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PURPOSE Rituximab/chemotherapy is a cornerstone of treatment for Waldenström's macroglobulinemia (WM). In addition, bortezomib has shown significant activity in WM. This study evaluated the efficacy and safety of dexamethasone, rituximab, and cyclophosphamide (DRC) as first-line treatment in WM. METHODS In this European study, treatment-naïve patients were randomly assigned to DRC or bortezomib-DRC B-DRC for six cycles. The primary end point was progression-free survival. Secondary end points included response rates, overall survival, and safety. RESULTS Two hundred four patients were registered. After a median follow-up of 27.5 months, the estimated 24-month progression-free survival was 80.6% (95% CI, 69.5 to 88.0) for B-DRC and 72.8% (95% CI, 61.3 to 81.3) for DRC ( P = .32). At the end of treatment, B-DRC and DRC induced major responses in 80.6% versus 69.9% and a complete response/very good partial response in 17.2% versus 9.6% of patients, respectively. The median time to first response was shorter for B-DRC with 3.0 (95% CI, 2.8 to 3.2) versus 5.5 (95% CI, 2.9 to 5.8) months for DRC. This resulted in higher major response rates (57.0% v 32.5%; P < .01) after three cycles of B-DRC compared with DRC. At best response, the complete response/very good partial response increased to 32.6% for B-DRC. Both treatments were well tolerated: grade ≥ 3 adverse events occurred in 49.2% of all patients (B-DRC, 49.5%; DRC, 49.0%). Peripheral sensory neuropathy grade 3 occurred in two patients treated with B-DRC and in none with DRC. CONCLUSION This large randomized study illustrates that B-DRC is highly effective and well tolerated in WM. The data demonstrate that fixed duration immunochemotherapy remains an important pillar in the clinical management of WM.

Preclinical, epidemiological, and small clinical studies suggest that green tea extract (GTE) and its major active component epigallocatechingallate (EGCG) exhibit antineoplastic effects in the colorectum.A randomized, double-blind trial of GTE standardized to 150 mg of EGCG b.i.d. vs placebo over 3 years was conducted to prevent colorectal adenomas (n = 1,001 with colon adenomas enrolled, 40 German centers). Randomization (1:1, n = 879) was performed after a 4-week run-in with GTE for safety assessment. The primary end point was the presence of adenoma/colorectal cancer at the follow-up colonoscopy 3 years after randomization.The safety profile of GTE was favorable with no major differences in adverse events between the 2 well-balanced groups. Adenoma rate in the modified intention-to-treat set (all randomized participants [intention-to-treat population] and a follow-up colonoscopy 26-44 months after randomization; n = 632) was 55.7% in the placebo and 51.1% in the GTE groups. This 4.6% difference was not statistically significant (adjusted relative risk 0.905; P = 0.1613). The respective figures for the per-protocol population were 54.3% (151/278) in the placebo group and 48.3% (129/267) in the GTE group, indicating a slightly lower adenoma rate in the GTE group, which was not significant (adjusted relative risk 0.883; P = 0.1169).GTE was well tolerated, but there was no statistically significant difference in the adenoma rate between the GTE and the placebo groups in the whole study population.

The aim was to investigate the vertical root fracture (VRF) resistance and crack formation of root filled teeth treated with (+) or without (–) minimally invasive endodontic (MIE) preparation. Human maxillary central incisors of similar size were decoronated, randomized into six groups (n = 18, power = 0.9) and embedded in acrylic blocks with artificial periodontal ligament. In the +MIE group, root canals were prepared with nickel-titanium (NiTi) rotary files up to size #40, taper 0.04 and filled with conventional gutta-percha/sealer (C) or adhesive (A) single-cone obturation. Preparations of the –MIE group were enlarged with NiTi rotary and K-files up to ISO size #80 and filled according to C or A. Controls either received no treatment or left unfilled after preparation. After thermocycling and staircase loading in a chewing simulator, the crack formation on the root surface was microscopically examined and classified as no defect, craze line, vertical crack, and horizontal crack. Subsequently, the samples were loaded until root fracture. Data were analyzed by Kruskal-Wallis test and Mann-Whitney U test with Bonferroni correction. Post hoc analysis revealed no significant difference in the incidence of defects between the groups (P ≥0.0772). VRF resistance was significantly higher in untreated teeth than in +MIE/C (P = 0.0202), but not significantly different between other groups (P ≥ 0.0680). Both VRF resistance and crack formation of root filled teeth were statistically indistinguishable with or without MIE preparation. Adhesive root filling did not improve the fracture susceptibility. Most dentin defects were vertical root cracks.

Purpose In aut-idem or generic substitution, discrepancies between summaries of product characteristics (SmPCs) referring to the same active substance (AS) may cause difficulties regarding informed consent and medical liability. The qualitative and quantitative characteristics of such discrepancies are insufficiently studied, impeding harmonization of same-substance SmPCs and compromising safe drug treatment. Methods SmPCs of the one hundred most frequently prescribed ASs in Germany were analyzed for discrepancies in the presentation of indications (Inds) and contraindications (CInds). Inclusion and exclusion criteria of drugs/SmPCs were chosen according to the standards of the aut-idem substitution in Germany. Results According to the study protocol, we identified 1486 drugs, of which 1426 SmPCs could be obtained. 41% respectively 65% of the ASs had same-substance SmPCs that differed from the respective reference SmPC in the number of listed Inds respectively CInds. The number of listed Inds/CInds varied considerably between same-substance SmPCs with maximum ranges in Inds of 7 in amoxicillin, and in CInds of 11 in lisinopril. Many ASs had large proportions (> 50%) of associated same-substance SmPCs that differed from the respective reference SmPC. A considerable proportion of ASs had same-substance SmPCs with formal and content-related differences other than the discrepancy in the number of Inds/CInds. Conclusion This evaluation of same-substance SmPCs shows a clear lack of harmonization of same-substance SmPCs. Considering that generic substitution has become the rule and that physicians usually do not know which drug the patient receives in the pharmacy, these discrepancies raise several questions, that require a separate legal evaluation., publishedVersion

