Publications by authors named "Pablo Verde"

63 Publications

Peridural Anesthesia and Cancer-Related Survival after Surgery for Pancreatic Cancer-A Retrospective Cohort Study.

Clin Pract 2021 Aug 18;11(3):532-542. Epub 2021 Aug 18.

Department of Anesthesiology, University Hospital and Medical Faculty of the Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.

Background: In patients with prostatic and breast cancer the application of peridural anesthesia (PDA) showed a beneficial effect on prognosis. This was explained by reduced requirements for general anesthetics and perioperative opioids as well as a lower perioperative stress level. The impact of PDA in patients with more aggressive types of cancer has not been completely elucidated. Here, we analyzed the prognostic influence of PDA on overall survival after surgery as primary in patients that underwent radical resection of pancreatic adenocarcinoma.

Methods: Records of 98 consecutive patients were reviewed. In 70 of these cases PDA was applied. Patient characteristics such as demographics, TNM stage, and operative data were retrospectively collected from medical records and analyzed. Survival data were analyzed by Cox's proportional hazard regression model.

Results: Overall, no significant prognostic influence of PDA on recurrence or overall survival ( = 0.762, Hazard Ratio [HR] 0.884, 95% confidence interval [CI] 0.398-1.961) was found. However, there was a trend towards a longer overall survival ( = 0.069, HR 0.394, 95% CI 0.144-1.078) associated with PDA in a subgroup of patients with better differentiation of pancreatic adenocarcinoma.

Conclusion: The observation of longer survival associated with PDA in our subgroup of patients with better-differentiated pancreatic carcinomas is in line with previous reports on various other less aggressive tumor entities. Our results indicate that PDA might improve the oncological outcome of patients with pancreatic adenocarcinoma.
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http://dx.doi.org/10.3390/clinpract11030070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395495PMC
August 2021

Prognostic Discrimination of Alternative Lymph Node Classification Systems for Patients with Radically Resected Non-Metastatic Colorectal Cancer: A Cohort Study from a Single Tertiary Referral Center.

Cancers (Basel) 2021 Aug 2;13(15). Epub 2021 Aug 2.

Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.

Background: Lymph node ratio (LNR) and the Log odds of positive lymph nodes (LODDS) have been proposed as a new prognostic indicator in surgical oncology. Various studies have shown a superior discriminating power of LODDS over LNR and lymph node category (N) in diverse cancer entities, when examined as a continuous variable. However, for each of the classification systems various cut-off values have been defined, with the question of the most appropriate for patients with CRC still remaining open. The present study aimed to compare the predictive impact of different lymph node classification systems and to define the best cut-off values regarding accurate evaluation of overall survival in patients with resectable, non-metastatic colorectal cancer (CRC).

Methods: CRC patients who underwent surgical resection from 1996 to 2018 were extracted from our medical data base. Cox proportional hazards regression models and C-statistics were performed to assess the discriminative power of 25 LNR and 26 LODDS classifications. Regression models were adjusted for age, sex, extent of the tumor, differentiation, tumor size and localization.

Results: Our study group consisted of 654 consecutive patients with non-metastatic CRC. C-statistic revealed 2 LNR and 5 LODDS classifications that demonstrated superior prognostic performance in patients with UICC III CRC, compared to the N category. No clear advantage of one classification over another could be demonstrated in any other patient subgroup.

Conclusions: Distinct LNR and LODDS classifications demonstrate a prognostic superiority over the N category only in patients with Stage III radically resected CRC.
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http://dx.doi.org/10.3390/cancers13153898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345552PMC
August 2021

Effects of high-frequency prefrontal rTMS on heart frequency rates and blood pressure in schizophrenia.

J Psychiatr Res 2021 08 7;140:243-249. Epub 2021 Jun 7.

Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, University of Augsburg, BKH, Augsburg, Germany.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a safe non-invasive neuromodulation technique used for the treatment of various neuropsychiatric disorders. The effect of rTMS applied to the cortex on autonomic functions has not been studied in detail in patient cohorts, yet patients who receive rTMS may have disease-associated impairments in the autonomic system and may receive medication that may pronounce autonomic dysfunctions.

Methods: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we evaluated the effect of rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) on autonomic nervous system-related parameters such as blood pressure (BP) and heart rate (HR) in both reclining and standing postures from screening up to 105 days after intervention among patients with schizophrenia.

Results: 157 patients received either active (n = 76) or sham (n = 81) rTMS treatment. Apart from gender no significant group differences were observed. During intervention, Linear Mixed Model (LMM) analyses showed no significant time × group interactions nor time effects for any of the variables (all p > 0.055). During the whole trial beside a significant time × group interaction for diastolic BP (p = 0.017) in the standing posture, no significant time × group interactions for other variables (all p > 0.140) were found.

Conclusion: These secondary analyses of the largest available rTMS trial on the treatment of negative symptoms in schizophrenia did not show a significant effect of active rTMS compared to sham rTMS on heart rate or blood pressure, neither during the intervention period nor during the follow-up period.
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http://dx.doi.org/10.1016/j.jpsychires.2021.06.010DOI Listing
August 2021

Reconvalescent plasma/camostat mesylate in early SARS-CoV-2 Q-PCR positive high-risk individuals (RES-Q-HR): a structured summary of a study protocol for a randomized controlled trial.

Trials 2021 May 17;22(1):343. Epub 2021 May 17.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty Heinrich-Heine-University Duesseldorf, Moorenstr. 5, D-40225, Duesseldorf, Germany.

Objectives: Currently, there are no approved treatments for early disease stages of COVID-19 and few strategies to prevent disease progression after infection with SARS-CoV-2. The objective of this study is to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate administered within 72 h of diagnosis of SARS-CoV-2 infection in adult individuals with pre-existing risk factors at higher risk of getting seriously ill with COVID-19. Camostat mesylate acts as an inhibitor of the host cell serine protease TMPRSS2 and prevents the virus from entering the cell. CP represents another antiviral strategy in terms of passive immunization. The working hypothesis to be tested in the RES-Q-HR study is that the early use of CP or camostat mesylate reduces the likelihood of disease progression to (modified) WHO stages 4b-8 in SARS-CoV-2-positive adult patients at high risk of moderate or severe COVID-19 progression.

Trial Design: This study is a 4-arm (parallel group), multicenter, randomized (2:2:1:1 ratio), partly double-blind, controlled trial to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate with control or placebo in adult patients diagnosed with SARS-CoV-2 infection and high risk for progression to moderate/severe COVID-19. Superiority of the intervention arms will be tested.

