Publications by authors named "Kurt Ulm"

89 Publications

PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients.

Breast Care (Basel) 2021 Oct 17;16(5):523-531. Epub 2020 Dec 17.

Therawis Diagnostics GmbH, Munich, Germany.

Background: PITX2 DNA methylation has been shown to predict outcomes in high-risk breast cancer patients after anthracycline-based chemotherapy. To determine its prognostic versus predictive value, the impact of PITX2 DNA methylation on outcomes was studied in an untreated cohort vs. an anthracycline-treated triple-negative breast cancer (TNBC) cohort.

Material And Methods: The percent DNA methylation ratio (PMR) of paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time PCR test. Patient samples of routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue and clinical data from 144 TNBC patients of 2 independent cohorts (i.e., 66 untreated patients and 78 patients treated with anthracycline-based chemotherapy) were analyzed.

Results: The risk of 5- and 10-year overall survival (OS) increased continuously with rising PITX2 DNA methylation in the anthracycline-treated population, but it increased only slightly during 10-year follow-up time in the untreated patient population. PITX2 DNA methylation with a PMR cutoff of 2 did not show significance for poor vs. good outcomes (OS) in the untreated patient cohort (HR = 1.55; = 0.259). In contrast, the PITX2 PMR cutoff of 2 identified patients with poor (PMR >2) vs. good (PMR ≤2) outcomes (OS) with statistical significance in the anthracycline-treated cohort (HR = 3.96; = 0.011). The results in the subgroup of patients who did receive anthracyclines only (no taxanes) confirmed this finding (HR = 5.71; = 0.014).

Conclusion: In this hypothesis-generating study PITX2 DNA methylation demonstrated predominantly predictive value in anthracycline treatment in TNBC patients. The risk of poor outcome (OS) correlates with increasing PITX2 DNA methylation.
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http://dx.doi.org/10.1159/000510468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543364PMC
October 2021

Prognostic and predictive value of PD-L1 expression and tumour infiltrating lymphocytes (TiLs) in locally advanced NSCLC treated with simultaneous radiochemotherapy in the randomized, multicenter, phase III German Intergroup lung Trial (GILT).

Lung Cancer 2021 10 20;160:17-27. Epub 2021 Jul 20.

Department of Internal Medicine V, Thoracic Oncology Centre Munich, LMU Munich, Ziemssenstr. 1, 80336 Munich, Germany; Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Max-Lebsche-Platz 31, 81377 Munich, Germany. Electronic address:

Objectives: Immune checkpoint inhibition after radiochemotherapy (RTCT) has become a new standard of care for locally advanced non-small cell lung cancer with programmed death-ligand 1 (PD-L1) expression. However, little is known about the prognostic role of immune response markers in this setting. We analysed PD-L1 expression and tumour infiltrating lymphocytes (TiLs) in tumour biopsies from the multicenter German Intergroup Lung Trial (GILT), which previously randomised patients with stage III NSCLC to RTCT with or without consolidation chemotherapy.

Materials And Methods: We retrospectively analyzed tumour biopsies from patients treated in the GILT trial. PD-L1 expression was analysed using the Ventana SP263 assay and TiL score (low, intermediate, high) and pattern (excluded, inflamed, desert) were assessed. The primary endpoint of the biomarker analysis was PFS in patients with PD-L1 ≥ 1% vs. PD-L1 < 1% NSCLC. Secondary endpoints explored the prognostic relevance of additional PD-L1 expression levels and TiL score and pattern.

Results: Biopsies were available from 92 patients treated with RTCT. Patients with available tumor tissue did not differ significantly from the whole study population. PD-L1 scores from 78 samples were available for analysis. There was no difference in PFS in the PD-L1 < 1% vs. PD-L1 ≥ 1% subgroups. TiL score was available in 66 patients. Patients with high TiL score showed favourable overall survival compared to the low TiL subgroup. This trend was most pronounced in those patients treated with consolidative chemotherapy.

Conclusion: In this analysis, PD-L1 expression did not correlate with PFS following RTCT. However, patients with TiLs > 10% were found to have longer overall survival, especially for those patients treated with consolidation chemotherapy after the end of RTCT. Further analyses to explore the prognostic and predictive relevance of TiLs in the context of consolidative checkpoint inhibition with durvalumab are required.
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http://dx.doi.org/10.1016/j.lungcan.2021.07.008DOI Listing
October 2021

SARS-CoV-2 serology increases diagnostic accuracy in CT-suspected, PCR-negative COVID-19 patients during pandemic.

Respir Res 2021 Apr 23;22(1):119. Epub 2021 Apr 23.

Department of Internal Medicine II, School of Medicine, Technical University of Munich, Munich, Germany.

Background: In the absence of PCR detection of SARS-CoV-2 RNA, accurate diagnosis of COVID-19 is challenging. Low-dose computed tomography (CT) detects pulmonary infiltrates with high sensitivity, but findings may be non-specific. This study assesses the diagnostic value of SARS-CoV-2 serology for patients with distinct CT features but negative PCR.

Methods: IgM/IgG chemiluminescent immunoassay was performed for 107 patients with confirmed (group A: PCR + ; CT ±) and 46 patients with suspected (group B: repetitive PCR-; CT +) COVID-19, admitted to a German university hospital during the pandemic's first wave. A standardized, in-house CT classification of radiological signs of a viral pneumonia was used to assess the probability of COVID-19.

Results: Seroconversion rates (SR) determined on day 5, 10, 15, 20 and 25 after symptom onset (SO) were 8%, 25%, 65%, 76% and 91% for group A, and 0%, 10%, 19%, 37% and 46% for group B, respectively; (p < 0.01). Compared to hospitalized patients with a non-complicated course (non-ICU patients), seroconversion tended to occur at lower frequency and delayed in patients on intensive care units. SR of patients with CT findings classified as high certainty for COVID-19 were 8%, 22%, 68%, 79% and 93% in group A, compared with 0%, 15%, 28%, 50% and 50% in group B (p < 0.01). SARS-CoV-2 serology established a definite diagnosis in 12/46 group B patients. In 88% (8/9) of patients with negative serology > 14 days after symptom onset (group B), clinico-radiological consensus reassessment revealed probable diagnoses other than COVID-19. Sensitivity of SARS-CoV-2 serology was superior to PCR > 17d after symptom onset.

