Green Tea Extract to Prevent Colorectal Adenomas, Results of a Randomized, Placebo-Controlled Clinical Trial.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). DISCUSSION: 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.

Harmonization of summaries of product characteristics (SmPCs) of drugs with the same active ingredients: an evaluation of SmPCs of the most frequently prescribed active substances.

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.

Incidence of inpatient cases with mental disorders due to use of cannabinoids in Germany: a nationwide evaluation.

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<0.0001, trend analysis) in Germany between 2000 and 2018 and corresponding relative AFs increased considerably (4.8-fold increase when comparing 2000 and 2018). Specifically, absolute AFs of ICs with cannabinoid intoxications (P<0.0001), harmful use (P=0.0005), dependence syndrome (P< 0.0001), withdrawal state (P<0.0001), psychotic disorders (P< 0.0001) and residual and late-onset psychotic disorder (P<0.0001) statistically significantly increased. Absolute AFs of schizophrenia-spectrum disorders slightly, but statistically significantly decreased (P=0.008), and alcohol dependence did not statistically significantly change (P=0.844). 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.

A phase II study of the PI3K inhibitor copanlisib in combination with the anti-CD20 monoclonal antibody rituximab for patients with marginal zone lymphoma: treatment rationale and protocol design of the COUP-1 trial.

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.

The Impact of Serotonin Transporter Binding Affinity on the Risk of Bleeding Related to Antidepressants.

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.

A complex intervention to promote prevention of delirium in older adults by targeting caregiver's participation during and after hospital discharge - study protocol of the TRAnsport and DElirium in older people (TRADE) project.

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. TRIAL REGISTRATION: DRKS (Deutsches Register für klinische Studien) DRKS00017828 . Registered on 17th September 2019. Retrospectively registered.

Transbronchial cryobiopsy increases diagnostic confidence in interstitial lung disease: a prospective multicentre trial.

INTRODUCTION: The 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. METHODS: This 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. RESULTS: TBLC 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. INTERPRETATION: TBLC 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.

Phase II trial evaluating the efficacy and safety of the anti-CD20 monoclonal antibody obinutuzumab in patients with marginal zone lymphoma.

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.

[Cluster-Randomized Trials: Methodical and Practical Implications]. / Cluster-randomisierte Studien: Methodische und praktische Aspekte.

Quite often critics demand more randomized studies in rehabilitation science to gather methodological evidence of high quality. However, it is also recognized that the design of double-blind, placebo-controlled, randomized studies often cannot simply be transferred into rehabilitation science. Validity concerning the health care is here in the focus. Thus, treatment as-usual is mostly used as placebo treatment and double-blinding is partly not definable. Additionally, it is often difficult to offer 2 similar forms of treatment in one rehabilitation hospital due to lack of capacity. Additionally, contamination effects are to be expected when patients of different study arms communicate. Here cluster-randomized studies may be helpful. However, in comparison to individual randomized studies they need often higher sample sizes, a more complex methodology of sample size calculation as well as extensive methods of statistical analysis.Within this article advantages and disadvantages as well as the characteristics of cluster randomization are described and information is given how they can be implemented into the field of rehabilitation science.

[Different number of contraindications between summaries of product characteristics (SmPC) of drugs with the same active ingredients - an analysis of data from SmPCs of neuropsychiatric drugs]. / Unterschiedliche Anzahl von Kontraindikationen zwischen Fachinformationen wirkstoffgleicher Arzneimittel ­ eine Analyse von Daten aus Fachinformationen von neuropsychiatrischen Arzneimitteln.

OBJECTIVE: 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). METHODS: 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 Liste®/Fachinfo-Service® and communication with the manufacturer. RESULTS: N = 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). CONCLUSION(S): 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.

Bleeding risk of transbronchial cryobiopsy compared to transbronchial forceps biopsy in interstitial lung disease - a prospective, randomized, multicentre cross-over trial.