Participants: The trial is conducted at 10-15 tertiary care centers in Germany. Individuals aged 18 years or above with ability to provide written informed consent with SARS-CoV-2 infection, confirmed by PCR within 3 days or less before enrolment and the presence of at least one SARS-CoV-2 symptom (such as fever, cough, shortness of breath, sore throat, headache, fatigue, smell/and or taste disorder, diarrhea, abdominal symptoms, exanthema) and symptom duration of not more than 3 days. Further inclusion criteria comprise: Presence of at least one of the following criteria indicating increased risk for severe COVID-19: Age > 75 years Chronic obstructive pulmonary disease (COPD) and/or pulmonary fibrosis BMI > 40 kg/m Age > 65 years with at least one other risk factor (BMI > 35 kg/m, coronary artery disease (CAD), chronic kidney disease (CKD) with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) BMI > 35 kg/m with at least one other risk factor (CAD, CKD with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) Exclusion criteria: 1. Age < 18 years 2. Unable to give informed consent 3. Pregnant women or breastfeeding mothers 4. Previous transfusion reaction or other contraindication to a plasma transfusion 5. Known hypersensitivity to camostat mesylate and/or severe pancreatitis 6. Volume stress due to CP administration would be intolerable 7. Known IgA deficiency 8. Life expectancy < 6 months 9. Duration SARS-CoV-2 typical symptoms > 3 days 10. SARS-CoV-2 PCR detection older than 3 days 11. SARS-CoV-2 associated clinical condition ≥ WHO stage 3 (patients hospitalized for other reasons than COVID-19 may be included if they fulfill all inclusion and none of the exclusion criteria) 12. Previously or currently hospitalized due to SARS-CoV-2 13. Previous antiviral therapy for SARS-CoV-2 14. ALT or AST > 5 x ULN at screening 15. Liver cirrhosis > Child A (patients with Child B/C cirrhosis are excluded from the trial) 16. Chronic kidney disease with GFR < 30 ml/min 17. Concurrent or planned anticancer treatment during trial period 18. Accommodation in an institution due to legal orders (§40(4) AMG). 19. Any psycho-social condition hampering compliance with the study protocol. 20. Evidence of current drug or alcohol abuse 21. Use of other investigational treatment within 5 half-lives of enrolment is prohibited 22. Previous use of convalescent plasma for COVID-19 23. Concomitant proven influenza A infection 24. Patients with organ or bone marrow transplant in the three months prior to screening visit INTERVENTION AND COMPARATOR: Participants will be randomized to the following 4 groups: 1) Convalescent plasma (CP), 2 units at screening/baseline visit (day 0) or day 1; CP is defined by the presence of neutralizing anti-SARS-CoV-2 antibodies with titers ≥ 1:160; individuals with body weight ≥ 150 kg will receive a third unit of plasma on day 3 2) Camostat mesylate (200 mg per capsule, one capsule taken each in the morning, afternoon and evening on days 1-7) 3) Standard of care (SOC, control for CP) 4) Placebo (identical in appearance to camostat mesylate capsules, one capsule taken each morning, afternoon and evening on days 1-7; for camostat mesylate control group) Participants will be monitored after screening/baseline on day 3, day 5, day 8, and day 14. On day 28 and day 56, telephone visits and on day 90, another outpatient visit are scheduled. Adverse events and serious adverse events will be monitored and reported until the end of the study. An independent data safety monitoring committee will review trial progression and safety.

Main Outcomes: The primary endpoint of the study is the cumulative number of individuals who progress to or beyond category 4b on the modified WHO COVID-19 ordinal scale (defined as hospitalization with COVID-19 pneumonia and additional oxygen demand via nasal cannula or mask) within 28 days after randomization.

Randomization: Participants will be randomized using the Alea-Tool ( aleaclinical.com ) in a 2:2:1:1 ratio to the treatment arms (1) CP, (2) camostat mesylate, (3) standard of care (SoC), and (4) placebo matching camostat mesylate. Randomization will be stratified by study center.

Blinding (masking): The camostat mesylate treatment arm and the respective placebo will be blinded for participants, caregivers, and those assessing outcomes. The treatment arms convalescent plasma and standard of care will not be blinded and thus are open-labeled, unblinded.

Numbers To Be Randomized (sample Size): Overall, n = 994 participants will be randomized to the following groups: n = 331 to convalescent plasma (CP), n = 331 to camostat mesylate, n = 166 to standard of care (SoC), and n = 166 to placebo matching camostat mesylate.

Trial Status: The RES-Q-HR protocol (V04F) was approved on the 18 December 2020 by the local ethics committee and by the regulatory institutions PEI/BfARM on the 2 December 2020. The trial was opened for recruitment on 26 December 2020; the first patient was enrolled on 7 January 2021 and randomized on 8 January 2021. Recruitment shall be completed by June 2021. The current protocol version RES-Q HR V05F is from 4 January 2021, which was approved on the 18 January 2021.

Trial Registration: EudraCT Number 2020-004695-18 . Registered on September 29, 2020. ClinicalTrial.gov NCT04681430 . Registered on December 23, 2020, prior to the start of the enrollment (which was opened on December 26, 2020).

Full Protocol: The full protocol (V05F) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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http://dx.doi.org/10.1186/s13063-021-05181-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127198PMC
May 2021

A bias-corrected meta-analysis model for combining, studies of different types and quality.

Biom J 2021 02 30;63(2):406-422. Epub 2020 Sep 30.

Coordination Center for Clinical Trials, Düsseldorf University Hospital, Düsseldorf, Germany.

Public health researchers may have to decide whether to perform a meta-analysis including only high-quality randomized clinical trials (RCTs) or whether to include a mixture of all the available evidence, namely RCTs of varying quality and observational studies (OS). The main hurdle when combining disparate evidence in a meta-analysis is that we are not only combining results of interest but we are also combining multiple biases. Therefore, commonly applied meta-analysis methods may lead to misleading conclusions. In this paper, we present a new Bayesian hierarchical model, called the bias-corrected (BC) meta-analysis model, to combine different study types in meta-analysis. This model is based on a mixture of two random effects distributions, where the first component corresponds to the model of interest and the second component to the hidden bias structure. In this way, the resulting model of interest is adjusted by the internal validity bias of the studies included in a systematic review. We illustrate the BC model with two meta-analyses: The first one combines RCTs and OS to assess effectiveness of vaccination to prevent invasive pneumococcal disease. The second one investigates the effectiveness of stem cell treatment in heart disease patients. Our results show that ignoring internal validity bias in a meta-analysis may lead to misleading conclusions. However, if a meta-analysis model contemplates a bias adjustment, then RCTs results may increase their precision by including OS in the analysis. The BC model has been implemented in JAGS and R, which facilitate its application in practice.
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http://dx.doi.org/10.1002/bimj.201900376DOI Listing
February 2021

Concordance-analysis and evaluation of different diagnostic algorithms used in first trimester screening for late-onset preeclampsia.

Hypertens Pregnancy 2020 May 18;39(2):172-185. Epub 2020 Apr 18.

Praenatal-Medizin und Genetik Ärztliche Partnerschaftsgesellschaft Kozlowski und Partner, Düsseldorf.

