multicenter, non-interventional study enrolled 376 patients with metastatic PDAC receiving gemcitabine/erlotinib. The primary endpoint was overall survival (OS) in patients with skin rash versus no skin rash. Secondary endpoints included progression-free survival (PFS), treatment satisfaction and safety. All data were analyzed using descriptive statistics. Survival time and time to disease progression were estimated using the Kaplan-Meier method. Effectiveness endpoints were analyzed for subgroups by skin rash grade (no rash, rash grade 1, rash grade ≥ 2), duration of erlotinib treatment (≤8 weeks, 〉  8 weeks), Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0–1, 2) and age (≤65 years, 〉  65 years). Results Within the full analysis set (FAS; N  = 270), 48 patients (17.8%) developed grade 1 rash, 51 patients (18.9%) grade ≥ 2 rash, while 171 patients (63.3%) did not develop a rash. Median OS of all patients was 9.11 months with an OS of 9.93 months in rash-positive and 8.68 months in rash-negative patients. Median PFS was 5.06 months for rash-positive and 4.11 months for rash-negative patients. PFS was longer in patients with rash grade ≥ 2 and in older patients ( 〉  65 years). Examination using a multivariate Cox proportional model revealed that an age  〉  65 years was associated with longer OS (hazard ratio 0.640; p  = 0.0327) and PFS (hazard ratio 0.642; p  = 0.0026). Out of the 338 patients in the SAF, 310 patients (91.7%) experienced at least one AE, and 176 patients (52.1%) experienced skin-related side effects, all of which were CTC grade 1 to 3. Conclusions Comparing rash-positive with rash-negative patients showed no significant difference in survival. While patients with rash grade ≥ 2 and older patients (independent of skin reactions) showed longer PFS, this did not translate into prolonged OS. The study did not reveal new safety signals. Trial registration ClinicalTrials.gov Identifier: NCT01782690 , retrospectively registered on 4 February 2013.

Abstract: There is no prospective, randomised head‐to‐head trial comparing first‐line FOLFIRINOX and gemcitabine/nab‐paclitaxel in advanced pancreatic cancer. We assess real‐world effectiveness and quality of life (QoL) of both regimens using a new prognostic score. This analysis includes 1540 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer separated into learning (n = 1027) and validation sample (n = 513). The Pancreatic Cancer Score (PCS) was developed using multivariate Cox regression. We compared overall survival (OS) and time to deterioration (TTD) for longitudinal QoL between first‐line FOLFIRINOX (n = 407) and gemcitabine/nab‐paclitaxel (n = 655) according to patients' prognostic risk, after inverse probability of treatment weighting (IPTW) by propensity score analysis. The PCS includes nine independent prognostic factors for survival: female sex, BMI ≥24/unknown, ECOG performance status ≥1, Charlson comorbidity index ≥1, tumour staging IV/unknown at primary diagnosis, liver metastases, bilirubin 〉 1.5× upper limit of normal (ULN), leukocytes 〉 ULN and neutrophil‐to‐lymphocyte ratio ≥4. Median OS of the validation sample was 11.4 (95% confidence interval [CI]: 10.4‐14.4), 8.5 (95% CI: 6.8‐9.6) and 5.9 months (95% CI: 4.0‐7.4) for favourable‐ (0‐3 risk factors), intermediate‐ (4‐5 factors) and poor‐risk group (6‐9 factors), respectively. After IPTW, only poor‐risk patients had significantly longer median OS and TTD of overall QoL with FOLFIRINOX (OS: 6.9 months, 95% CI: 3.9‐13.3; TTD: 10.6 months, 95% CI: 2.0‐14.1) vs gemcitabine/nab‐paclitaxel (OS: 4.0 months, 95% CI: 2.8‐4.8; TTD: 4.1 months, 95% CI: 2.4‐4.5). Our novel PCS may facilitate treatment decisions in clinical routine of advanced pancreatic cancer, since only poor‐risk, but not favourable‐risk patients, seem to benefit from intensified treatment with FOLFIRINOX.