BACKGROUND: Bronchoscopic cryobiopsy is a new method of bronchoscopic tissue sampling in interstitial lung disease. In case of transbronchial biopsies, the resultant tissue samples are of high quality, and the lung parenchyma seen in the samples is adequate for a histological diagnosis in most cases. Bleeding after transbronchial biopsy is the most important procedure- associated complication and may be life threatening. This study addresses the risk of bleeding of transbronchial cryobiopsy. METHODS: In this prospective, randomized, controlled multicentre study 359 patients with interstitial lung disease requiring diagnostic bronchoscopic tissue sampling were included. Both conventional transbronchial forceps biopsy and transbronchial cryobiopsy were undertaken in each patient. The sequence of the procedures was randomized. Bleeding severity was evaluated semi-quantitatively as "no bleeding", "mild" (suction alone), "moderate" (additional intervention) or "severe" (prolonged monitoring necessary or fatal outcome), for each intervention. RESULTS: In 359 patients atotal of 1160 cryobiopsies and 1302 forceps biopsies were performed. Bleeding was observed after forceps biopsy in 173 patients (48.2%) and after cryobiopsy in 261 patients (72.7%). Bleeding was significantly greater in the cryobiopsy group (cryobiopsy/forceps biopsy: no bleeding 27.3%/51.8%; mild 56.5%/44.0%; moderate 15.0%/4.2%; severe 1.2%/0%; p < 0.001). The rate of clinically relevant bleeding (moderate or severe) was higher after the cryobiopsy procedures compared to the forceps biopsies (16.2% vs. 4.2%, p < 0.05). No fatal bleeding complications occurred. CONCLUSIONS: Compared to transbronchial forceps biopsy, transbronchial cryobiopsy was associated with an increased risk of bleeding which is of clinical relevance. Therefore training and additional precautions for bleeding control should be considered. TRIAL REGISTRATION: The study was registered with clinicaltrials.gov ( NCT01894113 ).

Identification of symbol digit modality test score extremes in Huntington's disease.

Studying individuals with extreme phenotypes could facilitate the understanding of disease modification by genetic or environmental factors. Our aim was to identify Huntington's disease (HD) patients with extreme symbol digit modality test (SDMT) scores. We first examined in HD the contribution of cognitive measures of the Unified Huntington's Disease Rating Scale (UHDRS) in predicting clinical endpoints. The language-independent SDMT was used to identify patients performing very well or very poorly relative to their CAG and age cohort. We used data from REGISTRY and COHORT observational study participants (5,603 HD participants with CAG repeats above 39 with 13,868 visits) and of 1,006 healthy volunteers (with 2,241 visits), included to identify natural aging and education effects on cognitive measures. Separate Cox proportional hazards models with CAG, age at study entry, education, sex, UHDRS total motor score and cognitive (SDMT, verbal fluency, Stroop tests) scores as covariates were used to predict clinical endpoints. Quantile regression for longitudinal language-independent SDMT data was used for boundary (2.5% and 97.5% quantiles) estimation and extreme score analyses stratified by age, education, and CAG repeat length. Ten percent of HD participants had an extreme SDMT phenotype for at least one visit. In contrast, only about 3% of participants were consistent SDMT extremes at two or more visits. The thresholds for the one-visit and two-visit extremes can be used to classify existing and new individuals. The identification of these phenotype extremes can be useful in the search for disease modifiers.

Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group.

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.

[Prescription of Benzodiazepines and Z-Drugs by German General Practitioners: A Cross-Sectional Study]. / Verordnung von Benzodiazepinen und Z-Drugs in hausärztlichen Praxen ­ eine Querschnittanalyse.