: Concordance-analysis and evaluation of existing algorithms detecting late-onset preeclampsia during first trimester screening: Retrospective cohort study investigating risk algorithms of late-onset preeclampsia during first trimester screening in a German prenatal center. Three previously developed algorithms including anamnestic factors (Apriori) and biophysical markers (BioM) were investigated by using detection rates (DR) with fixed FPR 10% and fixed cutoff >1:100. Furthermore, we set up a concordance-analysis of test results in late-onset preeclampsia cases to examine the effect of influencing factors and to detect potential weaknesses of the algorithms. Therefore, we modeled the probability of discordances as a function of the influencing factors based on a logistic regression, that was fitted using a Bayesian approach.: 6,113 pregnancies were considered, whereof 700 have been excluded and 5,413 pregnancies were analyzed. 98 (1.8%) patients developed preeclampsia (79 late-onsets, 19 early-onsets). The Apriori-algorithm reaches a DR of 34.2%, by adding BioM (MAP and UtA-PI) the DR improves to 57.0% (FPR of 10%). In concordance-analysis of Apriori algorithm and Apriori+BioM algorithms, influencing factor BMI<25 increases the chance of discordances sigificantly. Additional, in the subgroup of late-onset preeclampsias with BMI<25 the DR is higher in Apriori+BioM algorithms than in Apriori algorithm alone. If both compared algorithms include BioM, influencing factor MAP decreases the chance of discordances significantly. All other tested influencing factors do not have a statistically significant effect on discordances: Normal-weight patients benefit more from the integration of MAP and UtA-PI compared to overweight/obese patients.
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http://dx.doi.org/10.1080/10641955.2020.1750627DOI Listing
May 2020

Isolated Echogenic Cardiac Focus: Assessing Association with Trisomy 21 by Combining Results from a Prenatal Center with a Bayesian Meta-Analysis.

Ultrasound Int Open 2019 Nov 9;5(3):E98-E106. Epub 2020 Mar 9.

Praenatal-Medizin und Genetik, Düsseldorf, Kozlowski und Partner- Fachärzte für Gynäkologie und Humangenetik, Düsseldorf, Germany.

To investigate the clinical relevance of an isolated echogenic cardiac focus (iECF) as a marker for trisomy 21 using a large second-trimester collective including a low-risk subgroup. We retrospectively evaluated 1 25 211 pregnancies from 2000-2016 and analyzed all iECF cases with regard to chromosomal anomalies. It consisted of an early second-trimester collective from 14+0-17+6 weeks (n=34 791) and a second-trimester anomaly scan collective from 18+0-21+6 weeks. Two a priori risk subgroups (high and low risk) of the latter were built based on maternal age and previous screening test results using a cut-off of 1:300. Likelihood ratios (LR) of iECF for the detection of trisomy 21, trisomy 13, trisomy 18 and structural chromosomal anomalies were estimated. In total, 1 04 001 patients were included. An iECF was found in 4416 of 1 02 847 euploid fetuses (4.29%) and in 64 of 557 cases with trisomy 21 (11.49%) giving a positive LR of 2.68 (CI: 2.12-3.2). The sensitivity was 11.5% at a false-positive rate of 4.29% (CI:4.17-4.42) with p≤0.01%. In the high-and low-risk subgroups, the prevalence of iECF was comparable: 5.08% vs. 5.05%. The frequency of trisomy 21 was 0.39%, 98/24 979 vs 0.16%, 69/44 103. LR+was 3.86 (2.43-5.14) and 2.59 (1.05-4). For both subgroups the association of iECF with trisomy 21 was statistically significant. The prevalence of structural chromosomal anomalies in the second-trimester anomaly scan collective was 0.08% (52/68 967), of which 2 showed an iECF. The detection of an iECF at the time of 14+0-21+6 weeks significantly increases the risk for trisomy 21 in the high-risk and in the low-risk subgroups and does not statistically change the risks for trisomy 13/18 or structural abnormalitie.
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http://dx.doi.org/10.1055/a-1118-3974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062549PMC
November 2019

Symptomatic medial synovial plica of the knee joint: an underestimated pathology in young patients.

Arch Orthop Trauma Surg 2019 Nov 20;139(11):1625-1631. Epub 2019 Aug 20.

Klinik für Orthopädie, Heinrich-Heine-Universität Düsseldorf, Universitätsklinik Düsseldorf, Moorenstr 5, 40225, Düsseldorf, Germany.

Introduction: To prospectively evaluate the outcome of arthroscopic resection of a symptomatic medial plica in patients under 30 years with evaluating the influence of sports, knee trauma and plica type.

Methods: 35 consecutive patients (38 knees), mean age 16.2 ± 4.7 years (9-26 years), 28 females (73.7%) were prospectively included. Patients with any additional surgical procedures or cartilage lesions > ICRS grade I were excluded. The influence of trauma to the knee, level of sport and the morphologic plica type on the outcome was evaluated in addition to standard knee scores before and 20.1 ± 9.3 months (12-44 months) after surgery.

Results: The Knee Injury and Osteoarthritis Outcome Score improved significantly from 50.2 ± 19.1% (12.5-94.6) to 80.7 ± 15.3% (48.2-100; p < 0.001). The Tegner Activity Scale improved significantly from 2.2 ± 1.5 (0-6) to 4.9 ± 1.7 (3-10; p < 0.001) and the Kujala Anterior Knee Pain Scale improved significantly from 52.6 ± 16.6 (16-86) to 80.7 ± 16.5 (46-100; p < 0.001). The level of pain in the knee decreased from 7.9 ± 2.0 (1-10) to 3.1 ± 2.6 (0-9; p < 0.001) at follow-up on a numeric rating scale (0-10). Neither trauma to the knee, high impact sport, cartilage lesions to the medial femoral condyle nor the plica type or associated ICRS grade I cartilage lesion to the medial femoral condyle had a significant effect on the outcome parameters.

Conclusion: Arthroscopic resection of a symptomatic medial plica provides excellent clinical results in young patients. Trauma, high impact sports, ICRS grade I cartilage lesions to the medial femoral condyle or the plica type are not associated with a poorer outcome.

Level Of Evidence: Level IV, prospective case series with no control group.
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http://dx.doi.org/10.1007/s00402-019-03249-wDOI Listing
November 2019

The association between a low critical shoulder angle and SLAP lesions.

Knee Surg Sports Traumatol Arthrosc 2019 Dec 27;27(12):3944-3951. Epub 2019 Jun 27.

Orthopaedic Department, Shoulder-Elbow-Section, University of Duesseldorf, Moorenstr. 1-5, 40225, Duesseldorf, Germany.

Purpose: To evaluate the critical shoulder angle (CSA), acromion index (AI) and further acromion parameters in patients with isolated SLAP lesions compared with patients without SLAP lesions.