PURPOSE/BACKGROUND The alleged primary mechanism underlying bleeding events associated with antidepressants is inhibition of serotonin uptake in platelets resulting in reduced platelet aggregability and activity, and prolonged bleeding time. There is some evidence that a substance's degree of serotonin reuptake inhibition in terms of its binding affinity to the serotonin transporter (SERT) affects the magnitude of bleeding risk increase. METHODS/PROCEDURE To test this hypothesis, we performed data mining in the worldwide largest pharmacovigilance database (VigiBase) and conducted pharmacodynamically informed quantitative signal detection. Reporting odds ratios related to the standardized Medical Dictionary of Regulatory Activities query term "haemorrhages" and 24 antidepressants were calculated, and SERT binding affinities (pKi) were obtained and correlated (Pearson correlation). FINDINGS/RESULTS A strong and statistically significant correlation between substance-related reporting odds ratios and SERT binding affinities was found (r = 0.63; 95% confidence interval, 0.30-0.82; P = 0.00097). IMPLICATIONS/CONCLUSIONS Our findings strengthen the hypothesis that inhibition of serotonin uptake contributes to the antidepressant-related bleeding risk and suggest an association between the degree of the SERT binding affinity and the bleeding risk. This supports the preferential use of antidepressants with low or no SERT binding affinity in depressed patients at risk of bleeding.

Background Advanced stage marginal zone lymphoma (MZL) is an incurable indolent B-cell lymphoma, for which a wide variety of treatments ranging from single agent rituximab to more dose intense immunochemotherapy exists. One of the major goals in this palliative setting is to develop chemotherapy-free treatments, which approach the efficacy of immunochemotherapies, but avoid chemotherapy associated toxicity in this often elderly patient population. The PI3K inhibitor copanlisib has recently shown remarkable clinical activity in refractory or relapsed indolent B–cell lymphomas, among them MZL. Based on these data, copanlisib monotherapy was granted breakthrough designation by the FDA for the treatment of adult patients with relapsed marginal zone lymphoma who have received at least two prior therapies. However, data are still limited in particular for MZL. Based on this, the COUP-1 trial aims at testing the toxicity and efficacy of copanlisib in combination with rituximab in treatment naive and relapsed MZL. Methods COUP-1 is a prospective, multicenter, single-arm, open-label, non-randomized phase II trial of 6 cycles (28 days cycle) of copanlisib (60 mg intravenous day 1, 8, 15) and rituximab (375 mg/m2 intravenous day 1) in the induction phase followed by a maintenance phase of copanlisib (d1, d15 every 4 weeks for a maximum of 12 cycles) and rituximab (d1 every 8 weeks for a maximum of 12 cycles) in patients aged ≥18 years with previously untreated or relapsed MZL in need of treatment. A total of 56 patients are to be enrolled. Primary endpoint is the complete response (CR) rate determined 12 months after start of induction therapy. Secondary endpoints include the overall response (OR) rate, progression free survival (PFS), overall survival (OS), safety and patient related outcome with quality of life. The study includes a translational bio-sampling program with the prospect to measure minimal residual disease. The study was initiated in November 2019. Discussion The COUP-1 trial evaluates the efficacy and toxicity of the treatment of copanlisib in combination with rituximab in patients with MZL and additionally offers the chance for translational research in this heterogenous type of lymphoma. Trial registration ClinicalTrials.gov: NCT03474744. Registration date: 03/23/2018.

Zusammenfassung Hintergrund Die Fachinformationen (FI) wirkstoffgleicher Arzneimittel konnen inhaltliche Unterschiede aufweisen. Dies kann bei Verordnungen von Arzneimitteln im Rahmen der Aut-idem-Regelung zu Schwierigkeiten fur die arztliche Aufklarung fuhren. Zur Beurteilung des Nutzungsverhaltens von FI, der zur Informationsbeschaffung uber Arzneimittel herangezogenen Quellen und der Kenntnis von der Existenz von Unterschieden zwischen FI wirkstoffgleicher Arzneimittel wurde eine Befragung von Hausarzten (HA) und Apothekern (AP) durchgefuhrt. Methode Es wurde ein explorative/nicht-reprasentative, fragenbogengestutzte, telefonbasierte, semistrukturierte Querschnittsbefragung durchgefuhrt (Juni bis August 2018). Ergebnisse Die Teilnahmequoten lagen bei 29,8% (34/114) der HA bzw. 73,0% (73/100) der AP. Im letzten Monat hatten alle AP und 82,4% der HA mindestens einmal eine FI genutzt (p = 0,001). Die HA gaben an, FI monatlich 6,4 ± 4,9 Mal zu nutzen, AP 65,0 ± 52,5 Mal (p Diskussion Die Ergebnisse der vorliegenden Befragung ergaben Hinweise auf eine geringe Nutzung von FI durch HA sowie geringe Kenntnis von der Existenz von Unterschieden zwischen FI wirkstoffgleicher Handelspraparate in dieser Berufsgruppe. Beide Aspekte konnen zu einer nicht ordnungsgemasen Aufklarung fuhren, insbesondere bei der Aut-idem-Verordnung von Substanzen, fur die zahlreiche wirkstoffgleiche Handelspraparate mit unterschiedlichen FI verfugbar sind. Schlussfolgerung Arzte sollten FIs regelmasig nutzen und uber Unterschiede zwischen FIs wirkstoffgleicher Handelspraparate informiert sein.