Abstract: Chronic kidney diseases and acute kidney injury are mechanistically distinct kidney diseases. While chronic kidney diseases are associated with podocyte injury, acute kidney injury affects renal tubular epithelial cells. Despite these differences, a cardinal feature of both acute and chronic kidney diseases is dysregulated actin cytoskeleton. We have shown that pharmacological activation of GTPase dynamin ameliorates podocyte injury in murine models of chronic kidney diseases by promoting actin polymerization. Here we establish dynamin’s role in modulating stiffness and polarity of renal tubular epithelial cells by crosslinking actin filaments into branched networks. Activation of dynamin’s crosslinking capability by a small molecule agonist stabilizes the actomyosin cortex of the apical membrane against injury, which in turn preserves renal function in various murine models of acute kidney injury. Notably, a dynamin agonist simultaneously attenuates podocyte and tubular injury in the genetic murine model of Alport syndrome. Our study provides evidence for the feasibility and highlights the benefits of novel holistic nephron-protective therapies.

Abstract: We examined how migration background is associated with awareness and usage of psycho-oncology services. Methods Oncologists in community-based practices and outpatient clinics asked their patients and their relatives to complete a questionnaire. Migrants were purposely over-sampled. The questionnaire was provided in Arabic, English, Farsi, French, German, Hindi, Kurdish, Pashto, Russian, Somali, Turkish, Urdu, and Vietnamese. Results From 9 collaborators, 177 participants were enrolled (130 with and 47 without migration background). The existence of outpatient cancer counselling centres was known to 38% of the participants without and 32% with migration background, self-help groups to 32 vs. 12%, and psychotherapy to 43 vs. 25%. Respondents from the Near and Middle East were less likely to know about psychotherapy (odds ratio (OR) 0.1, p  = 0.01); those from the Commonwealth of the Independent States or former Yugoslavia were less often informed about self-help groups (OR 0.1, p  = 0.06). Migrants retrieved information less frequently from the internet than non-migrants (10 vs. 25%). At least one service had been used by 27% of migrants and 42% of non-migrants (OR 0.5, p  = 0.06). After adjusting for gender, age, education, and patient-relative status, there was no evidence for an association between migration background and service use. Conclusions Migrants should be better informed about psychotherapy and self-help groups, in particular the ones coming from the Near or Middle East and the Commonwealth of the Independent States or former Yugoslavia. The under-use of psychosocial services can largely be explained by confounding factors. Therefore, these factors must always be taken into account when analysing the use of psychosocial services in the aforementioned populations.

Abstract: The study investigated the concurrent validity and reliability of the load-velocity relationship to predict the one-repetition maximum (1RM) of the power clean from the knee (PCK), high pull from the knee (HPK), and mid-thigh clean pull (MTCP). For each exercise, 12 participants performed two 1RM sessions tests and two sessions to measure the barbell’s load-velocity relationship at 30, 45, 60, 75, and 90% of 1RM. The velocity recorded at each load was used to establish the linear regression equation and, consequently, to predict 1RM value. A low validity between the 1RM direct test and predicted 1RM was observed for PCK (typical error [TE]=3.96 to 4.50 kg, coefficient of variation [CV]=4.68 to 5.27%, effect size [ES] =-0.76 to -0.58, Bland-Altman bias [BAB] =9.83 to 11.19 kg), HPK (TE=4.58 to 5.82 kg, CV=6.44 to 8.14%, ES=-0.40 to -0.39, BAB=3.52 to 4.17 kg), and MTCP (TE=6.33 to 8.08 kg, CV=4.78 to 6.16%, ES=-0.29 to -0.19, BAB=3.98 to 6.17 kg). Adequate reliability was observed for the 1RM direct test and for the predicted 1RM. However, based on Bland-Altman limits of agreement, lower measurement errors were obtained for the 1RM direct test in comparison to the predicted 1RM for all the exercises. In conclusion, the load-velocity relationship was not able to predict 1RM values with high accuracy in the PCK, HPK, and MTCP. Moreover, the 1RM direct test was the most reliable for PCK, HPK and MTCP.