Conclusions: Approximately one-third of patients with distinct COVID-19 CT findings are tested negative for SARS-CoV-2 RNA by PCR rendering correct diagnosis difficult. Implementation of SARS-CoV-2 serology testing alongside current CT/PCR-based diagnostic algorithms improves discrimination between COVID-19-related and non-related pulmonary infiltrates in PCR negative patients. However, sensitivity of SARS-CoV-2 serology strongly depends on the time of testing and becomes superior to PCR after the 2 week following symptom onset.
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http://dx.doi.org/10.1186/s12931-021-01717-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062836PMC
April 2021

Microbiota alteration at different stages in gastric lesion progression: a population-based study in Linqu, China.

Am J Cancer Res 2021 1;11(2):561-575. Epub 2021 Feb 1.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute Beijing, China.

In addition to Helicobacter pylori (H.pylori), gastric microbiota may be involved in carcinogenesis process. However, the longitudinal study to assess changes in the gastric microbiota associated with the development of gastric carcinogenesis is still limited. The aim of this study is to explore dynamic microbial alterations in gastric cancer (GC) development based on a 4-year endoscopic follow-up cohort in Linqu County, China. Microbial alterations were investigated by deep sequencing of the microbial 16S ribosomal RNA gene in 179 subjects with various gastric lesions, and validated in paired gastric biopsies prospectively collected before and after lesion progression and in non-progression controls. Significant differences were found in microbial diversity and community structure across various gastric lesions, with 62 candidate differential taxa between at least two lesion groups. Further validations identified Helicobacter, Bacillus, Capnocytophaga and Prevotella to be associated with lesion progression-to-dysplasia (DYS)/GC (all P < 0.05), especially for subjects progressing from intestinal metaplasia (IM) to DYS/GC. The combination of the four genera in a microbial dysbiosis index showed a significant difference after lesion progression-to-DYS/GC compared to controls (P = 0.027). The panel including the four genera identified subjects after progression-to-DYS/GC with an area under the receiver-operating curve (AUC) of 0.941. Predictive significance was found before lesion progression-to-DYS/GC with an AUC = 0.776 and an even better AUC (0.927) for subjects progressing from IM to DYS/GC. Microbiota may play different roles at different stages in gastric carcinogenesis. A panel of bacterial genera associated with gastric lesions may help to assess gastric microbial dysbiosis and show potential predictive values for lesion progression. Our findings provide new clues for the microbial mechanism of H.pylori-associated carcinogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868750PMC
February 2021

Polyscore of autonomic parameters for risk stratification of the elderly general population: the Polyscore study.

Europace 2021 05;23(5):789-796

Klinik für Innere Medizin I, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.

Aims: Present society is constantly ageing and elderly frequently suffer from conditions that are difficult and/or costly to treat if detected late. Effective screening of the elderly is therefore needed so that those requiring detailed clinical work-up are identified early. We present a prospective validation of a screening strategy based on a Polyscore of seven predominantly autonomic, non-invasive risk markers.

Methods And Results: Within a population-based survey in Germany (INVADE study), participants aged ≥60 years were enrolled between August 2013 and February 2015. Seven prospectively defined Polyscore components were obtained during 30-min continuous recordings of electrocardiogram, blood pressure, and respiration. Out of 1956 subjects, 168 were excluded due to atrial fibrillation, implanted pacemaker, or unsuitable recordings. All-cause mortality over a median 4-year follow-up was prospectively defined as the primary endpoint. The Polyscore divided the investigated population (n = 1788, median age: 72 years, females: 58%) into three predefined groups with low (n = 1405, 78.6%), intermediate (n = 326, 18.2%), and high risk (n = 57, 3.2%). During the follow-up, 82 (4.6%) participants died. Mortality in the Polyscore-defined risk groups was 3.4%, 7.4%, and 17.5%, respectively (P < 0.0001). The Polyscore-based mortality prediction was independent of Framingham score, diabetes, chronic kidney disease, and major stroke and/or myocardial infarction history. It was particularly effective in those aged <75 years (n = 1145).

Conclusion: The Polyscore-based mortality risk assessment from short-term non-invasive recordings is effective in the elderly general population, especially those aged 60-74 years. Implementation of a comprehensive Polyscore screening of this age group is proposed to advance preventive medical care.
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http://dx.doi.org/10.1093/europace/euaa359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139819PMC
May 2021

Fixed or adjustable sling in the treatment of male stress urinary incontinence: results from a large cohort study.

Transl Androl Urol 2020 Jun;9(3):1099-1107

Department of Urology and Pediatric Urology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.

Background: Fixed and adjustable male slings for the treatment of male urinary stress incontinence became increasingly popular during the last decade. Although fixed slings are recommended for the treatment of mild to moderate stress urinary incontinence, there is still a lack of evidence regarding the precise indication for an adjustable male sling. Furthermore, there is still no evidence that one type of male sling is superior to another. However, both, adjustable and fixed slings, are commonly utilized in daily clinical practice. This current investigation aims to evaluate the differences between fixed and adjustable male slings regarding indications, complication rates and functional outcome in the treatment of male stress urinary incontinence in current clinical practice.

Methods: A total of 294 patients with a fixed and 176 patients with an adjustable male sling were evaluated in a multicenter single arm cohort trial. Data collection was performed retrospectively according the medical record. Functional outcome was prospectively analyzed by standardized, validated questionnaires. Descriptive statistics was performed to present patient characteristics, complication rates and functional outcome. A chi2-test for categorical and independent t-test for continuous variables was performed to identify heterogeneity between the groups and to correlate preoperative characteristics with the outcome. A P value <0.05 was considered statistically significant.

Results: Patients with higher degree of urinary incontinence (P<0.001) and risk factors such as history of pelvic irradiation (P<0.001) or prior surgery for urethral stricture (P=0.032) were more likely to receive an adjustable MS. Complication rates were comparable except for infection (P=0.009, 0 2.3%) and pain (P=0.001, 1.7% 11.3%) which occurred more frequently in adjustable slings. Functional outcome according validated questionnaires demonstrated no differences between fixed and adjustable male slings.

Conclusions: Adjustable male slings are more frequently utilized in patients with higher degree of incontinence and risk factors compared to fixed slings. No differences could be identified between functional outcome which may imply an advantage for adjustability. However, pain and infection rates were significantly higher in adjustable MS and should be considered in the decision process for sling type.
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http://dx.doi.org/10.21037/tau-19-852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354336PMC
June 2020

Microbiota-associated Risk Factors for Clostridioides difficile Acquisition in Hospitalized Patients: A Prospective, Multicentric Study.