Background The German guideline on psychosocial interventions for people with severe mental disorders recommends a broad spectrum of evidence-based treatments. Structured implementation of the associated patient version of the guideline is missing to date. The study aims to assess whether structured implementation of a patient guideline improves the empowerment of patients with severe mental disorders, as well as knowledge, attitudes and experiences regarding psychosocial interventions, service use, treatment satisfaction, treatment needs, quality of life and burden of care. Methods The study is a multicentre, cluster-randomised, controlled study with two parallel groups. Inpatients and day hospital patients (all sexes; 18–65 years) with severe mental disorders will be included. Additionally, relatives of patients with mental disorders (all sexes; ≥ 18 years) will be included. In the experimental group, the patient guideline will be implemented using a multimodal strategy. Participants in the control group will receive treatment as usual but will be made aware of the patient guideline. The primary outcome is the change of empowerment, assessed by using the ‘empowerment in the process of psychiatric treatment of patients with affective and schizophrenia disorders’ (EPAS) scale. In addition, knowledge, attitudes and experiences regarding psychosocial interventions will be assessed as secondary outcomes, as well as service use, satisfaction with care, patient need and quality of life and participation and social inclusion. For relatives, the perceived burden of care also will be recorded. Results will be analysed using hierarchical linear models. For the health economic evaluation, the incremental cost-utility ratios will be computed using the differences in total costs of illness and the differences in quality-adjusted life years (QALY) between study groups. Discussion The study will be the first to assess the effects of a structured implementation of the patient version of a psychiatric treatment guideline. The study has some limitations regarding the transferability of the results to other patients and other regions. Furthermore, problems with the recruitment of patients and relatives and with the implementation of intervention could occur during the study. Trial registration The study is registered in the German Clinical Trials Register (DRKS) and the WHO International Clinical Trials Registry Platform (ICTRP) under registration number DRKS00017577 (Date of registration: 23 October 2019.

Background Quantitative (e.g. increasing recreational cannabinoid use) and qualitative (e.g. increasing availability and use of synthetic cannabinoids and cannabis preparations with increased tetrahydrocannabinol content) changes in cannabinoid use may be associated with changes in the prevalence of cannabinoid-related mental and behavioural disorders and, accordingly, changes in the need for medical care. We aimed to investigate if there are changes in the number of inpatient cases (ICs) due to cannabinoid-related disorders in Germany. Methods Data were obtained from the Federal Statistical Office of Germany (Destatis) and comprised type and number of hospital main diagnoses (according to ICD-10) of all ICs in Germany in the period 2000–18. Linear trend analysis of absolute and relative annual frequencies (AFs) of ICs with diagnoses related to the use of cannabinoids (DRUCs), and, as controls, alcohol-related psychiatric disorders and schizophrenia-spectrum disorders was performed. Results Absolute AFs of ICs with DRUCs increased statistically significantly (P Conclusions Our evaluation demonstrates increasing numbers of ICs with mental and behavioural disorders due to use of cannabinoids in Germany and emphasizes the need for adequate prevention of such disorders.

Zusammenfassung Gegenstand und Ziel Bei Verordnungen von Arzneimitteln im Rahmen der Aut-idem-Regelung ist für den Arzt häufig unklar, welches wirkstoffgleiche Handelspräparat in der Apotheke abgegeben wird; die in Frage kommenden wirkstoffgleichen Handelspräparate können sich jedoch in zahlreichen Merkmalen unterscheiden, was Fragen in Bezug auf die Aufklärungspflicht und Arzthaftung aufwirft. Gegenwärtig fehlen systematische Auswertungen in Bezug auf Unterschiede zwischen Fachinformationen (FI) wirkstoffgleicher Handelspräparate. Zur Bestimmung von Größe und Art von derartigen Unterschieden wurden FI der meisten in Deutschland zugelassenen (Neuro-)Psychopharmaka exemplarisch hinsichtlich der aufgeführten Anzahl von Kontraindikationen (KI) untersucht. Methodik Grundlage für die Selektion von Wirkstoffen war das Anatomisch-Therapeutisch-Chemische (ATC) Klassifikationssystem (Gruppe ATC N Nervensystem). Eingeschlossen wurden Wirkstoffe, die in Deutschland zur Behandlung psychischer Störungen gemäß ICD-10 F zugelassen sind. Anhand weiterer Ein- und Ausschlusskriterien erfolgte die Suche von Handelspräparaten und FI mithilfe der Online-Dienste von PharmNet.Bund, Gelber Liste, Roter Liste®/Fachinfo-Service® und über Herstellerkontakt. Ergebnisse Es wurden n = 941 FI (= 116 Wirkstoffe) ausgewertet. Bei alleiniger Betrachtung der Gruppen von FI wirkstoffgleicher Handelspräparate mit > 1 eingeschlossenen FI (n = 78; 67,2 %) fanden sich bei mehr als der Hälfte der Wirkstoffe (n = 43; 55,1 %) Unterschiede in der Anzahl der KIs. Innerhalb der Indikationsgruppen fanden sich die meisten Gruppen von FI wirkstoffgleicher Handelspräparate mit Unterschieden in der Anzahl der KIs – nur Wirkstoffe mit > 1 wirkstoffgleichen Handelspräparat berücksichtigend – bei den Hypnotika und Sedativa (77,8 %), Anxiolytika (75,0 %), Mittel zur Behandlung von Abhängigkeitserkrankungen (66,7 %), Antidepressiva (61,9 %), Antikonvulsiva und Phasenprophylaktika (53,8 %), gefolgt von den Antipsychotika (41,2 %), Antidementiva (20,0 %) und Psychostimulantien (0 %). Die größten Spannweiten bei der Anzahl der aufgeführten KIs fanden sich bei den FI von Morphin (14), Amitriptylin (8), Chlorprothixen (6), Lorazepam (6) und Citalopram (4). Schlussfolgerung(en) Bei zahlreichen (neuro-)psychopharmakologischen Wirkstoffen bestehen zwischen den FI der zugehörigen wirkstoffgleichen Handelspräparate Unterschiede in der Anzahl von KIs. Die Relevanz dieses Ergebnisses für die klinische Praxis ist infolge ausstehender Bewertung der inhaltlichen Aspekte und juristischer Bewertung dieser Unterschiede noch unklar.