BACKGROUND: Due to their addictive potential, benzodiazepine (BZ) and non-benzodiazepine-agonists (NBZ, so-called Z-drugs) should be taken no longer than 6 weeks. BZ and NBZ are primarily prescribed by general practitioners (GPs). Therefore, we aimed to analyze GPs' data on the patients collective, the amount of BZ/NBZ prescribed and the rate of private prescriptions. METHODS: We analyzed person years of 2-year intervals from 2009 to 2014 of the primary care CONTENT register that contains routine data from 31 general practitioners' practices. We classified BZ/NBZ prescriptions according to risk groups. The association of BZ/NBZ prescription and potential influencing factors was analyzed by calculating the odds ratio with 95% confidence interval (and corresponding p-value) on the basis of a multiple logistic regression model (adjusted by age, sex and type of health insurance). All patients with drug prescription with and without BZ/NBZ-prescription were compared. RESULTS: Almost 5% of patients with drug prescriptions received at least one prescription of BZ/NBZ during 1 year of observation. On average these patients were older (67.5 vs. 48 years respectively) and the proportion of women was higher than in the comparison group (69 vs. 58%). About one-third of these patients received more than 600 mg diazepam equivalent dose per person year (according to a 2-month daily intake of more than 10 mg diazepam). About one-third of the prescriptions were private prescriptions. A number of variables were significantly associated with the prescription of BZ/NBZ (e. g. age, gender, diagnosis codes, practices). CONCLUSION: The results provide valuable information about BZ/NBZ prescription routines in general practice. For continuous medical education as well as the development of interventions to reduce the use of BZ/NBZ, patient characteristics (e. g. sex, age, comorbidities, type of insurance) as well as different prescription routines (e. g. private prescriptions, reason and frequency of prescriptions, guideline orientation) should be considered.

[Preterm Birth Rate at 6 Centres for Perinatal Medicine in Baden-Württemberg - Potential to Reduce Prematurity]. / Frühgeburtenrate in 6 Perinatalzentren in Baden-Württemberg ­ Potential zur Reduktion der Frühgeborenenzahl.

BACKGROUND: The Federal Joint Committee of Germany defined structural and staff requirements for the care of preterm and term infants as a proxy measure for quality. Neonatal outcome has been evaluated as a quality marker for a long time. While Germany has one of the highest preterm birth rates in Europe, no data exist on centre-specific preterm birth rates. METHODS: Over 2 years, all pregnant women admitted to six centres for perinatal medicine in Baden-Württemberg at a gestational age between 22+0 and 31+6 weeks were eligible (n=2972). The preterm birth rate before 32 wks of gestation was evaluated if at least one of the following secondary inclusion criteria was present within 24 h after admission: 1) premature rupture of membranes, 2) cervical length less than 25 mm, or 3) more than 3 contractions of at least 30-s duration within a 30-min period. Neonatal outcome could be documented for 70.6% of infants. RESULTS: Of the women who met at least one secondary inclusion criterion (n=1325), 21.1% (n=279) delivered 344 preterm infants before 32 weeks. The preterm birth rate was between 16.8 and 27.9% (11.1% difference). A lower preterm birth rate was not associated with a worse neonatal outcome. CONCLUSION: Preterm birth rate should become a quality indicator for perinatal care. A reduction of the preterm birth rate of 5% could help to reduce the number of preterm infants by up to 2,400 per year in Germany (about 25%).

Lipoarabinomannan-Responsive Polycytotoxic T Cells Are Associated with Protection in Human Tuberculosis.

RATIONALE: The development of host-targeted, prophylactic, and therapeutic interventions against tuberculosis requires a better understanding of the immune mechanisms that determine the outcome of infection with Mycobacterium tuberculosis. OBJECTIVES: To identify T-cell-dependent mechanisms that are protective in tuberculosis. METHODS: Multicolor flow cytometry, cell sorting and growth inhibition assays were employed to compare the frequency, phenotype and function of T lymphocytes from bronchoalveolar lavage or the peripheral blood. MEASUREMENTS AND MAIN RESULTS: At two independent study sites, bronchoalveolar lavage cells from donors with latent tuberculosis infection limited the growth of virulent Mycobacterium tuberculosis more efficiently than those in patients who developed disease. Unconventional, glycolipid-responsive T cells contributed to reduced mycobacterial growth because antibodies to CD1b inhibited this effect by 55%. Lipoarabinomannan was the most potent mycobacterial lipid antigen (activation of 1.3% T lymphocytes) and activated CD1b-restricted T cells that limited bacterial growth. A subset of IFN-γ-producing lipoarabinomannan-responsive T cells coexpressed the cytotoxic molecules perforin, granulysin, and granzyme B, which we termed polycytotoxic T cells. Taking advantage of two well-defined cohorts of subjects latently infected with Mycobacterium tuberculosis or patients who developed active disease after infection, we found a correlation between the frequency of polycytotoxic T cells and the ability to control infection (latent tuberculosis infection, 62%; posttuberculosis patients, 26%). CONCLUSIONS: Our data define an unconventional CD8(+) T-cell subset (polycytotoxic T cells) that is based on antigen recognition and function. The results link clinical and mechanistic evidence that glycolipid-responsive, polycytotoxic T cells contribute to protection against tuberculosis.