Clin Infect Dis 2021 11;73(9):e2625-e2634

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background: Asymptomatic C. difficile colonization is believed to predispose to subsequent C. difficile infection (CDI). While emerging insights into the role of the commensal microbiota in mediating colonization resistance against C. difficile have associated CDI with specific microbial components, corresponding prospectively collected data on colonization with C. difficile are largely unavailable.

Methods: C. difficile status was assessed by GDH EIA and real-time PCR targeting the toxin A (tcdA) and B (tcdB) genes. 16S V3 and V4 gene sequencing results from fecal samples of patients tested positive for C. difficile were analyzed by assessing alpha and beta diversity, LefSe, and the Piphillin functional inference approach to estimate functional capacity.

Results: 1506 patients were recruited into a prospective observational study (DRKS00005335) upon admission into one of five academic hospitals. 936 of them provided fecal samples on admission and at discharge and were thus available for longitudinal analysis. Upon hospital admission, 5.5% (83/1506) and 3.7% (56/1506) of patients were colonized with toxigenic (TCD) and non-toxigenic C. difficile (NTCD), respectively. During hospitalization, 1.7% (16/936) acquired TCD. Risk factors for acquisition of TCD included pre-existing lung diseases, lower GI endoscopy and antibiotics. Species protecting against hospital-related C. difficile acquisition included Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococcus spp. Metagenomic pathway analysis identified steroid biosynthesis as the most underrepresented metabolic pathway in patients who later acquire C. difficile colonization.

Conclusions: Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococci were associated with a decreased risk of C. difficile acquisition.

Clinical Trials Registration: DRKS00005335.
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http://dx.doi.org/10.1093/cid/ciaa871DOI Listing
November 2021

Effect of on gastrointestinal microbiota: a population-based study in Linqu, a high-risk area of gastric cancer.

Gut 2020 09 19;69(9):1598-1607. Epub 2019 Dec 19.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China

Objective: Gastrointestinal microbiota may be involved in associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential dysbiosis arising from infection.

Design: Deep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti- treatment, relative to 49 negative subjects.

Results: In positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between and , , , , were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased after successful eradication and more upregulated drug-resistant functional orthologs after failed treatment.

Conclusion: infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.
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http://dx.doi.org/10.1136/gutjnl-2019-319696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456744PMC
September 2020

Confidence interval estimation for the changepoint of treatment stratification in the presence of a qualitative covariate-treatment interaction.

Stat Med 2020 01 7;39(1):70-96. Epub 2019 Nov 7.

School of Medicine, Institute for Medical Informatics, Statistics and Epidemiology, Technical University of Munich, Munich, Germany.

The goal in stratified medicine is to administer the "best" treatment to a patient. Not all patients might benefit from the same treatment; the choice of best treatment can depend on certain patient characteristics. In this article, it is assumed that a time-to-event outcome is considered as a patient-relevant outcome and a qualitative interaction between a continuous covariate and treatment exists, ie, that patients with different values of one specific covariate should be treated differently. We suggest and investigate different methods for confidence interval estimation for the covariate value, where the treatment recommendation should be changed based on data collected in a randomized clinical trial. An adaptation of Fieller's theorem, the delta method, and different bootstrap approaches (normal, percentile-based, wild bootstrap) are investigated and compared in a simulation study. Extensions to multivariable problems are presented and evaluated. We observed appropriate confidence interval coverage following Fieller's theorem irrespective of sample size but at the cost of very wide or even infinite confidence intervals. The delta method and the wild bootstrap approach provided the smallest intervals but inadequate coverage for small to moderate event numbers, also depending on the location of the true changepoint. For the percentile-based bootstrap, wide intervals were observed, and it was slightly conservative regarding coverage, whereas the normal bootstrap did not provide acceptable results for many scenarios. The described methods were also applied to data from a randomized clinical trial comparing two treatments for patients with symptomatic, severe carotid artery stenosis, considering patient's age as predictive marker.
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http://dx.doi.org/10.1002/sim.8404DOI Listing
January 2020

Use of a train-of-four ratio of 0.95 versus 0.9 for tracheal extubation: an exploratory analysis of POPULAR data.

Br J Anaesth 2020 01 10;124(1):63-72. Epub 2019 Oct 10.

Department of Medical Statistics and Epidemiology, School of Medicine, Technical University of Munich, Munich, Germany.

Background: The prospective observational European multicentre cohort study (POPULAR) of postoperative pulmonary complications (NCT01865513) did not demonstrate that adherence to the recommended train-of-four ratio (TOFR) of 0.9 before extubation was associated with better pulmonary outcomes from the first postoperative day up to hospital discharge. We re-analysed the POPULAR data as to whether there existed a better threshold for TOFR recovery before extubation to reduce postoperative pulmonary complications in patients who had quantitative neuromuscular monitoring (87% acceleromyography).

Methods: To identify the optimal TOFR, the complete case cohort of patients with quantitative neuromuscular monitoring (n=3150) was split into several pairs of sub-cohorts related to TOFR values from 0.86 to 0.96; values of 0.97 and higher could not be used as the sub-cohorts were too small. The optimal TOFR was considered to have the lowest P-value from multivariate logistic regression calculated for each of the TOFR values. Data are presented as adjusted absolute risk reduction or median difference with 95% confidence interval.

Results: Extubating patients with TOFR >0.95 rather than >0.9 reduced the adjusted risk of postoperative pulmonary complications by 3.5% (0.7-6.0%) from that reported in POPULAR (11.3%). Increasing the recommended TOFR from 0.9 to 0.95 reduced the adjusted risk by 4.9% (1.2-8.5%). Sub-cohorts resulting from 1:1 propensity score matching revealed that sugammadex had been given in higher doses by 0.30 (0.13-0.48) mg kg in the sub-cohort with TOFR > 0.95.

Conclusions: A post hoc analysis of patients receiving quantitative monitoring of neuromuscular function suggests that postoperative pulmonary complications are reduced for TOFR > 0.95 before tracheal extubation compared with TOFR > 0.9.

Trial Registration Number: NCT01865513.
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http://dx.doi.org/10.1016/j.bja.2019.08.023DOI Listing
January 2020

A Simulation Study Comparing Different Statistical Approaches for the Identification of Predictive Biomarkers.

Comput Math Methods Med 2019 13;2019:7037230. Epub 2019 Jun 13.

Technical University of Munich, School of Medicine, Institute of Medical Informatics, Statistics and Epidemiology, Ismaninger Str. 22, 81675 Munich, Germany.