ZusammenfassungHäufig wird kritisiert, dass in der Rehabilitationsforschung zu wenig randomisierte Studien durchgeführt werden, um methodisch hochwertige Evidenz zu erhalten. Allerdings wird auch anerkannt, dass sich das Design der doppel-blinden, Placebo-kontrollierten, randomisierten Studie häufig nicht einfach in die Rehabilitationsforschung übertragen lässt. Zum einen steht hier die Validität in Bezug auf den Versorgungsaspekt im Fokus, sodass Treatment-as-usual anstelle der Placebo-Behandlung als Referenz dient und eine Doppelverblindung teilweise nicht definierbar ist. Weiterhin ist es aufgrund fehlender Kapazitäten oft schwierig, 2 ähnliche Therapieformen in einer Rehabilitationseinrichtung parallel durchzuführen. Ferner sind Kontaminationseffekte zu befürchten, wenn sich Rehabilitanden unterschiedlicher Studienarme über ihre Therapie austauschen. Hier bieten sich cluster-randomisierte Studien an, welche allerdings im Vergleich zu individuell randomisierten Studien meist höhere Fallzahlen, eine komplexere Methodik der Fallzahlplanung sowie umfassendere Methoden der statistischen Auswertung erfordern.Im Beitrag werden Vor- und Nachteile sowie Besonderheiten der Cluster-Randomisierung dargestellt und Hinweise zu ihrer Umsetzung im Bereich der Rehabilitationsforschung gegeben.

Background Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. Methods NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. Discussion The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. Trial registration ClinicalTrials.gov : NCT02047513, 08/13/2014. Open-Access-Publikationsfonds 2018

Background Among potentially modifiable risk factors for delirium, transfers between wards, hospitals and other facilities have been mentioned with low evidence. TRADE (TRAnsport and DElirium in older people) was set up to investigate i) the impact of transfer and/or discharge on the onset of delirium in older adults and ii) feasibility and acceptance of a developed complex intervention targeting caregiver’s participation during and after hospital discharge or transfer on cognition and the onset of delirium in older adults. Methods The study is designed according to the guidelines of the UK Medical Research Council (MRC) for development and evaluation of complex interventions and comprises two steps: development and feasibility/piloting. The development phase includes i) a multicenter observational prospective cohort study to assess delirium incidence and cognitive decline associated with transfer and discharge, ii) a systematic review of the literature, iii) stakeholder focus group interviews and iv) an expert workshop followed by a Delphi survey. Based on this information, a complex intervention to better and systematically involve family caregivers in discharge and transport was developed. The intervention will be tested in a pilot study using a stepped wedge design with a detailed process and health economic evaluation. The study is conducted at four acute care hospitals in southwest Germany. Primary endpoints are the delirium incidence and cognitive function. Secondary endpoints include prevalence of caregiver companionship, functional decline, cost and cost effectiveness, quality of discharge management and quality of admission management in admitting hospitals or nursing homes. Data will be collected prior to discharge as well as after 3, 7 and 90 days. Discussion TRADE will help to evaluate transfer and discharge as a possible risk factor for delirium. In addition, TRADE evaluates the impact and modifiability of caregiver’s participation during patient’s transfer or discharge on delirium incidence and cognitive decline providing the foundation for a confirmatory implementation study., publishedVersion

In der Biometrie-Ausbildung wird der Inhalt oft in Statistiksoftwarekursen vermittelt. Ziel ist es, neben den inhaltlichen Aspekten auch gleich eine praktische Umsetzung anhand einer Statistiksoftware zu vermitteln, sodass die Studierenden anschliesend eigene Projekte umsetzen und auswerten konnen. Die Erfahrung in solchen Kursen ist aber oft, dass die Studierenden in den Seminaren lange fur die Umsetzung der Technik benotigen und so die Vermittlung, Grundlagen und Interpretation der statistischen Methoden zu kurz kommen. Die notwendige Ubung und Umsetzung des Inhalts wird dann von den Studierenden in der nachfolgenden individuellen Nachbereitung erwartet. Das Problem hierbei ist, dass diese Phase unbegleitet ist und mogliche Fehler nicht korrigiert werden konnen. Die didaktische Methode des Flipped Classroom dreht dieses Szenario um. Hier sollen sich die Studierenden vor dem Kurstermin selbststandig in die Materie bzw. Statistiksoftware einarbeiten und Ubungen durchfuhren. Im Kurs konnen dann technische Probleme zu Beginn geklart werden und es bleibt (in der Theorie) mehr Zeit fur die Abhandlung der biometrischen Inhalte. Vorteil ist hier, dass diese Phase durch die Dozenten begleitet und supervisiert wird. Die Voraussetzungen fur die Umsetzung des Konzeptes in Statistiksoftwarekursen sind, dass die Software den Studierenden in der Vorbereitungszeit jederzeit und von uberall zur Verfugung steht, damit jeder Studierende sich eigenstandig vorbereiten kann. Dazu gehort auch eine moglichst selbsterklarende Grundlage an Hilfsmitteln (Skript, Videos, Ubungsaufgaben und –daten). Im Seminar Q1/Biometrie im Studiengang Humanmedizin an der Universitat Ulm soll dieser Ansatz im Rahmen eines Lehrprojekts umgesetzt werden. Mit der SAS-Applikation „SAS Studio“ in der Online-Umgebung „SAS on Demand for Academics (SODA)“ stellt SAS eine maus- und menugesteuerte Softwarelosung zur Verfugung, welche die Studierenden kostenlos jederzeit nutzen konnen, wenn nur ein Internetanschluss und ein Browser zur Verfugung steht. Da dies heutzutage als Ausstattungsstandard anzusehen ist, kann diese Voraussetzung als gegeben angenommen werden. Zur selbststandigen Einarbeitung wird den Studierenden ein Skript sowie weitere Lehrmaterialien zur Verfugung gestellt.