Identification of extreme motor phenotypes in Huntington's disease.

The manifestation of motor signs in Huntington's disease (HD) has a well-known inverse relationship with HTT CAG repeat length, but the prediction is far from perfect. The probability of finding disease modifiers is enhanced in individuals with extreme HD phenotypes. We aimed to identify extreme HD motor phenotypes conditional on CAG and age, such as patients with very early or very late onset of motor manifestation. Retrospective data were available from 1,218 healthy controls and 9,743 HD participants with CAG repeats ≥40, and a total of about 30,000 visits. Boundaries (2.5% and 97.5% quantiles) for extreme motor phenotypes (UHDRS total motor score (TMS) and motor age-at-onset) were estimated using quantile regression for longitudinal data. More than 15% of HD participants had an extreme TMS phenotype for at least one visit. In contrast, only about 4% of participants were consistent TMS extremes at two or more visits. Data from healthy controls revealed an upper cut-off of 13 for the TMS representing the extreme of motor ratings for a normal aging population. In HD, boundaries of motor age-at-onset based on diagnostic confidence or derived from the TMS data cut-off in controls were similar. In summary, a UHDRS TMS of more than 13 in an individual carrying the HD mutation indicates a high likelihood of motor manifestations of HD irrespective of CAG repeat length or age. The identification of motor phenotype extremes can be useful in the search for disease modifiers, for example, genetic or environmental such as medication. © 2016 Wiley Periodicals, Inc.

Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients.

OBJECTIVES: Biomarkers for the diagnosis of motoneuron diseases (MND) are urgently needed to improve the diagnostic pathway, patient stratification and monitoring. The aim of this study was to validate candidate markers for MND in cerebrospinal fluid (CSF) and specify cut-offs based on large patient cohorts by especially considering patients who were seen under the initial differential diagnosis (MND mimics). METHODS: In a prospective study, we investigated CSF of 455 patients for neurofilament light chain (NfL), phosphorylated heavy chain (pNfH), tau protein (Tau) and phospho-tau protein (pTau). Analysed cohorts included patients with apparently sporadic and familial amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) (MND, n=253), MND mimics (n=85) and neurological control groups. Cut-off values were specified, and diagnostic performance and correlation with progression were analysed. RESULTS: Nfs were significantly higher in the MND group compared to the control groups, whereas Tau and pTau did not differ. At a cut-off level of 2200 pg/mL for NfL, a 77% diagnostic sensitivity (CI 71% to 82%), 85% specificity (CI 79% to 90%) and 87% positive predictive value (PPV) (CI 81% to 91%) were achieved. For pNfH, we calculated 83% sensitivity (CI 78% to 88%), 77% specificity (CI 71% to 83%) and 82% PPV (CI 77% to 86%) at 560 pg/mL. There were no significant differences between sporadic and genetic ALS or PLS. Nf levels were elevated at early disease stage, and correlated moderately with MND progression and duration. CONCLUSIONS: Neurofilaments in CSF have a high relevance for the differential diagnosis of MNDs and should be included in the diagnostic work-up of patients. Their value as prognostic markers should be investigated further.