Identification of relevant biomarkers that are associated with a treatment effect is one requirement for adequate treatment stratification and consequently to improve health care by administering the best available treatment to an individual patient. Various statistical approaches were proposed that allow assessing the interaction between a continuous covariate and treatment. Nevertheless, categorization of a continuous covariate, e.g., by splitting the data at the observed median value, appears to be very prevalent in practice. In this article, we present a simulation study considering data as observed in a randomized clinical trial with a time-to-event outcome performed to compare properties of such approaches, namely, Cox regression with linear interaction, Multivariable Fractional Polynomials for Interaction (MFPI), Local Partial-Likelihood Bootstrap (LPLB), and the Subpopulation Treatment Effect Pattern Plot (STEPP) method, and of strategies based on categorization of continuous covariates (splitting the covariate at the median, splitting at quartiles, and using an "optimal" split by maximizing a corresponding test statistic). In different scenarios with no interactions, linear interactions or nonlinear interactions, type I error probability and the power for detection of a true covariate-treatment interaction were estimated. The Cox regression approach was more efficient than the other methods for scenarios with monotonous interactions, especially when the number of observed events was small to moderate. When patterns of the biomarker-treatment interaction effect were more complex, MFPI and LPLB performed well compared to the other approaches. Categorization of data generally led to a loss of power, but for very complex patterns, splitting the data into multiple categories might help to explore the nature of the interaction effect. Consequently, we recommend application of statistical methods developed for assessment of interactions between continuous biomarkers and treatment instead of arbitrary or data-driven categorization of continuous covariates.
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http://dx.doi.org/10.1155/2019/7037230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595324PMC
February 2020

Clinical Validation of DNA Methylation to Predict Outcome in High-Risk Breast Cancer Patients Treated with Anthracycline-Based Chemotherapy.

Breast Care (Basel) 2018 Dec 28;13(6):425-433. Epub 2018 Sep 28.

Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Breast cancer patients at high risk for recurrence are treated with anthracycline-based chemotherapy, but not all patients do equally benefit from such a regimen. To further improve therapy decision-making, biomarkers predicting outcome are of high unmet medical need. The percent DNA methylation ratio (PMR) of the promoter gene coding for the Paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time polymerase chain reaction (PCR) test. The multicenter study was conducted in routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue from 205 lymph node-positive breast cancer patients treated with adjuvant anthracycline-based chemotherapy. The cut-off for the methylation status (PMR = 12) was confirmed in a randomly selected cohort (n = 60) and validated (n = 145) prospectively with disease-free survival (DFS) at the 10-year follow-up. DFS was significantly different between the PMR ≤ 12 versus the PMR > 12 group with a hazard ratio (HR) of 2.74 (p < 0.001) in the validation cohort and also for the patient subgroup treated additionally with endocrine therapy (HR 2.47; p = 0.001). Early-stage lymph node-positive breast cancer patients with low methylation do benefit from adjuvant anthracycline-based chemotherapy. Patients with a high DNA methylation ratio, approximately 30%, show poor outcome and should thus be considered for alternative chemotherapy regimens.
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http://dx.doi.org/10.1159/000493016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381917PMC
December 2018

Neuromuscular monitoring and reversal: responses to the POPULAR study - Authors' reply.

Lancet Respir Med 2019 02;7(2):e7-e8

Department of Anaesthesiology, Academic Medical Centre, Amsterdam University, Amsterdam, Netherlands.

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http://dx.doi.org/10.1016/S2213-2600(18)30462-4DOI Listing
February 2019

Effects of a lifestyle intervention during pregnancy to prevent excessive gestational weight gain in routine care - the cluster-randomised GeliS trial.

BMC Med 2019 01 14;17(1). Epub 2019 Jan 14.

Else Kröner-Fresenius-Centre for Nutritional Medicine, Klinikum rechts der Isar, Technical University of Munich, Georg-Brauchle-Ring 62, 80992, Munich, Germany.

Background: Excessive gestational weight gain (GWG) leads to obstetric complications, maternal postpartum weight retention and an increased risk of offspring obesity. The GeliS study examines the effect of a lifestyle intervention during pregnancy on the proportion of women with excessive GWG and pregnancy and obstetric complications, as well as the long-term risk of maternal and infant obesity.

Methods: The GeliS study is a cluster-randomised multicentre controlled trial including 2286 women with a pre-pregnancy BMI between 18.5 and 40.0 kg/m recruited from gynaecological and midwifery practices prior to the end of the 12 week of gestation in five Bavarian regions. In the intervention regions, four lifestyle counselling sessions covering a balanced healthy diet, regular physical activity and self-monitoring of weight gain were performed by trained healthcare providers alongside routine pre- and postnatal practice visits. In the control regions, leaflets with general recommendations for a healthy lifestyle during pregnancy were provided.

Results: The intervention did not result in a significant reduction of women showing excessive GWG (adjusted OR 0.95, 95% CI 0.66-1.38, p = 0.789), with 45.1% and 45.7% of women in the intervention and control groups, respectively, gaining weight above the Institute of Medicine recommendations. Gestational diabetes mellitus was diagnosed in 10.8% and 11.1% of women in the intervention and control groups, respectively (p = 0.622). Mean birth weight and length were slightly lower in the intervention group (3313 ± 536 g vs. 3363 ± 498 g, p = 0.020; 51.1 ± 2.7 cm vs. 51.6 ± 2.5 cm, p = 0.001).

Conclusion: In the setting of routine prenatal care, lifestyle advice given by trained healthcare providers was not successful in limiting GWG and pregnancy complications. Nevertheless, the potential long-term effects of the intervention remain to be assessed.

Trial Registration: NCT01958307 , ClinicalTrials.gov, retrospectively registered October 9, 2013.
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http://dx.doi.org/10.1186/s12916-018-1235-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330753PMC
January 2019

Clinical performance of an analytically validated assay in comparison to microarray technology to assess PITX2 DNA-methylation in breast cancer.

Sci Rep 2018 11 15;8(1):16861. Epub 2018 Nov 15.

Therawis Diagnostics GmbH, Grillparzerstrasse 14, 81675, Munich, Germany.