The detection of molecular alterations is crucial for the individualized treatment of advanced non-small cell lung cancer (NSCLC). Missing targetable alterations may have a major impact on patient’s progression free and overall survival. Although laboratory testing for molecular alterations has continued to improve; little is known about how biopsy technique affects the detection rate of different mutations. In the retrospective study detection rate of epidermal growth factor (EGFR) mutations in tissue extracted by bronchoscopic cryobiopsy (CB was significantly higher compared to other standard biopsy techniques. This prospective, randomized, multicenter, single blinded study evaluates the accuracy of molecular genetic characterization of NSCLC for different cell sampling techniques. Key inclusion criteria are suspected lung cancer or the suspected relapse of known NSCLC that is bronchoscopically visible. Patients will be randomized, either to have a CB or a bronchoscopic forceps biopsy (FB). If indicated, a transbronchial needle aspiration (TBNA) of suspect lymph nodes will be performed. Blood liquid biopsy will be taken before tissue biopsy. The primary endpoint is the detection rate of molecular genetic alterations in NSCLC, using CB and FB. Secondary endpoints are differences in the combined detection of molecular genetic alterations between FB and CB, TBNA and liquid biopsy. This trial plans to recruit 540 patients, with 178 evaluable patients per study cohort. A histopathological and molecular genetic evaluation will be performed by the affiliated pathology departments of the national network for genomic medicine in lung cancer (nNGM), Germany. We will compare the diagnostic value of solid tumor tissue, lymph node cells and liquid biopsy for the molecular genetic characterization of NSCLC. This reflects a real world clinical setting, with potential direct impact on both treatment and survival.

Marginal zone lymphoma (MZL) belongs to the group of indolent B-cell non-Hodgkin’s lymphomas, which is characterized by an indolent course. In this mostly elderly patient population, the development of chemotherapy-free approaches is of particular interest. In this situation, single-agent treatment with the next-generation anti-CD20 antibody obinutuzumab is an attractive approach, which promises high efficacy without major toxicity. We describe here an open-label, multicentric Phase II trial evaluating the efficacy and safety of obinutuzumab in de novo MZL patients, who are treatment naive for systemic therapy and not eligible for or failed local treatment. ClinicalTrials.gov identifier NCT03322865

IntroductionThe accurate diagnosis of individual interstitial lung diseases (ILD) is often challenging, but is a critical determinant of appropriate management. If a diagnosis cannot be made after multidisciplinary team discussion (MDTD), surgical lung biopsy is the current recommended tissue sampling technique according to the most recent guidelines. Transbronchial lung cryobiopsy (TBLC) has been proposed as an alternative to surgical lung biopsy.MethodsThis prospective, multicentre, international study analysed the impact of TBLC on the diagnostic assessment of 128 patients with suspected idiopathic interstitial pneumonia by a central MDTD board (two clinicians, two radiologists, two pathologists). The level of confidence for the first-choice diagnoses were evaluated in four steps, as follows: 1) clinicoradiological data alone; 2) addition of bronchoalveolar lavage (BAL) findings; 3) addition of TBLC interpretation; and 4) surgical lung biopsy findings (if available). We evaluated the contribution of TBLC to the formulation of a confident first-choice MDTD diagnosis.ResultsTBLC led to a significant increase in the percentage of cases with confident diagnoses or provisional diagnoses with high confidence (likelihood ≥70%) from 60.2% to 81.2%. In 32 out of 52 patients nondiagnostic after BAL, TBLC provided a diagnosis with a likelihood ≥70%. The percentage of confident diagnoses (likelihood ≥90%) increased from 22.7% after BAL to 53.9% after TBLC. Pneumothoraces occurred in 16.4% of patients, and moderate or severe bleeding in 15.7% of patients. No deaths were observed within 30 days.InterpretationTBLC increases diagnostic confidence in the majority of ILD patients with an uncertain noninvasive diagnosis, with manageable side-effects. These data support the integration of TBLC into the diagnostic algorithm for ILD.

Zusammenfassung Hintergrund Zur Qualitätssicherung der Versorgung Früh- und Reifgeborener wurden vom Gemeinsamen Bundesausschuss umfangreiche Struktur- und Personalvorgaben formuliert. Die Ergebnisqualität für das neonatale Outcome wird bereits seit langer Zeit erhoben. Obwohl Deutschland einer der höchsten Frühgeburtenraten in Europa aufweist, existieren bislang keine zentrumsspezifischen Daten zur Frühgeburtenrate. Methoden An 6 Perinatalzentren Level 1 in Baden-Württemberg wurden über 2 Jahre alle Schwangeren erfasst, die mit einem Schwangerschaftsalter zwischen 22+0 und 31+6 Wochen in der Frauenklinik aufgenommen wurden (n=2972). Sofern sie innerhalb von 24 h nach Aufnahme mindestens eines der folgenden sekundären Einschlusskriterien 1. Gesicherte Amnionruptur, 2. Zervixlänge3 Wehen von je mind. 30 sec. Dauer in 30 min erfüllten, wurde die Frühgeburtenrate vor 32+0 Schwangerschaftswochen bestimmt. Für 70,6% der Frühgeborenen konnte das neonatale Outcome erhoben werden. Ergebnis Bei 21,1% (n=279) der Schwangeren, die mindestens ein sekundäres Einschlusskriterium erfüllten (n=1325), kam es vor 32+0 SSW zur Geburt von 344 Frühgeborenen. Die Frühgeburtenrate lag zwischen 16,8 und 27,9% (Differenz 11,1%). Eine niedrigere Frühgeburtenrate war nicht mit einem schlechteren neonatalen Outcome vergesellschaftet. Schlussfolgerung Um die Ergebnisqualität eines Perinatalzentrums beurteilen zu können, sollte die Frühgeburtenrate als Qualitätsindikator Einzug finden. Eine Reduktion der Frühgeburtenrate um 5% könnte die Zahl der Frühgeborenen