Methods: Between 2012 and 2016, the CSA, AI, lateral acromion angle (LAA) and acromion slope (AS) were radiologically examined in consecutive patients > 18 years having had a shoulder arthroscopy with isolated SLAP lesion types II-IV. These were compared to controls without SLAP lesions and without (control group I) or with (control group II) complete supraspinatus tendon (SSP) tears.

Results: 75/103 patients with isolated SLAP lesion types II-IV with a mean age of 46.5 years (± 13.0, 18.1-76.3) were analyzed, 61% of them being male. For control, n = 211 consecutive patients (47% male) with an intact SSP and SLAP complex and a mean age of 52.3 years (± 15.0, 18.6-88.4) and n = 115 patients (60% male) with an intact SLAP complex but complete SSP tears, mean age 66.6 years (± 9.3, 44.7-87.9) were examined. The CSA in SLAP patients was 29.6° (± 3.5, 21.0-38.0), 33.8° (± 3.7, 25.1-46.9) in no SLAP and no SSP (p < 0.001) and 36.7° (± 3.6, 29.1-46.6) in no SLAP but SSP (p < 0.001). The area under the curve (AUC) for CSA was 0.83 for SLAP lesions resulting in a probability of 83% for patients with SLAP lesion to be associated with a specific CSA.

Conclusions: Isolated SLAP lesion types II-IV are associated with a low CSA < 30°. The AI, the AS as well as the LAA showed no correlation with SLAP lesions.

Level Of Evidence: Retrospective comparative study, Level III.
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http://dx.doi.org/10.1007/s00167-019-05569-1DOI Listing
December 2019

A Bayesian risk analysis for Trisomy 21 in isolated choroid plexus cyst: combining a prenatal database with a meta-analysis.

J Matern Fetal Neonatal Med 2021 Mar 11;34(6):889-897. Epub 2019 Jun 11.

Praenatal-Medizin und Genetik Düesseldorf, Düsseldorf, Germany.

Objective: The purpose of this study was to quantify the possible additional risk of a fetus with an isolated choroid plexus cyst (ICPC) for Trisomy 21 by combining a large controlled cohort study with data from existent studies.

Methods: We searched our prenatal database between 2000 and 2014 for all singleton pregnancies between 18 + 0 and 26 + 6 gestational weeks with either an isolated choroid plexus cyst (study group) or no abnormality found in the detailed ultrasound scan (control group). We assessed all prenatal karyotyping results if invasive testing was performed and attempted to collect the postnatal outcome reports of all patients. The prevalence of Down syndrome was calculated. By using previous studies that met our inclusion criteria, a meta-analysis following the Bayesian Independent Model was created. From this meta-analysis, we computed the posterior predictive distribution of the probability (Trisomy 21 | ICPC) = P1 including posterior means, standard deviations, quantiles (2.5, 50, and 97.5%). By calculating the posterior of the difference (Δ) between the probability (Trisomy 21 | ICPC) and the probability (Trisomy 21 | Normal Ultrasound) = P2, we investigated the additional risk of an ICPC (ΔB = P1-P2).

Results: Overall, we detected 1220 fetuses with an isolated plexus cyst at 19-27 weeks of gestational age (GA). In our study group, the prevalence of Trisomy 21 was 2/1220 (0.16, 95% CI: 0.1-0.6%). The median of the pooled probability of Trisomy 21 given isolated PC across the studies included in the meta-analysis was 0.2% (CI: 0.1-0.4%). In the given periods (GA and time), 66,606 (74.8%) out of 89,056 investigated fetuses met the inclusion criteria and had a normal ultrasound result without any abnormality. The Δ between our study group and the control group was 0.08% (CIΔA: 0-0.5%). Including the meta-analysis, the median of the posterior distribution of Δ between P1 and P2 was 0.08% (CIΔB: 0-0.4%) (ΔB = P1-P2).

Conclusion: The posterior distribution of Δ between P1 and P2 including the meta-analysis corresponds to showing no difference between the cases and controls (95% CIΔB: 0-0.4%). The additional risk of a fetus with an ICPC for Trisomy 21 is 97.5% likely to be lower than 0.4% (about 1/250). However, in our collective, the positive predictive value of ICPC for Down syndrome was 0.16% (about 1/625). In prenatal counseling, the additional risk should be added to the individual risk (based on maternal age, earlier screening test results, and sonographic markers) and the diagnostic options including fetal DNA and diagnostic procedures should be discussed according to the posterior individual risk.
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http://dx.doi.org/10.1080/14767058.2019.1622666DOI Listing
March 2021

Biceps tenodesis versus tenotomy in isolated LHB lesions: a prospective randomized clinical trial.

Arch Orthop Trauma Surg 2019 Jul 6;139(7):961-970. Epub 2019 Feb 6.

Universitätsklinikum Düsseldorf, Klinik für Orthopädie, Moorenstr 5, 40225, Düsseldorf, Germany.

Introduction: Currently there exists no clear evidence concerning the surgical treatment of LHB lesions with either tenotomy or tenodesis. The aim of the study is therefore to evaluate elbow flexion and forearm supination force as well as the biceps muscle distalization according to both techniques in isolated LHB lesions.

Methods: Consecutive patients aged 40-70 years with shoulder arthroscopies for isolated SLAP or biceps pulley lesions were prospectively randomized to arthroscopic suprapectoral intraosseous LHB tenodesis or tenotomy. Pre-, 6 and 12 months postoperatively, the SST, ASES, Constant-Murley and LHB scores were recorded. The elbow flexion force was measured in 10°/90° flexion, the supination force in neutral/pronation position. In addition, the maximum upper-arm circumference and its position relative to the radial epicondyle of the humerus were evaluated preoperatively and in follow-up.

Results: 20/22 patients (mean age 52.0 ± 8.5; range 36-63 years, 11 male) completed the follow-up. 9/20 were treated with LHB tenodesis (mean age 51.5 ± 9.5; range 37-63 years, 7 male) and 11/20 with tenotomy (mean age 52.8 ± 8.0; range 36-62 years, 4 male). The force measurements and scores showed no significant difference after 12 months. Tenodesis achieved a significant increase in force 6 months postoperatively compared to preoperatively. One tenodesis patient and three tenotomy patients showed a postoperative popeye-sign deformity.

Conclusion: This prospective randomized study comparing LHB tenodesis and tenotomy in isolated LHB lesions has shown no significant difference in elbow flexion and forearm supination force and clinical scores after 12 months. After LHB tenotomy, there was a non-significant trend for a higher rate of popeye-sign deformities of the upper arm and biceps muscle cramps.
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http://dx.doi.org/10.1007/s00402-019-03136-4DOI Listing
July 2019

Immediate and Sustained Effect of Neonatal Teaching in a Perinatal Setting in Urban Laos.

Am J Perinatol 2020 03 5;37(4):375-377. Epub 2019 Feb 5.