Significant evidence has accumulated that DNA-methylation of the paired-like homeodomain transcription factor 2 (PITX2) gene can serve as a prognostic and predictive biomarker in breast cancer. PITX2 DNA-methylation data have been obtained so far from microarray and polymerase chain reaction (PCR)-based research tests. The availability of an analytically validated in vitro methylation-specific real-time PCR assay format (therascreen PITX2 RGQ PCR assay) intended for the determination of the percent methylation ratio (PMR) in the (PITX2) promoter 2 prompted us to investigate whether the clinical performance of these different assay systems generate comparable clinical outcome data. Mathematically converted microarray data of a previous breast cancer study (n = 204) into PMR values leads to a PITX2 cut-off value at PMR 14.73. Recalculation of the data to experimentally equivalent PMRs with the PCR PITX2 assay leads to a cut-off value at PMR 12 with the highest statistical significance. This cut-off predicts outcome of high-risk breast cancer patients to adjuvant anthracycline-based chemotherapy (n = 204; Hazard Ratio 2.48; p < 0.001) comparable to microarray generated results (n = 204; Hazard ratio 2.32; p < 0.0001). The therascreen PITX2 RGQ PCR assay is an analytically validated test with high reliability and robustness and predicts outcome of high-risk breast cancer patients to anthracycline-based chemotherapy.
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http://dx.doi.org/10.1038/s41598-018-34919-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237923PMC
November 2018

Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study.

Lancet Respir Med 2019 02 14;7(2):129-140. Epub 2018 Sep 14.

Department of Anaesthesiology, Technical University of Munich, Munich, Germany. Electronic address:

Background: Results from retrospective studies suggest that use of neuromuscular blocking agents during general anaesthesia might be linked to postoperative pulmonary complications. We therefore aimed to assess whether the use of neuromuscular blocking agents is associated with postoperative pulmonary complications.

Methods: We did a multicentre, prospective observational cohort study. Patients were recruited from 211 hospitals in 28 European countries. We included patients (aged ≥18 years) who received general anaesthesia for any in-hospital procedure except cardiac surgery. Patient characteristics, surgical and anaesthetic details, and chart review at discharge were prospectively collected over 2 weeks. Additionally, each patient underwent postoperative physical examination within 3 days of surgery to check for adverse pulmonary events. The study outcome was the incidence of postoperative pulmonary complications from the end of surgery up to postoperative day 28. Logistic regression analyses were adjusted for surgical factors and patients' preoperative physical status, providing adjusted odds ratios (OR) and adjusted absolute risk reduction (ARR). This study is registered with ClinicalTrials.gov, number NCT01865513.

Findings: Between June 16, 2014, and April 29, 2015, data from 22 803 patients were collected. The use of neuromuscular blocking agents was associated with an increased incidence of postoperative pulmonary complications in patients who had undergone general anaesthesia (1658 [7·6%] of 21 694); OR 1·86, 95% CI 1·53-2·26; ARR -4·4%, 95% CI -5·5 to -3·2). Only 2·3% of high-risk surgical patients and those with adverse respiratory profiles were anaesthetised without neuromuscular blocking agents. The use of neuromuscular monitoring (OR 1·31, 95% CI 1·15-1·49; ARR -2·6%, 95% CI -3·9 to -1·4) and the administration of reversal agents (1·23, 1·07-1·41; -1·9%, -3·2 to -0·7) were not associated with a decreased risk of postoperative pulmonary complications. Neither the choice of sugammadex instead of neostigmine for reversal (OR 1·03, 95% CI 0·85-1·25; ARR -0·3%, 95% CI -2·4 to 1·5) nor extubation at a train-of-four ratio of 0·9 or more (1·03, 0·82-1·31; -0·4%, -3·5 to 2·2) was associated with better pulmonary outcomes.

Interpretation: We showed that the use of neuromuscular blocking drugs in general anaesthesia is associated with an increased risk of postoperative pulmonary complications. Anaesthetists must balance the potential benefits of neuromuscular blockade against the increased risk of postoperative pulmonary complications.

Funding: European Society of Anaesthesiology.
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http://dx.doi.org/10.1016/S2213-2600(18)30294-7DOI Listing
February 2019

Ice water test in multiple sclerosis: A pilot trial.

Int J Urol 2018 11 13;25(11):938-943. Epub 2018 Aug 13.

Department of Urology and Pediatric Urology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.

Objectives: To investigate the significance of the ice water test in patients with multiple sclerosis and to evaluate a novel ice water test nomogram in a large patient cohort.

Methods: A total of 201 ice water tests of patients with multiple sclerosis were retrospectively evaluated. Incontinence episodes in 24 h and sex were correlated with the ice water test. Furthermore, an ice water test nomogram was developed in order to categorize the detrusor overactivity in severity degrees. Descriptive statistics were carried out for population characteristics. Correlations of categorical variables were calculated by the χ -test. The independent t-test was carried out for correlations of continuous variables. Furthermore, the data were evaluated in the novel ice water test nomogram.

Results: The patient population consisted of 141 (70.1%) women and 60 (39.9%) men. A clinically positive ice water test (maximum detrusor pressure >15 cmH O) was identified in 75 patients (37.3%). Significantly more men presented a clinically positive ice water test (P = 0.006). In 16.5%, the ice water test unmasked an involuntary detrusor contraction, although routine cystometry did not show any detrusor overactivity. The ice water test nomogram could be successfully applied. The incontinence episodes and maximum detrusor pressure correlated positively with a higher categorization in the nomogram. Therapeutic interventions and follow-up controls could be successfully illustrated by the nomogram.

Conclusions: The ice water test is a simple tool for unmasking non-identified detrusor overactivity in neurogenic bladder dysfunction. A severity categorization of the detrusor overactivity can be facilitated by the use of the ice water test nomogram. After further validation, the ice water test could be ultimately used in future as objective assessment for bladder dysfunction.
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http://dx.doi.org/10.1111/iju.13786DOI Listing
November 2018

Association Between Gut Microbiota and -Related Gastric Lesions in a High-Risk Population of Gastric Cancer.

Front Cell Infect Microbiol 2018 19;8:202. Epub 2018 Jun 19.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China.

Eradication of has been found to be effective for gastric cancer prevention, but uncertainties remain about the possible adverse consequences such as the potential microbial dysbiosis. In our study, we investigated the association between gut microbiota and -related gastric lesions in 47 subjects by deep sequencing of microbial 16S ribosomal RNA (rRNA) gene in fecal samples. The dominant phyla in fecal samples were , and with average relative abundances of 54.77, 31.37 and 12.91%, respectively. Microbial diversity analysis showed that observed species and Shannon index were increased in subjects with past or current infection compared with negative subjects. As for the differential bacteria, the average relative abundance of was found to significantly decrease from negative (66.16%) to past infection group (33.01%, = 0.007), as well as from normal (76.49%) to gastritis (56.04%) and metaplasia subjects (46.83%, = 0.027). For and , the average relative abundances showed elevated trends in the past infection group (47.11, 20.53%) compared to negative group (23.44, 9.05%, = 0.068 and 0.246, respectively), and similar increased trends were also found from normal (18.23, 5.05%) to gastritis (35.31, 7.23%, = 0.016 and 0.294, respectively) or metaplasia subjects (32.33, 20.07%, both < 0.05). These findings suggest that the alterations of fecal microbiota, especially the dominant phyla of and , may be involved in the process of -related gastric lesion progression and provide hints for future evaluation of microbial changes after eradication.
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http://dx.doi.org/10.3389/fcimb.2018.00202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018392PMC
July 2019

The AdVance and AdVanceXP male sling in urinary incontinence: is there a difference?