BACKGROUND In patients at increased surgical risk, transcatheter edge-to-edge mitral valve repair by MitraClip implantation for severe mitral regurgitation (MR) has proven to relieve symptoms of MR, reduce New York Heart Association (NYHA) functional class and improve quality of life. Rehospitalization for decompensated heart failure occurs frequently after MitraClip implantation, negatively impacting quality of life. We aimed here to determine predictors of 1-year rehospitalization for decompensated heart failure. METHODS AND RESULTS A total of 355 consecutive patients who underwent MitraClip implantation at our centre were evaluated for their baseline and procedural characteristics, peri-procedural outcome and clinical endpoints. Rate of rehospitalization for decompensated heart failure was reduced from 52.7% (n = 187) in the year before MitraClip procedure to 18.0% (n = 64) (P

Statistical sample size calculation is a crucial part of planning nonhuman animal experiments in basic medical research. The 3R principle intends to reduce the number of animals to a sufficient minimum. When planning experiments, one may consider the impact of less rigorous assumptions during sample size determination as it might result in a considerable reduction in the number of required animals. Sample size calculations conducted for 111 biometrical reports were repeated. The original effect size assumptions remained unchanged, but the basic properties (type 1 error 5%, two-sided hypothesis, 80% power) were varied. The analyses showed that a less rigorous assumption on the type 1 error level (one-sided 5% instead of two-sided 5%) was associated with a savings potential of 14% regarding the original number of required animals. Animal experiments are predominantly exploratory studies. In light of the demonstrated potential reduction in the numbers of required animals, researchers should discuss whether less rigorous assumptions during the process of sample size calculation may be reasonable for the purpose of optimizing the number of animals in experiments according to the 3R principle.

Background: Levels or fluctuations in the partial pressure of CO2 (PCO2) may affect outcomes for extremely low birth weight infants. Objectives: In an exploratory analysis of a randomized trial, we hypothesized that the PCO2 values achieved could be related to significant outcomes. Methods: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO2. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ2 test, and the Fisher exact test as well as by multiple logistic regression. Results: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO2. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO2). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO2 (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01). Conclusions: Birth weight and respiratory morbidity, as measured by MAP × FiO2, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO2. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.

Zusammenfassung Ziel der Studie Benzodiazepine (BZ) und Nicht-Benzodiazepin-Agonisten (NBZ, so genannte Z-Drugs) werden überwiegend von Hausärzten verordnet. Genauere Daten über den hausärztlichen Bereich liegen nicht vor. Ziel war es, hausärztliche Daten zu Kollektiv, Menge von BZ-/NBZ-Verordnungen und Anteil von Privatrezepten zu analysieren. Methoden Analyse von Personenjahren 2-jähriger Intervalle von 2009 bis 2014 des CONTENT-Registers mit 31 Hausarztpraxen. Einteilung von BZ/NBZ-Verordnungen nach Risikogruppen. Berechnung des Assoziationsausmaßes mit potenziellen Einflussgrößen auf Basis eines multiplen logistischen Regressionsmodells (adjustiert nach Alter, Geschlecht und Versicherungsart). Vergleich von Patienten mit Arzneimittelverordnungen mit und ohne BZ-/NBZ-Verordnungen. Ergebnisse Rund 5% erhielten in einem Jahr BZ/NBZ verordnet. Diese Patienten waren im Mittel älter (67,5 bzw. 48 Jahre) und der Frauenanteil war höher als in der Vergleichsgruppe (69 bzw. 58%). Etwa ein Drittel dieser Patienten erhielt im Personenjahr mehr als 600 mg Diazepam-Äquivalenzdosis (entsprechend einer 2-monatigen täglichen Einnahme von mehr als 10 mg Diazepam). Rund ein Drittel der Rezepte waren Privatrezepte. Eine Reihe von Variablen war signifikant assoziiert mit der Verschreibung von BZ/NBZ (z. B. Alter, Geschlecht, Diagnosekodierungen, Praxen). Schlußfolgerung Die vorliegenden Ergebnisse liefern wertvolle Informationen über die Verschreibungshäufigkeit von BZ/NBZ im hausärztlichen Bereich. Für Aus-, Weiter- und Fortbildung sowie bei der Entwicklung von Interventionen zur Reduktion von BZ/NBZ sollten patientenbezogene Spezifika (z. B. Geschlecht, Alter, Vorerkrankungen, Versicherungsart) und unterschiedliche Verschreibungspraktiken (z. B. Privatrezepte, Grund und Häufigkeit der Verordnungen, Orientierung an Leitlinien) berücksichtigt werden.