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Health Sciences, Vientiane, Laos.

Objective: This study aimed to quantify knowledge on neonatal topics among obstetricians and pediatricians participating in a perinatal teaching program aimed at reducing neonatal mortality in Laos.

Study Design: Obstetricians and pediatricians from Vientiane and the surrounding areas participated in a 1-week teaching program in obstetric and neonatal topics and responded to pre- and posttests questionnaires to quantify their knowledge.

Results: Although questions were predominantly related to neonatal topics, obstetricians performed significantly better than pediatricians during the pretest. Both groups increased their knowledge significantly as quantified by the results of the posttest.

Conclusion: The teaching program was effective in improving knowledge on perinatal mortality related topics of the participants. These results may be related to the fact that most of the obstetricians had participated in a structured teaching program previously, whereas the pediatricians did not. We thus speculate that there is a sustained effect of even a 1-week teaching program in neonatology even several years after the initial teaching.
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http://dx.doi.org/10.1055/s-0039-1678668DOI Listing
March 2020

Efficacy of high-frequency repetitive transcranial magnetic stimulation in schizophrenia patients with treatment-resistant negative symptoms treated with clozapine.

Schizophr Res 2019 06 29;208:370-376. Epub 2019 Jan 29.

Department of Psychiatry and Psychotherapy, Klinikum der Universität München, University Hospital, LMU Munich, Germany.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation treatment for schizophrenia, however there are few controlled studies of rTMS augmentation of clozapine.

Methods: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we examined the impact of rTMS on PANSS total, general, positive and negative symptoms among participants on clozapine. rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) for five treatment sessions/week for 3-weeks as augmentation for patients with a predominant negative syndrome of schizophrenia, as rated on PANSS.

Results: 26 participants from the RESIS trial were on clozapine, receiving active (N=12) or sham (N=14) rTMS treatment. In our Linear Mixed Model (LMM) analysis, time×group interactions were significant in the PANSS positive subscale (p=0.003) (not being the corresponding behavioral output for DLPFC stimulation), the PANSS general subscale (p<0.001), the PANSS total scale (p=0.015), but not the PANSS negative subscale (p=0.301) (primary endpoint of the RESIS trial), when all PANSS measurements from screening to day 105 were included. Descriptive data suggests that in the active group the improvement was more pronounced compared to the sham rTMS group.

Conclusions: In this largest available clozapine cohort, active rTMS may be more effective than sham rTMS when added to clozapine for positive and total psychotic symptoms. These findings should be interpreted with caution given this is a secondary analysis with a limited number of participants.
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http://dx.doi.org/10.1016/j.schres.2019.01.021DOI Listing
June 2019

The hierarchical metaregression approach and learning from clinical evidence.

Biom J 2019 05 2;61(3):535-557. Epub 2019 Jan 2.

Coordination Center for Clinical Trials, Düsseldorf University Hospital, Moorenstr, Düsseldorf, Germany.

The hierarchical metaregression (HMR) approach is a multiparameter Bayesian approach for meta-analysis, which generalizes the standard mixed effects models by explicitly modeling the data collection process in the meta-analysis. The HMR allows to investigate the potential external validity of experimental results as well as to assess the internal validity of the studies included in a systematic review. The HMR automatically identifies studies presenting conflicting evidence and it downweights their influence in the meta-analysis. In addition, the HMR allows to perform cross-evidence synthesis, which combines aggregated results from randomized controlled trials to predict effectiveness in a single-arm observational study with individual participant data (IPD). In this paper, we evaluate the HMR approach using simulated data examples. We present a new real case study in diabetes research, along with a new R package called jarbes (just a rather Bayesian evidence synthesis), which automatizes the complex computations involved in the HMR.
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http://dx.doi.org/10.1002/bimj.201700266DOI Listing
May 2019

Quantification of fetal steroids in nails of neonates to quantify prenatal stress and growth restriction.

Biol Psychol 2019 01 10;140:81-85. Epub 2018 Dec 10.

General Pediatrics, Neonatology and Pediatric Cardiology, Heinrich-Heine-University, Moorenstraße 5, 40225, Düsseldorf, Germany. Electronic address:

This study assesses the impact of prenatal stress and intrauterine growth restriction (IUGR) on the dehydroepiandrosterone (DHEA) and dehydroepiandrosteronesulfate (DHEAS) concentrations in nails of newborns. Nail samples were gained from 56 newborn infants. The concentration of DHEA and DHEAS was measured by liquid chromatography/tandem mass spectrometry. Prenatal stress was assessed by the Prenatal Distress Questionnaire and by the Life Experience Survey. Prenatal stress was not associated with infant nail DHEA or DHEAS concentrations. The concentration of DHEA and DHEAS was decreased in infants with IUGR (DHEA: p =  0.037, DHEAS p < 0.01). Nail-DHEAS increased with gestational age (p < 0.01). In this study prenatal life event stress or pregnancy specific stress do not correlate with higher DHEA or DHEAS concentrations in nails of newborns. Concentration of DHEAS is rather affected by length of gestation. Our approach is an easily applicable method to assess intrauterine life with the potential to give insights in the activity of fetal hormone systems and mechanism underlying fetal programming.
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http://dx.doi.org/10.1016/j.biopsycho.2018.12.001DOI Listing
January 2019

Feasibility, safety and effectiveness in measuring microvascular resistance with regadenoson.

Clin Hemorheol Microcirc 2019 ;71(3):299-310

Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University, Düsseldorf, Medical Faculty, Germany.

AIMThe study aims to test whether simultaneous measurement of fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) is feasible, safe and effective during regadenoson-induced hyperemia.METHODS AND RESULTSFFR, CFR and IMR were measured simultaneously during regadenoson (Rapiscan 400 μg) -induced hyperemia in 50 patients with stable coronary artery disease with a SYNTAX score of <22. Simultaneous measurement of FFR, CFR and IMR was technically feasible in all cases (50/50). No side effects occurred and even patients fulfilling classical contraindications for the use of adenosine (10/50) could be included. Regadenoson-induced hyperemia remained stable after maximal pressure drop for more than 35 sec as measured by systemic aortic and distal coronary pressure. There was a significant drop in transit mean time from baseline to hyperemia of more than 50% (1.0 ± 0.6 s vs. 0.4 ± 0.2 s, p <  0.01). Patients' mean IMR value was 23.4, and IMR values above 75th percentile significantly correlated with metformin demanding diabetes mellitus with OR 21.76 and nicotine abuse with OR 10.28.CONCLUSIONA single intravenous regadenoson bolus via peripheral line increases coronary blood flow without harmful systemic side effects enabling interventionists to simultaneously assess FFR, CFR and IMR in patients with stable coronary artery disease.
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http://dx.doi.org/10.3233/CH-180386DOI Listing
August 2019

CXCR4/CXCR7/CXCL12-Axis in Follicular Thyroid Carcinoma.