World J Urol 2018 Oct 4;36(10):1657-1662. Epub 2018 May 4.

Department of Urology and Pediatric Urology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.

Purpose: To compare the efficacy and perioperative complications of the AdVanceXP with the original AdVance male sling.

Methods: We retrospectively enrolled 109 patients with an AdVance and 185 patients with an AdVanceXP male sling. The baseline characteristics and complication rates were analyzed retrospectively. Functional outcome and quality of life were evaluated prospectively by standardized, validated questionnaires. The Chi-test for categorical and Mann-Whitney U test for continuous variables were performed to identify heterogeneity between the groups.

Results: Regarding operation time, there was no significant difference between the slings (p = 0.146). The complication rates were comparable in both groups except for postoperative urinary retention. This occurred significantly more often in patients with the AdVanceXP (p = 0.042). During follow-up, no differences could be identified regarding ICIQ-SF, PGI or I-QoL or number of pad usage.

Conclusions: The AdVance and AdVanceXP are safe and effective treatment options for male stress urinary incontinence. However, the innovations of the AdVanceXP sling did not demonstrate a superiority over the original AdVance sling regarding functional outcome.
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http://dx.doi.org/10.1007/s00345-018-2316-5DOI Listing
October 2018

A simulation study on estimating biomarker-treatment interaction effects in randomized trials with prognostic variables.

Trials 2018 Feb 20;19(1):128. Epub 2018 Feb 20.

Institute of Medical Informatics, Statistics and Epidemiology, Technical University of Munich, Ismaninger Str. 22, Munich, 81675, Germany.

Background: To individualize treatment decisions based on patient characteristics, identification of an interaction between a biomarker and treatment is necessary. Often such potential interactions are analysed using data from randomized clinical trials intended for comparison of two treatments. Tests of interactions are often lacking statistical power and we investigated if and how a consideration of further prognostic variables can improve power and decrease the bias of estimated biomarker-treatment interactions in randomized clinical trials with time-to-event outcomes.

Methods: A simulation study was performed to assess how prognostic factors affect the estimate of the biomarker-treatment interaction for a time-to-event outcome, when different approaches, like ignoring other prognostic factors, including all available covariates or using variable selection strategies, are applied. Different scenarios regarding the proportion of censored observations, the correlation structure between the covariate of interest and further potential prognostic variables, and the strength of the interaction were considered.

Results: The simulation study revealed that in a regression model for estimating a biomarker-treatment interaction, the probability of detecting a biomarker-treatment interaction can be increased by including prognostic variables that are associated with the outcome, and that the interaction estimate is biased when relevant prognostic variables are not considered. However, the probability of a false-positive finding increases if too many potential predictors are included or if variable selection is performed inadequately.

Conclusions: We recommend undertaking an adequate literature search before data analysis to derive information about potential prognostic variables and to gain power for detecting true interaction effects and pre-specifying analyses to avoid selective reporting and increased false-positive rates.
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http://dx.doi.org/10.1186/s13063-018-2491-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819679PMC
February 2018

The TiLOOP® Male Sling: Did We Forejudge.

Urol Int 2018 26;100(2):216-221. Epub 2017 Oct 26.

Department of Urology and Pediatric Urology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.

Introduction: To evaluate the safety and efficacy of the TiLOOP® male sling (pfm medical, Cologne, Germany) used in the treatment for male stress urinary incontinence (SUI).

Material And Methods: We retrospectively evaluated a total of 34 patients with a TiLOOP® male sling. Perioperative complication rates were assessed and validated questionnaires were prospectively evaluated to assess quality of life and satisfaction rate. Outcome and complication rates were analysed by using descriptive statistics. Correlation of continence outcome and risk factors was performed with the chi-square test. A p value below 0.05 was considered statistically significant.

Results: The majority of patients (70.6%) were diagnosed with mild or moderate male SUI. During surgery, one instance (2.9%) of intraoperative urethral injury was observed. There were no immediate postoperative complications. The mean follow-up time was 44.6 months. An improvement of male SUI was reported by 61.9% of the patients and 38.1% reported no change according the Patient Global Impression of Improvement. The mean perineal pain score was 0.5 according to the international index of pain.

Conclusions: The TiLOOP® is a safe treatment option for male SUI in our cohort with a low complication rate. However, the functional outcome of the TiLOOP® was inferior when compared to the outcome of the AdVance® male sling.
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http://dx.doi.org/10.1159/000477765DOI Listing
September 2018

Development of an algorithm using clinical tests to avoid post-operative residual neuromuscular block.

BMC Anesthesiol 2017 Aug 4;17(1):101. Epub 2017 Aug 4.

Klinik für Anaesthesiologie, Klinikum rechts der Isar, Technische Universität München, Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Background: Quantitative neuromuscular monitoring is the gold standard to detect postoperative residual curarization (PORC). Many anesthesiologists, however, use insensitive, qualitative neuromuscular monitoring or unreliable, clinical tests. Goal of this multicentre, prospective, double-blinded, assessor controlled study was to develop an algorithm of muscle function tests to identify PORC.

Methods: After extubation a blinded anesthetist performed eight clinical tests in 165 patients. Test results were correlated to calibrated electromyography train-of-four (TOF) ratio and to a postoperatively applied uncalibrated acceleromyography. A classification and regression tree (CART) was calculated developing the algorithm to identify PORC. This was validated against uncalibrated acceleromyography and tactile judgement of TOF fading in separate 100 patients.