The objective of this study was to compare structured case management (CM) to usual care (UC) for helping victims of child abuse and neglect (CAN) with mental disorders access evidence-based treatment (EBT). N = 121 children and adolescents aged 4–17 with a history of CAN and a current mental disorder were recruited in three German states in a multi-center parallel group trial. They were randomly assigned, stratified by study site and level of psychosocial functioning, to receive CM additionally to UC or only UC. CM was delivered by trained professionals and volunteers, most of them affiliated to local child welfare agencies or NGOs. UC comprised child welfare services typically delivered in Germany. The primary outcome was EBT utilization after 6 months. Secondary outcome was the time until commencement of EBT. Outcomes were determined by semi-structured clinical interviews with assessors blinded to group allocation. Predictors of access to EBT and barriers to utilization of treatment were analyzed. The intent to treat analysis showed that after 6 months 23 of 60 participants recruited to CM (38%) and 19 of 61 participants recruited to UC (31%) were using EBT, χ 2 (1, N = 121) = 0.689, p = .261. Female gender, out-of-home placement, and home state were significant predictors of access to EBT. Less than 40% of participants across both groups were successfully referred to EBT. Access to EBT seems to be in part due to system-level barriers, namely lack of implementation of EBT in community settings. Trial Registration: DRKS00003979 German Clinical Trials Register

Hypothyroidism, defined as thyrotropin (TSH) above and free thyroxine (fT4) serum level below the reference rage, as well as hyperthyroidism, defined as suppressed TSH and elevated thyroid hormones exceeding the upper limit of the reference range, may have major impacts on fertility and pregnancy outcome. Ideally, euthyroidism, defined as TSH and fT4 in the reference range, should be established and preserved during pregnancy prior to gestation. High estrogen levels during pregnancy stimulate the synthesis of maternal thyroxine-binding-globulin (TBG) in the liver, increasing TBG serum concentration by 2 - 3 fold compared to the initial value and affecting thus maternal fT4 serum level. As a consequence, maternal thyroid function adapts by increasing synthesis and secretion of thyroxine. TBG-induced elevation of serum thyroxine either total or free in the absence of hyperthyroidism is defined as euthyroid hyperthyroxinemia. Since TBG concentration declines first after delivery, pregnancy-induced euthyroid hyperthyroxinemia constitutes a physiological metabolic state. Depending on functional capacity, maternal thyroid may exhaust, resulting in hypothyroxinemia, which increases the risk of fetal neurodevelopmental impairment and preterm birth. The study aims to determine whether L-Thyroxine (L-T4) replacement, sustaining pregnancy-induced maternal euthyroid hyperthyroxinemia during the whole pregnancy by keeping fT4 level in the high normal reference range might reduce preterm birth rate. Preterm birth rate of women with singleton gestation and L-T4-induced high normal fT4 level constituting the study group (n = 918) was compared with the preterm birth rate of women with singleton gestation (n = 6414) who completed a questionnaire concerning L-T4 administration during pregnancy. Two groups were formed. In group A we compared the preterm birth rate between women with L-T4-induced high normal fT4 level and a control group without L-T4 administration during pregnancy. In group B we compared the preterm birth rate of women already receiving L-T4 prior to conception, maintaining dosage to keep fT4 level in the high normal reference range during gestation to a control group with L-T4 intake during pregnancy. The preterm birth rates in group A declined by 51% (p = 0.01) and in group B by 87% (p = 0.001) in multiparous women, while in primiparous the preterm birth rate was similar between study and the control group. Sustaining a high normal fT4 level during pregnancy with L-T4 may significantly reduce preterm birth rate in multiparous women.

Summaries of product characteristics (SmPC) of same-substance medications may feature content-related differences. This may cause difficulties regarding informed consent in the case of prescriptions of drugs in the context of the aut-idem regulation. A survey among family doctors (FD) and pharmacists (PH) was conducted in order to evaluate the usage behaviour of SmPCs, sources used to obtain information about drugs and the awareness of the existence of differences between SmPCs of same-substance medications.An exploratory/non-representative, questionnaire- and telephone-based, semi-structured cross-sectional survey was performed (June to August 2018).Participation rate of FD and PH was 29.8 % (34/114) and 73.0 % (73/100), respectively. In the previous month, all PH and 82.4 % of FD said that they had used a SmPC at least once (p=0.001). FD used SmPCs 6.4±4.9 and PH 65.0±52.5 times a month (p0.001). In both occupational groups SmPCs were used most frequently to obtain information about dosing and/or type of application (FD: 97.1 %; PH: 98.6 %) and contraindications (97.1 % and 86.3 %, resp.). In both samples, the internet was the most frequently used drug information source (FD: 97.1 %; PH: 98.6 %), followed by the Rote/Gelbe Liste (97.1 % and 71.2 %, resp.) and the SmPCs of the original product (52.9 % and 65.8 %, resp.) or generic drug (52.9 % and 61.6 %, resp.). Only 32.4 % of the FD vs. 79.5 % of PH believed that differences might exist between SmPCs of same-substance medications (p0.001). FD stated that they never (11.8 %) or rarely (85.3 %) use SmPCs for informed consent. It was indicated that the aut-idem substitution is excluded in 10.3 %±5.0 (FD) and 9.6 %±6,1 (PH) of issued or received prescriptions.The results of the present survey indicate a low utilization rate of SmPCs by FD and little awareness of the existing differences of SmPCs of same-substance medications in this occupational group. Both aspects may impede proper information of patients, particularly in cases of aut-idem prescriptions of substances for which many same-substance medications with different SmPCs are available.Physicians should use SmPCs regularly and keep themselves informed about differences between SmPCs of same-substance medications.