J Cancer 2018 27;9(6):929-940. Epub 2018 Feb 27.

Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.

Follicular thyroid carcinoma's (FTC) often benign course is partially due to adjuvant radioactive iodine (RAI) treatment. However, once the tumour has spread and fails to retain RAI, the therapeutic options are limited and the outcome is poor. In this subset of patients, the identification of novel druggable biomarkers appears invaluable. Here, we investigated the stage dependent expression and functional role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in FTC. CXCR4/7 expression was examined in 44 FTC and corresponding non-neoplastic thyroid specimens as well as 10 FTC distant metastases and 18 follicular adenomas using tissue microarray technology. Expression levels were correlated with clinicopathological variables as well as overall and recurrence free survival. Changes regarding cell cycle activation, tumour cell invasiveness and mRNA expression of genes related to epithelial-mesenchymal transition (EMT) were investigated after treatment with recombinant human SDF1α/CXCL12 (rh-SDF1α) and CXCR4 antagonists AMD3100 and WZ811. CXCR4/7 expression was associated with large tumour size, advanced UICC stage as well as shorter overall and recurrence free survival. CXCR4 was significantly higher expressed in distant metastases than in primary tumour cores. In addition, rh-SDF1α induced invasive growth, cell cycle activation and EMT, while CXCR4 antagonists significantly reduced FTC invasiveness . Here we provide first evidence of the biological importance of the CXCR4/CXCR7/CXCL12 axis in FTC. Our findings underscore the therapeutic potential of this chemokine receptor family in advanced FTC and offer new valuable insight into the oncogenesis of metastatic FTC.
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http://dx.doi.org/10.7150/jca.23042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868160PMC
February 2018

Efficacy of high-frequency repetitive transcranial magnetic stimulation on PANSS factors in schizophrenia with predominant negative symptoms - Results from an exploratory re-analysis.

Psychiatry Res 2018 05 17;263:22-29. Epub 2018 Feb 17.

Department of Psychiatry and Psychotherapy, Klinikum der Universität München, Ludwig-Maximilians-University, München, Germany.

Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking. For this purpose, we used the available PANSS data of the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial. In an exploratory re-analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores. In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group. Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS.
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http://dx.doi.org/10.1016/j.psychres.2018.02.030DOI Listing
May 2018

Clinicopathological and functional implications of the inhibitor of apoptosis proteins survivin and XIAP in esophageal cancer.

Oncol Lett 2018 Mar 9;15(3):3779-3789. Epub 2018 Jan 9.

Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, D-40225 Düsseldorf, Germany.

Based on their overexpression and important roles in progression and therapy-resistance in malignant diseases, the inhibitor of apoptosis protein family (IAP) members, survivin and X-linked inhibitor of apoptosis protein (XIAP), represent attractive candidates for targeted therapy. The present study investigated the prognostic and biological relevance of survivin and XIAP in esophageal squamous-cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Survivin and XIAP expression was analyzed by immunohistochemistry using tissue microarrays containing 120 ESCC and 90 EAC samples as well as the corresponding non-neoplastic esophageal mucosa samples. IAP expression levels were then correlated to clinicopathological parameters and overall survival to identify any associations. In addition, esophageal cancer cell lines were treated with the survivin inhibitor YM155, and the XIAP inhibitors Birinapant and GDC-0152 . Survivin and XIAP expression were significantly increased in EAC and ESCC when compared with tumor-adjacent mucosa. In patients with ESCC XIAP expression was associated with female gender and advanced tumor stages, and nuclear survivin expression was associated with poor grading. High XIAP expression was identified as an independent negative prognostic marker in ESCC. By contrast, XIAP inhibitors did not affect cancer cell viability , and the small molecule survivin inhibitor YM155 significantly reduced cell viability and proliferation in esophageal cancer cell lines. Western blot analysis revealed a dose dependent decrease of survivin accompanied by an increased poly (adenosine diphosphate-ribose) polymerase cleavage following YM155 treatment. These findings underline the potential role of survivin and XIAP in the oncogenesis of esophageal cancer and provide a rationale for future clinical studies investigating the therapeutic efficacy of IAP directed therapies in patients with esophageal cancer.
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http://dx.doi.org/10.3892/ol.2018.7755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796362PMC
March 2018

Prevalence of Propionibacterium acnes in the glenohumeral compared with the subacromial space in primary shoulder arthroscopies.

J Shoulder Elbow Surg 2018 May 1;27(5):771-776. Epub 2018 Feb 1.

Orthopaedic Department, Shoulder-Elbow Section, University of Düsseldorf, Düsseldorf, Germany.

Hypothesis: We hypothesized that the prevalence of Propionibacterium acnes in patients undergoing primary shoulder arthroscopy is equal in the glenohumeral space compared with the subacromial space.

Methods: Patients aged 18 years or older with shoulder arthroscopies were included. The exclusion criteria were prior shoulder operations, complete rotator cuff tears, systemic inflammatory diseases, tumors, shoulder injections within 6 months of surgery, and antibiotic therapy within 14 days preoperatively. After standardized skin disinfection with Kodan Tinktur Forte Gefärbt, a skin swab was taken at the posterior portal. Arthroscopy was performed without cannulas, prospectively randomized to start either in the glenohumeral space or in the subacromial space, with direct harvesting of a soft-tissue biopsy specimen. Sample cultivation was conducted according to standardized criteria for bone and joint aspirate samples and incubated for 14 days. Matrix-assisted laser desorption-ionization time-of-flight spectrometry was used for specimen identification in positive culture results.

Results: The study prospectively included 115 consecutive patients with normal C-reactive protein levels prior to surgery (54.8% men; mean age, 47.2 ± 14.6 years). P acnes was detected on the skin after disinfection in 36.5% of patients, in the glenohumeral space in 18.9%, and in the subacromial space in 3.5% (P = .016).

Conclusion: The prevalence of P acnes is significantly higher in the glenohumeral space compared with the subacromial space in primary shoulder arthroscopies. The results do not confirm the contamination theory but also cannot clarify whether P acnes is a commensal or enters the joint hematologically or even lymphatically or via an unknown pathway. Despite standardized surgical skin disinfection, P acnes can be detected in skin swab samples in more than one-third of patients.
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http://dx.doi.org/10.1016/j.jse.2017.10.039DOI Listing
May 2018

IAPs cause resistance to TRAIL-dependent apoptosis in follicular thyroid cancer.

Endocr Relat Cancer 2018 03 9;25(3):295-308. Epub 2018 Jan 9.