Results: After eliminating three tests with poor correlation, a model with four tests (r = 0.844) and uncalibrated acceleromyography (r = 0.873) were correlated to electromyographical TOF-values without losing quality of prediction. CART analysis showed that three consecutively performed tests (arm lift, head lift and swallowing or eye opening) can predict electromyographical TOF. Prediction coefficients reveal an advantage of the uncalibrated acceleromyography in terms of specificity to identify the EMG measured train-of-four ratio < 0.7 (100% vs. 42.9%) and <0.9 (89.7% vs. 34.5%) compared to the algorithm. However, due to the high sensitivity of the algorithm (100% vs. 94.4%), the risk to overlook an awake patient with a train-of-four ratio < 0.7 was minimal. Tactile judgement of TOF fading showed poorest sensitivity and specifity at train of four ratio < 0.9 (33.7%, 0%) and <0.7 (18.8%, 16.7%).

Conclusions: Residual neuromuscular blockade can be detected by uncalibrated acceleromyography and if not available by a pathway of four clinical muscle function tests in awake patients. The algorithm has a discriminative power comparable to uncalibrated AMG within TOF-values >0.7 and <0.3.

Trial Registration: Clinical Trials.gov (principal investigator's name: CU, and identifier: NCT03219138) on July 8, 2017.
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http://dx.doi.org/10.1186/s12871-017-0393-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545011PMC
August 2017

Importance of Non-invasive Right and Left Ventricular Variables on Exercise Capacity in Patients with Tetralogy of Fallot Hemodynamics.

Pediatr Cardiol 2017 Dec 3;38(8):1569-1574. Epub 2017 Aug 3.

Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich, Technical University of Munich, Munich, Germany.

Good quality of life correlates with a good exercise capacity in daily life in patients with tetralogy of Fallot (ToF). Patients after correction of ToF usually develop residual defects such as pulmonary regurgitation or stenosis of variable severity. However, the importance of different hemodynamic parameters and their impact on exercise capacity is unclear. We investigated several hemodynamic parameters measured by cardiovascular magnetic resonance (CMR) and echocardiography and evaluated which parameter has the most pronounced effect on maximal exercise capacity determined by cardiopulmonary exercise testing (CPET). 132 patients with ToF-like hemodynamics were tested during routine follow-up with CMR, echocardiography and CPET. Right and left ventricular volume data, ventricular ejection fraction and pulmonary regurgitation were evaluated by CMR. Echocardiographic pressure gradients in the right ventricular outflow tract and through the tricuspid valve were measured. All data were classified and correlated with the results of CPET evaluations of these patients. The analysis was performed using the Random Forest model. In this way, we calculated the importance of the different hemodynamic variables related to the maximal oxygen uptake in CPET (VO%predicted). Right ventricular pressure showed the most important influence on maximal oxygen uptake, whereas pulmonary regurgitation and right ventricular enddiastolic volume were not important hemodynamic variables to predict maximal oxygen uptake in CPET. Maximal exercise capacity was only very weakly influenced by right ventricular enddiastolic volume and not at all by pulmonary regurgitation in patients with ToF. The variable with the most pronounced influence was the right ventricular pressure.
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http://dx.doi.org/10.1007/s00246-017-1697-3DOI Listing
December 2017

Validation of a Novel Immunoline Assay for Patient Stratification according to Virulence of the Infecting Strain and Eradication Status.

J Immunol Res 2017 30;2017:8394593. Epub 2017 May 30.

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.

infection shows a worldwide prevalence of around 50%. However, only a minority of infected individuals develop clinical symptoms or diseases. The presence of virulence factors, such as CagA and VacA, has been associated with disease development, but assessment of virulence factor presence requires gastric biopsies. Here, we evaluate the Line test for risk stratification of infected patients by comparing the test score and immune recognition of type I or type II strains defined by the virulence factors CagA, VacA, GroEL, UreA, HcpC, and gGT with patient's disease status according to histology. Moreover, the immune responses of eradicated individuals from two different populations were analysed. Their immune response frequencies and intensities against all antigens except CagA declined below the detection limit. CagA was particularly long lasting in both independent populations. An isolated CagA band often represents past eradication with a likelihood of 88.7%. In addition, a high Line score was significantly associated with high-grade gastritis, atrophy, intestinal metaplasia, and gastric cancer. Thus, the Line is a sensitive and specific noninvasive test for detecting serum responses against in actively infected and eradicated individuals. Moreover, it allows stratifying patients according to their disease state.
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http://dx.doi.org/10.1155/2017/8394593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468576PMC
April 2018

Cut-off optimization for C-urea breath test in a community-based trial by mathematic, histology and serology approach.

Sci Rep 2017 05 18;7(1):2072. Epub 2017 May 18.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, China.

The performance of diagnostic tests in intervention trials of Helicobacter pylori (H.pylori) eradication is crucial, since even minor inaccuracies can have major impact. To determine the cut-off point for C-urea breath test (C-UBT) and to assess if it can be further optimized by serologic testing, mathematic modeling, histopathology and serologic validation were applied. A finite mixture model (FMM) was developed in 21,857 subjects, and an independent validation by modified Giemsa staining was conducted in 300 selected subjects. H.pylori status was determined using recomLine H.pylori assay in 2,113 subjects with a borderline C-UBT results. The delta over baseline-value (DOB) of 3.8 was an optimal cut-off point by a FMM in modelling dataset, which was further validated as the most appropriate cut-off point by Giemsa staining (sensitivity = 94.53%, specificity = 92.93%). In the borderline population, 1,468 subjects were determined as H.pylori positive by recomLine (69.5%). A significant correlation between the number of positive H.pylori serum responses and DOB value was found (r = 0.217, P < 0.001). A mathematical approach such as FMM might be an alternative measure in optimizing the cut-off point for C-UBT in community-based studies, and a second method to determine H.pylori status for subjects with borderline value of C-UBT was necessary and recommended.
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http://dx.doi.org/10.1038/s41598-017-02180-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437005PMC
May 2017

Antibiotic Coating of the Artificial Urinary Sphincter (AMS 800): Is it Worthwhile?

Urology 2017 05 16;103:179-184. Epub 2017 Jan 16.

Department of Urology and Pediatric Urology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.

Objective: To investigate the impact of the antibiotic coating InhibiZone on the infection and explantation rates of the AMS 800 in comparison to the AMS 800 without InhibiZone.

Materials And Methods: We retrospectively identified 305 patients with an AMS 800 in a multicenter cohort study. Patients were subsequently divided into InhibiZone and without InhibiZone-coated groups. Infection and explantation rates were analyzed by univariate and consecutively by multivariate logistic regression adjusted to variable risk factors. The infection-free interval was estimated by Kaplan-Meier plot and compared by the log-rank test. A P value below .05 was considered statistically significant.