DocOx (AIO-PK0106): a phase II trial of docetaxel and oxaliplatin as a second line systemic therapy in patients with advanced pancreatic ductal adenocarcinoma.

BACKGROUND: The current study was conducted to examine the activity of a docetaxel/oxaliplatin (DocOx) combination as second line treatment for advanced pancreatic ductal adenocarcinoma (Trial registration: NCT00690300. Registered June 2, 2008) METHODS: DocOx is a prospective, multi-center, single arm, phase II trial using docetaxel (75 mg/m(2), 60 min, d 1) and oxaliplatin (80 mg/m(2), 120 min, d 2) in 21-day cycles. The treatment period was scheduled for up to 8 cycles. Primary endpoint was tumor response according to RECIST 1.0. Secondary endpoints were progression free survival, overall survival, safety/toxicity, quality of life and clinical benefit. RESULTS: Data represent the intention to treat analysis of 44 patients with chemorefractory pancreatic cancer enrolled between 2008 and 2012 at five institutions in Germany. The primary endpoint of tumor response was achieved in 15.9% of the patients (7 partial remissions, no complete remission), with a disease control rate of 48% after the first two treatment cycles. Median progression free survival (PFS) was 1.82 months (CI 95% 1.5-3.96 months) and median overall survival (OS) was 10.1 months (CI 95% 5.1-14.1 months). CONCLUSIONS: This single-arm trial demonstrates that the combination of docetaxel and oxaliplatin yields promising results for the treatment of advanced pancreatic ductal adenocarcinoma patients. Selected patients had particular benefit from this treatment as indicated by long PFS and OS times. Even after 8 cycles of treatment with DocOx a partial response was observed in 2 patients and stable disease was observed in another 6 patients. The data obtained with the DocOx protocol compare well with other second line protocols such as OFF (oxaliplatin, 5-FU, leucovorin). The DocOx regimen could be an interesting option for patients who received gemcitabine as first line treatment for metastatic pancreatic cancer.

Effectiveness of Trauma-Focused Cognitive Behavioral Therapy for Children and Adolescents: A Randomized Controlled Trial in Eight German Mental Health Clinics.

BACKGROUND: Trauma-focused cognitive behavioral therapy (Tf-CBT) is efficacious for children and adolescents with posttraumatic stress symptoms (PTSS). Its effectiveness in clinical practice has still to be investigated. AIMS: To determine whether Tf-CBT is superior to waiting list (WL), and to investigate the predictors of treatment response. METHOD: We conducted a single-blind parallel-group randomized controlled trial in eight German outpatient clinics with the main inclusion criteria of age 7-17 years, symptom score ≥35 on the Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA), and caregiver participation. Patients were randomly assigned to 12 sessions of Tf-CBT (n = 76) or a WL (n = 83). The primary outcome was the CAPS-CA symptom score assessed at 4 months by blinded evaluators. The secondary measures were diagnostic status, the Children's Global Assessment Scale (CGAS), self-reported and caregiver-reported PTSS (UCLA-PTSD Reaction Index), the Child Posttraumatic Cognitions Inventory (CPTCI), the Children's Depression Inventory (CDI), the Screen for Child Anxiety- Related Emotional Disorders (SCARED), the Child Behavior Checklist (CBCL/4-18), and the Quality of Life Inventory for Children. RESULTS: Intention-to-treat analyses showed that Tf-CBT was significantly superior to WL on the CAPS-CA (Tf-CBT: baseline = 58.51 ± 17.41; 4 months = 32.16 ± 26.02; WL: baseline = 57.39 ± 16.05; 4 months = 43.29 ± 25.2; F1, 157 = 12.3; p = 0.001; d = 0.50), in terms of secondary measures of the CGAS, UCLA-PTSD-RI, CPTCI, CDI, SCARED, and CBCL/4-18, but not in terms of quality of life. Age and comorbidity significantly predicted treatment response. CONCLUSIONS: Tf-CBT is effective for children and adolescents with heterogeneous trauma types in German service settings. Younger patients with fewer comorbid disorders show most improvement.