Background Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. Methods NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m2, 46 h infusion)/5-FU (2400 mg/m2, 46 h infusion)/leucovorin (400 mg/m2, 0.5 h infusion) d1 on 14 day-cycles; Arm B (standard of care) cisplatin (25 mg/m2, 1 h infusion)/gemcitabine (1000 mg/m2, 0.5 h infusion) d1 and d8 on 21 day-cycles. The randomization (1:1) is stratified for tumor site (intrahepatic vs. extrahepatic biliary tract), disease stage (advanced vs. metastatic), age (≤70 vs. > 70 years), sex (male vs. female) and WHO performance score (ECOG 0 vs. ECOG 1). Primary endpoint of the study is the progression free survival (PFS) rate at 4 months after randomization by an intention-to-treat analysis in each of the groups. Secondary endpoints are the overall PFS rate, the 3-year overall survival rate, the disease control rate after 2 months, safety and patient related outcome with quality of life. The initial assessment of tumor resectability for locally advanced BTCs is planned to be reviewed retrospectively by a central surgical board. Exploratory objectives aim at establishing novel biomarkers and molecular signatures to predict response. The study was initiated January 2018 in Germany. Discussion The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. Trial registration Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.

In the case of prescriptions of pharmaceuticals in the context of the aut-idem-regulation the physician frequently does not know, which same-substance medication is dispensed in the pharmacy; the contemplable same-substance medications may differ in numerous features which raises questions regarding the obligation to give information and medical liability for medical malpractice. Currently, systematic evaluations regarding differences between summaries of product characteristics (SmPCs) of same-substance medications are missing. To determine size and type of those differences SmPCs of most (neuro)psychiatric drugs that are approved in Germany were evaluated regarding the number of listed contraindications (CI).Basis for the selection of substances was the Anatomical Therapeutic Chemical (ATC) Classification System (group ATC N Nervous System). Substances that are approved in Germany for the treatment of mental disorders according to ICD-10 F were included. Brand-name medications and SmPCs were searched by means of further in- and exclusion criteria via the online services of PharmNet.Bund, Gelbe Liste, Rote ListeN = 941 SmPCs (=116 substances) were evaluated. Considering only the group of SmPCs with 1 brand-name medication (n = 78; 67.2 %) differences in the number of CIs were found in more than the half of substances (N = 43; 55.1 %). Considering indication groups most groups of SmPCs of same-substance medications with differences in the numbers of CIs were found in - considering only substances with 1 brand-name medication - hypnotics and sedatives (77.8 %), anxiolytics (75.0 %), drugs for treatment of substance use disorders (66.7 %), antidepressants (61,9 %), anticonvulsant drugs and mood stabilizers (53.8 %), followed by antipsychotics (41.2 %), antidementia-drugs (20.0 %), and psychostimulants (0 %). Largest ranges regarding the number of CIs were found in the SmPCs of morphine (14), amitriptyline (8), chlorprothixene (6), lorazepam (6) and citalopram (4).In numerous (neuro-)psychopharmacologic substances differences exists between the SmPCs of the associated same-substance medications regarding the number of CIs. Due to the outstanding evaluation of content aspects of these differences and legal evaluation the relevance of this result for clinical practice is not yet clear.Bei Verordnungen von Arzneimitteln im Rahmen der Aut-idem-Regelung ist für den Arzt häufig unklar, welches wirkstoffgleiche Handelspräparat in der Apotheke abgegeben wird; die in Frage kommenden wirkstoffgleichen Handelspräparate können sich jedoch in zahlreichen Merkmalen unterscheiden, was Fragen in Bezug auf die Aufklärungspflicht und Arzthaftung aufwirft. Gegenwärtig fehlen systematische Auswertungen in Bezug auf Unterschiede zwischen Fachinformationen (FI) wirkstoffgleicher Handelspräparate. Zur Bestimmung von Größe und Art von derartigen Unterschieden wurden FI der meisten in Deutschland zugelassenen (Neuro-)Psychopharmaka exemplarisch hinsichtlich der aufgeführten Anzahl von Kontraindikationen (KI) untersucht.Grundlage für die Selektion von Wirkstoffen war das Anatomisch-Therapeutisch-Chemische (ATC) Klassifikationssystem (Gruppe ATC N Nervensystem). Eingeschlossen wurden Wirkstoffe, die in Deutschland zur Behandlung psychischer Störungen gemäß ICD-10 F zugelassen sind. Anhand weiterer Ein- und Ausschlusskriterien erfolgte die Suche von Handelspräparaten und FI mithilfe der Online-Dienste von PharmNet.Bund, Gelber Liste, Roter ListeEs wurden n = 941 FI (= 116 Wirkstoffe) ausgewertet. Bei alleiniger Betrachtung der Gruppen von FI wirkstoffgleicher Handelspräparate mit 1 eingeschlossenen FI (n = 78; 67,2 %) fanden sich bei mehr als der Hälfte der Wirkstoffe (n = 43; 55,1 %) Unterschiede in der Anzahl der KIs. Innerhalb der Indikationsgruppen fanden sich die meisten Gruppen von FI wirkstoffgleicher Handelspräparate mit Unterschieden in der Anzahl der KIs – nur Wirkstoffe mit 1 wirkstoffgleichen Handelspräparat berücksichtigend – bei den Hypnotika und Sedativa (77,8 %), Anxiolytika (75,0 %), Mittel zur Behandlung von Abhängigkeitserkrankungen (66,7 %), Antidepressiva (61,9 %), Antikonvulsiva und Phasenprophylaktika (53,8 %), gefolgt von den Antipsychotika (41,2 %), Antidementiva (20,0 %) und Psychostimulantien (0 %). Die größten Spannweiten bei der Anzahl der aufgeführten KIs fanden sich bei den FI von Morphin (14), Amitriptylin (8), Chlorprothixen (6), Lorazepam (6) und Citalopram (4).Bei zahlreichen (neuro-)psychopharmakologischen Wirkstoffen bestehen zwischen den FI der zugehörigen wirkstoffgleichen Handelspräparate Unterschiede in der Anzahl von KIs. Die Relevanz dieses Ergebnisses für die klinische Praxis ist infolge ausstehender Bewertung der inhaltlichen Aspekte und juristischer Bewertung dieser Unterschiede noch unklar.