Results: We identified 47 patients with InhibiZone and 258 without InhibiZone coating. In univariate analysis, we could not identify a significant difference in infection (P = .932) or explantation (P = .715) rates between the groups. In multivariate analysis, impaired wound healing (P = .008) and urethral erosion (P < .001) were independent predictors for infection. The InhibiZone coating neither demonstrated significant influence on the infection rate (P = .534) nor on the explantation rate (P = .214). There was no significant difference in estimated infection-free survival between the groups (P = .265).

Conclusion: The antibiotic coating of the AMS 800 had no significant impact on infection or explantation rates in our cohort.
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http://dx.doi.org/10.1016/j.urology.2016.12.056DOI Listing
May 2017

Risk Factors for Failure of Male Slings and Artificial Urinary Sphincters: Results from a Large Middle European Cohort Study.

Urol Int 2017 3;99(1):14-21. Epub 2016 Sep 3.

University Medical Center of Johannes Gutenberg University Mainz, Department of Urology and Pediatric Urology, Mainz, Germany.

Introduction: We analysed the impact of predefined risk factors: age, diabetes, history of pelvic irradiation, prior surgery for stress urinary incontinence (SUI), prior urethral stricture, additional procedure during SUI surgery, duration of incontinence, ASA-classification and cause for incontinence on failure and complications in male SUI surgery.

Materials And Methods: We retrospectively identified 506 patients with an artificial urinary sphincter (AUS) and 513 patients with a male sling (MS) in a multicenter cohort study. Complication rates were correlated to the risk factors in univariate analysis. Subsequently, a multivariate logistic regression adjusted to the risk factors was performed. A p value <0.05 was considered statistically significant.

Results: A history of pelvic irradiation was an independent risk factor for explantation in AUS (p < 0.001) and MS (p = 0.018). Moreover, prior urethral stricture (p = 0.036) and higher ASA-classification (p = 0.039) were positively correlated with explantation in univariate analysis for AUS. Urethral erosion was correlated with prior urethral stricture (p < 0.001) and a history of pelvic irradiation (p < 0.001) in AUS. Furthermore, infection was correlated with additional procedures during SUI surgery in univariate analysis (p = 0.037) in MS.

Conclusions: We first identified the correlation of higher ASA-classification and explantation in AUS. Nevertheless, only a few novel risk factors had a significant influence on the failure of MS or AUS.
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http://dx.doi.org/10.1159/000449232DOI Listing
May 2018

Quality of life in women of non-reproductive age with transvaginal mesh repair for pelvic organ prolapse: A cohort study.

Int J Surg 2016 Sep 25;33 Pt A:36-41. Epub 2016 Jul 25.

Department of Urology and Pediatric Urology, University Hospital Mainz, Mainz, Germany.

Background: Transvaginal mesh repair has been discredited due to high complications rates in the past years. Therefore, we evaluated the quality of life (QoL) and complication rates after transvaginal mesh (TVM) repair for pelvic organ prolapse (POP).

Methods: A total of 148 women who underwent TVM repair for symptomatic POP were retrospectively enrolled. Complication rates and functional outcomes were retrospectively assessed and validated, standardised questionnaires were used prospectively for evaluation of QoL. Univariate analysis by the chi(2)-test as well as a multivariate Cox regression analysis was conducted to predict mesh exposure using various variables as predictors.

Results: Intraoperative complications with bowel or bladder injury appeared in 3.4%. Mesh exposure occurred in 2.7% whereas surgical revision was necessary only in 1.4%. No predictor for mesh exposure could be identified. Postoperative complications according to Clavien-Dindo classification ≥ III occurred in only 2.8%. An improvement of POP-symptoms was reported by 84.6% according the "patients' global impression of improvement" (PGI-I) and 88.2% women would repeat the surgery. The results of the "prolapse-quality of life"-questionnaire were comparable to asymptomatic women. Only 33% reported vaginal pain with a mean vaginal pain score of 0.6 according the international index of pain. Of sexually active women, 29% reported sexual impairments and mean score of sexual impairment was 1.52.

Conclusion: Low complication rates and a quality of life comparable to asymptomatic women following TVM repair could be achieved in our cohort. However, a high number of sexual impairments was identified although the impact of impairment was marginal.
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http://dx.doi.org/10.1016/j.ijsu.2016.07.062DOI Listing
September 2016

Postanaesthesia pulmonary complications after use of muscle relaxants in Europe: Study protocol of the POPULAR study.

Eur J Anaesthesiol 2016 May;33(5):381-3

From the Department of Anesthesiology, Surgical Services and Intensive Care, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden (MJF, LIE); Department of Anesthesiology, Technische Universität München, Munich, Germany (HF, EB, MB); Department of Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany (KU); Department of Anesthesiology, Academic Medical Centre, Amsterdam University, Amsterdam, The Netherlands (MH); Department of Anesthesiology, University of Nancy, Nancy, France (CM); Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, Liverpool University, Liverpool, UK (JMH); and Research department, European Society of Anaesthesiology, Brussels, Belgium (BL, SD).

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http://dx.doi.org/10.1097/EJA.0000000000000363DOI Listing
May 2016

The E3 ligase RNF43 inhibits Wnt signaling downstream of mutated β-catenin by sequestering TCF4 to the nuclear membrane.

Sci Signal 2015 Sep 8;8(393):ra90. Epub 2015 Sep 8.

Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich 81675, Germany.

Given its fundamental role in development and cancer, the Wnt-β-catenin signaling pathway is tightly controlled at multiple levels. RING finger protein 43 (RNF43) is an E3 ubiquitin ligase originally found in stem cells and proposed to inhibit Wnt signaling by interacting with the Wnt receptors of the Frizzled family. We detected endogenous RNF43 in the nucleus of human intestinal crypt and colon cancer cells. We found that RNF43 physically interacted with T cell factor 4 (TCF4) in cells and tethered TCF4 to the nuclear membrane, thus silencing TCF4 transcriptional activity even in the presence of constitutively active mutants of β-catenin. This inhibitory mechanism was disrupted by the expression of RNF43 bearing mutations found in human gastrointestinal tumors, and transactivation of the Wnt pathway was observed in various cells and in Xenopus embryos when the RING domain of RNF43 was mutated. Our findings indicate that RNF43 inhibits the Wnt pathway downstream of oncogenic mutations that activate the pathway. Mimicking or enhancing this inhibitory activity of RNF43 may be useful to treat cancers arising from aberrant activation of the Wnt pathway.
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http://dx.doi.org/10.1126/scisignal.aac6757DOI Listing
September 2015
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