Department of Surgery (A)Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany

Follicular thyroid cancer's (FTC) excellent long-term prognosis is mainly dependent on postoperative radioactive iodine (RAI) treatment. However, once the tumour becomes refractory, the 10-year disease-specific survival rate drops below 10%. The aim of our study was to evaluate the prognostic and biological role of the TRAIL system in FTC and to elucidate the influence of small-molecule-mediated antagonisation of inhibitor of apoptosis proteins (IAPs) on TRAIL sensitivity Tissue microarrays were constructed from forty-four patients with histologically confirmed FTC. Expression levels of TRAIL and its receptors were correlated with clinicopathological data and overall as well as recurrence-free survival. Non-iodine-retaining FTC cell lines TT2609-bib2 and FTC133 were treated with recombinant human TRAIL alone and in combination with Smac mimetics GDC-0152 or Birinapant. TRAIL-R2/DR5 as well as TRAIL-R3/DcR1 and TRAIL-R4/DcR2 were significantly higher expressed in advanced tumour stages. Both decoy receptors were negatively associated with recurrence-free and overall survival. TRAIL-R4/DcR2 additionally proved to be an independent negative prognostic marker in FTC (HR = 1.446, 95% CI: 1.144-1.826;  < 0.001). , the co-incubation of Birinapant or GDC-0152 with rh-TRAIL-sensitised FTC cell lines for TRAIL-induced apoptosis, through degradation of cIAP1/2. The TRAIL system plays an important role in FTC tumour biology. Its decoy receptors are associated with poor prognosis as well as earlier recurrence. The specific degradation of cIAP1/2 sensitises FTC cells to TRAIL-induced apoptosis and might highlight a new point of attack in patients with RAI refractory disease.
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http://dx.doi.org/10.1530/ERC-17-0479DOI Listing
March 2018

CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma.

Br J Cancer 2017 Dec 7;117(12):1837-1845. Epub 2017 Nov 7.

Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, Duesseldorf 40225, Germany.

Background: Medullary thyroid carcinoma (MTC) is a rare and challenging endocrine malignancy. Once spread, the therapeutic options are limited and the outcome poor. For these patients, the identification of new druggable biological markers is of great importance. Here, we investigated the prognostic and biological role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in MTC.

Methods: Eighty-six MTC and corresponding non-neoplastic thyroid specimens were immunohistochemically stained for CXCR4/7 using tissue microarray technology and expression levels correlated with clinicopathological variables. Medullary thyroid carcinoma cell line TT was treated with recombinant human SDF1α/CXCL12 (rh-SDF1α) and CXCR4 antagonists AMD3100 and WZ811. Changes in cell cycle activation, tumour cell invasiveness as well as changes in mRNA expression levels of genes associated with epithelial-mesenchymal transition (EMT) were investigated.

Results: High CXCR4 expression was associated with large tumour size and metastatic disease. CXCR4 antagonists significantly reduced tumour cell invasiveness, while the treatment with rh-SDF1α stimulated invasive growth, caused cell cycle activation and induced EMT.

Conclusions: The CXCR4/CXCR7/CXCL12 axis plays an important role in MTC. We provide first evidence that the chemokine receptors might serve as potential therapeutic targets in patients with advanced MTC and offer new valuable insight into the underlying molecular machinery of metastatic MTC.
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http://dx.doi.org/10.1038/bjc.2017.364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729476PMC
December 2017

Survivin and XIAP expression in distinct tumor compartments of surgically resected gastric cancer: XIAP as a prognostic marker in diffuse and mixed type adenocarcinomas.

Oncol Lett 2017 Dec 19;14(6):6847-6856. Epub 2017 Sep 19.

Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, D-40225 Duesseldorf, Germany.

There is considerable evidence that the inhibitor of apoptosis protein (IAP) family serves a role in tumorigenesis. The most studied IAP family members, survivin and X-linked inhibitor of apoptosis (XIAP), have been demonstrated to serve as biomarkers in distinct tumor entities. Thus, the present study aimed to investigate the expression levels of both IAPs in the tumor center, invasion front and lymph node metastases of surgically resected gastric cancer (GC) specimens. Tissue microarrays containing samples from 201 primary GCs were analyzed. IAP expression was detected using immunohistochemistry in different tumor compartments, normal mucosa and lymph node metastases. In addition, the association between the expression levels of these proteins, and clinicopathological parameters and overall survival was investigated. High levels of survivin and XIAP were evident in GC, when compared with normal mucosa, and were correlated with intestinal-type and well-differentiated GC, as well as low International Union Against Cancer stages. Increased XIAP expression was detected in lymph node metastases as compared with corresponding primary tumors. XIAP overexpression was identified to be an independent negative prognostic marker in diffuse and mixed type GC. These results suggest a potential role of survivin and XIAP in the early phase of gastric carcinogenesis. In addition, increased XIAP expression in lymph node metastases supports the observation that IAPs serve an essential role in metastatic tumor disease. Since XIAP expression was identified to be associated with poor survival in diffuse and mixed type GC, XIAP may serve as a novel therapeutic target in these types of GC.
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http://dx.doi.org/10.3892/ol.2017.6999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661605PMC
December 2017

Predicting Response to Repetitive Transcranial Magnetic Stimulation in Patients With Schizophrenia Using Structural Magnetic Resonance Imaging: A Multisite Machine Learning Analysis.

Schizophr Bull 2018 08;44(5):1021-1034

Department of Psychiatry and Psychotherapy, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich.

Background: The variability of responses to plasticity-inducing repetitive transcranial magnetic stimulation (rTMS) challenges its successful application in psychiatric care. No objective means currently exists to individually predict the patients' response to rTMS.

Methods: We used machine learning to develop and validate such tools using the pre-treatment structural Magnetic Resonance Images (sMRI) of 92 patients with schizophrenia enrolled in the multisite RESIS trial (http://clinicaltrials.gov, NCT00783120): patients were randomized to either active (N = 45) or sham (N = 47) 10-Hz rTMS applied to the left dorsolateral prefrontal cortex 5 days per week for 21 days. The prediction target was nonresponse vs response defined by a ≥20% pre-post Positive and Negative Syndrome Scale (PANSS) negative score reduction.

Results: Our models predicted this endpoint with a cross-validated balanced accuracy (BAC) of 85% (nonresponse/response: 79%/90%) in patients receiving active rTMS, but only with 51% (48%/55%) in the sham-treated sample. Leave-site-out cross-validation demonstrated cross-site generalizability of the active rTMS predictor despite smaller training samples (BAC: 71%). The predictive pre-treatment pattern involved gray matter density reductions in prefrontal, insular, medio-temporal, and cerebellar cortices, and increments in parietal and thalamic structures. The low BAC of 58% produced by the active rTMS predictor in sham-treated patients, as well as its poor performance in predicting positive symptom courses supported the therapeutic specificity of this brain pattern.

Conclusions: Individual responses to active rTMS in patients with predominant negative schizophrenia may be accurately predicted using structural neuromarkers. Further multisite studies are needed to externally validate the proposed treatment stratifier and develop more personalized and biologically informed rTMS interventions.
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http://dx.doi.org/10.1093/schbul/sbx114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101524PMC
August 2018

Survivin and XIAP - two potential biological targets in follicular thyroid carcinoma.

Sci Rep 2017 09 12;7(1):11383. Epub 2017 Sep 12.

Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.

Follicular thyroid carcinoma's (FTC) overall good prognosis deteriorates if the tumour fails to retain radioactive iodine. Therefore, new druggable targets are in high demand for this subset of patients. Here, we investigated the prognostic and biological role of survivin and XIAP in FTC. Survivin and XIAP expression was investigated in 44 FTC and corresponding non-neoplastic thyroid specimens using tissue microarrays. Inhibition of both inhibitor of apoptosis proteins (IAP) was induced by shRNAs or specific small molecule antagonists and functional changes were investigated in vitro and in vivo. Survivin and XIAP were solely expressed in FTC tissue. Survivin expression correlated with an advanced tumour stage and recurrent disease. In addition, survivin proved to be an independent negative prognostic marker. Survivin or XIAP knockdown caused a significant reduction in cell viability and proliferation, activated caspase3/7 and was associated with a reduced tumour growth in vivo. IAP-targeting compounds induced a decrease of cell viability, proliferation and cell cycle activity accompanied by an increase in apoptosis. Additionally, YM155 a small molecule inhibitor of survivin expression significantly inhibited tumour growth in vivo. Both IAPs demonstrate significant functional implications in the oncogenesis of FTCs and thus prove to be viable targets in patients with advanced FTC.
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http://dx.doi.org/10.1038/s41598-017-11426-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595817PMC
September 2017

Preclinical assesement of survivin and XIAP as prognostic biomarkers and therapeutic targets in gastroenteropancreatic neuroendocrine neoplasia.

Oncotarget 2017 Jan;8(5):8369-8382

Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) represent a rare and heterogenous tumor entity. Importantly, the highly proliferative subgroup of neuroendocrine carcinoma (GEP-NEC) is characterized by high resistance to conventional chemotherapy. Consequently, there is an urgent need to identify novel therapeutic targets, especially for GEP-NEC. Thus, we focused on Inhibitor of apoptosis protein (IAP) family members survivin and XIAP that orchestrate inhibition of apoptosis, induce resistance against chemotherapeutics and facilitate tumor metastasis. Copy number gains (CNGs) could be detected by microarray comparative genomic hybridization for survivin and XIAP in 60 % and 26.7 % of all GEP-NENs, respectively. Immunohistochemical staining of tissue specimens from 77 consecutive patients with GEP-NEN demonstrated increased survivin protein expression levels in tissue specimens of highly proliferative GEP-NEC or GEP-NEN located in the stomach and colon. In contrast, XIAP overexpression was associated with advanced tumor stages. Knockdown of survivin and XIAP markedly reduced cell proliferation and tumor growth. In vitro, YM155 induced apoptotic cell death accompanied by a reduction in cell proliferation and inhibited GEP-NEC xenograft growth. Taken together, our data provide evidence for a biological relevance of these IAPs in GEP-NEN and support a potential role of survivin as therapeutic target especially in the subgroup of aggressive GEP-NEC.
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http://dx.doi.org/10.18632/oncotarget.14207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352407PMC
January 2017

Red cell distribution width in anemic patients undergoing transcatheter aortic valve implantation.

World J Cardiol 2016 Feb;8(2):220-30

Katharina Hellhammer, Tobias Zeus, Verena Veulemanns, Lisa Kahlstadt, Georg Wolff, Ralf Erkens, Ralf Westenfeld, Eliano P Navarese, Marc W Merx, Tienush Rassaf, Malte Kelm, Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, University Düsseldorf, 40225 Düsseldorf, Germany.

Aim: To determine the impact of red blood cell distribution width on outcome in anemic patients undergoing transcatheter aortic valve implantation (TAVI).

Methods: In a retrospective single center cohort study we determined the impact of baseline red cell distribution width (RDW) and anemia on outcome in 376 patients with aortic stenosis undergoing TAVI. All patients were discussed in the institutional heart team and declined for surgical aortic valve replacement due to high operative risk. Collected data included patient characteristics, imaging findings, periprocedural in hospital data, laboratory results and follow up data. Blood samples for hematology and biochemistry analysis were taken from every patient before and at fixed intervals up to 72 h after TAVI including blood count and creatinine. Descriptive statistics were used for patient's characteristics. Kaplan-Meier survival curves were used for time to event outcomes. A recursive partitioning regression and classification was used to investigate the association between potential risk factors and outcome variables.

Results: Mean age in our study population was 81 ± 6.1 years. Anemia was prevalent in 63.6% (n = 239) of our patients. Age and creatinine were identified as risk factors for anemia. In our study population, anemia per se did influence 30-d mortality but did not predict longterm mortality. In contrast, a RDW > 14% showed to be highly predictable for a reduced short- and longterm survival in patients with aortic valve disease after TAVI procedure.

Conclusion: Age and kidney function determine the degree of anemia. The anisocytosis of red blood cells in anemic patients supplements prognostic information in addition to that derived from the WHO-based definition of anemia.
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http://dx.doi.org/10.4330/wjc.v8.i2.220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766272PMC
February 2016

Survivin and XIAP: two valuable biomarkers in medullary thyroid carcinoma.

Br J Cancer 2016 Feb 4;114(4):427-34. Epub 2016 Feb 4.

Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Building 12.46, Moorenstrasse 5, Duesseldorf, Germany.

Background: Medullary thyroid carcinoma (MTC) accounts for ∼5% of all thyroid malignancies. To date, surgery is the first-line therapy with curative intention. However, for advanced MTC, conventional chemotherapeutic agents do not provide convincing results. Therefore, the identification of biomarkers that can be antagonised by small-molecule therapeutics may lead to novel encouraging treatment options.

Methods: Seventy-nine patients with surgically resected and histologically confirmed MTC were included in this study. Tissue microarrays were constructed to assess the relationship between inhibitor of apoptosis proteins (IAPs) survivin or XIAP expression levels and clinicopathological variables as well as overall survival.

Results: High survivin or XIAP expression was associated with an advanced T-stage and metastatic disease. Whereas tissue expression levels of survivin correlated with serum calcitonin levels, XIAP was overexpressed in the subgroup of patients with sporadic MTC. Both IAPs were negatively associated with patient survival in the multivariate Cox regressions analysis (survivin: hazard ratio (HR) 1.62; 95% confidence interval (CI): 1.21-2.16; P=0.001; XIAP: HR 1.78; 95% CI: 1.16-2.72; P=0.008).

Conclusions: Survivin and XIAP demonstrate distinct expression patterns in MTCs, which are associated with advanced disease and poor prognosis. We thus provide first evidence that both IAPs might serve as viable targets in patients with MTC.
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http://dx.doi.org/10.1038/bjc.2016.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815780PMC
February 2016
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