Publications by authors named "Dirk Hasenclever"

75 Publications

Assessment of Waldeyer's ring in pediatric and adolescent Hodgkin lymphoma patients-Importance of multimodality imaging: Results from the EuroNet-PHL-C1 trial.

Pediatr Blood Cancer 2021 Apr 3;68(4):e28903. Epub 2021 Feb 3.

Department of Radiation Oncology, University Hospital Vienna, Vienna, Austria.

Background: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging.

Patients, Materials, And Methods: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment.

Results: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient.

Conclusions: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.
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http://dx.doi.org/10.1002/pbc.28903DOI Listing
April 2021

Interim positron emission tomography in diffuse large B-cell lymphoma.

J Nucl Med 2020 Nov 27. Epub 2020 Nov 27.

Universitaet Leipzig, Institut fuer Medizinische Informatik, Statistik und Epidemiologie, Germany.

In diffuse large B-cell lymphoma, early assessment of treatment response by 18-fluorodeoxyglucose positron emission tomography (PET) may trigger treatment modification. Reliable identification of good and poor responders is important. We compared three competing methods of interim PET evaluation. Images from 449 patients participating in the 'Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas' trial were re-analyzed by applying the visual Deauville score and the standardized uptake value (SUV)-based qPET and ΔSUV scales to interim PET scans performed after two cycles of chemotherapy. qPET relates residual lymphoma 18-fluorodeoxyglucose uptake to physiological liver uptake, converting the ordinal Deauville scale into a continuous scale and permitting a direct comparison with the continuous ΔSUV scale, which is based on SUV changes between baseline and interim scans. Positive and negative predictive values were calculated for progression-free survival. Using established thresholds to distinguish between good and poor responders (visual Deauville score 1-3 vs. 4-5; ΔSUV >66% vs. ΔSUV ≤66%), the positive predictive value was significantly lower with Deauville than ΔSUV (38.4% versus 56.6%; = 0.03). qPET and ΔSUV were strongly correlated on the log scale (Pearson's r=0.75). When plotted along corresponding percentiles, the positive predictive value curves for qPET and ΔSUV were superimposable, with low values up to the 85th percentile and a steep rise thereafter. The recommended threshold of 66% SUV reduction for the identification of poor responders was equivalent to qPET=2.26 corresponding to score 5 on the visual Deauville scale. The negative predictive value curves were also superimposable, but remained flat between 80% and 70%. Continuous scales are better suited for interim PET-based outcome prediction than the ordinal Deauville scale. qPET and ΔSUV essentially carry the same information. The proportion of poor risk patients identified is less than 15%.
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http://dx.doi.org/10.2967/jnumed.120.255034DOI Listing
November 2020

Systematic Review with Meta-Analysis: Endoscopic and Surgical Resection for Ampullary Lesions.

J Clin Med 2020 Nov 10;9(11). Epub 2020 Nov 10.

Medical Department II, Division of Gastroenterology, University of Leipzig Medical Center, 04103 Leipzig, Germany.

Ampullary lesions (ALs) can be treated by endoscopic (EA) or surgical ampullectomy (SA) or pancreaticoduodenectomy (PD). However, EA carries significant risk of incomplete resection while surgical interventions can lead to substantial morbidity. We performed a systematic review and meta-analysis for R0, adverse-events (AEs) and recurrence between EA, SA and PD. Electronic databases were searched from 1990 to 2018. Outcomes were calculated as pooled means using fixed and random-effects models and the Freeman-Tukey-Double-Arcsine-Proportion-model. We identified 59 independent studies. The pooled R0 rate was 76.6% (71.8-81.4%, I = 91.38%) for EA, 96.4% (93.6-99.2%, I = 37.8%) for SA and 98.9% (98.0-99.7%, I = 0%) for PD. AEs were 24.7% (19.8-29.6%, I = 86.4%), 28.3% (19.0-37.7%, I = 76.8%) and 44.7% (37.9-51.4%, I = 0%), respectively. Recurrences were registered in 13.0% (10.2-15.6%, I = 91.3%), 9.4% (4.8-14%, I = 57.3%) and 14.2% (9.5-18.9%, I = 0%). Differences between proportions were significant in R0 for EA compared to SA ( = 0.007) and PD ( = 0.022). AEs were statistically different only between EA and PD ( = 0.049) and recurrence showed no significance for EA/SA or EA/PD. Our data indicate an increased rate of complete resection in surgical interventions accompanied with a higher risk of complications. However, studies showed various sources of bias, limited quality of data and a significant heterogeneity, particularly in EA studies.
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http://dx.doi.org/10.3390/jcm9113622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696506PMC
November 2020

Factors influencing the bias between blood gas analysis versus central laboratory hemoglobin testing. A secondary analysis of a randomized controlled trial.

PLoS One 2020 30;15(10):e0240721. Epub 2020 Oct 30.

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany.

Background: Anemia is the most important complication during major surgery and transfusion of red blood cells is the mainstay to compensate for life threating blood loss. Therefore, accurate measurement of hemoglobin (Hb) concentration should be provided in real-time. Blood Gas Analysis (BGA) provides rapid point-of-care assessment using smaller sampling tubes compared to central laboratory (CL) services.

Objective: This study aimed to investigate the accuracy of BGA hemoglobin testing as compared to CL services.

Methods: Data of the ongoing LIBERAL-Trial (Liberal transfusion strategy to prevent mortality and anemia-associated ischemic events in elderly non-cardiac surgical patients, LIBERAL) was used to assess the bias for Hb level measured by BGA devices (ABL800 Flex analyzer®, GEM series® and RapidPoint 500®) and CL as the reference method. For that, we analyzed pairs of Hb level measured by CL and BGA within two hours. Furthermore, the impact of various confounding factors including age, gender, BMI, smoker status, transfusion of RBC, intraoperative hemodilution, and co-medication was elucidated. In order to ensure adequate statistical analysis, only data of participating centers providing more than 200 Hb pairs were used.

Results: In total, three centers including 963 patients with 1,814 pairs of Hb measurements were analyzed. Mean bias was comparable between ABL800 Flex analyzer® and GEM series®: - 0.38 ± 0.15 g/dl whereas RapidPoint 500® showed a smaller bias (-0.09 g/dl) but greater median absolute deviation (± 0.45 g/dl). In order to avoid interference with different standard deviations caused by the different analytic devices, we focused on two centers using the same BGA technique (309 patients and 1,570 Hb pairs). A Bland-Altman analysis and LOWESS curve showed that bias decreased with smaller Hb values in absolute numbers but increased relatively. The smoker status showed the greatest reduction in bias (0.1 g/dl, p<0.001) whereas BMI (0.07 g/dl, p = 0.0178), RBC transfusion (0.06 g/dl, p<0.001), statins (0.04 g/dl, p<0.05) and beta blocker (0.03 g/dl, p = 0.02) showed a slight effect on bias. Intraoperative substitution of volume and other co-medications did not influence the bias significantly.

Conclusion: Many interventions like substitution of fluids, coagulating factors or RBC units rely on the accuracy of laboratory measurement devices. Although BGA Hb testing showed a consistently stable difference to CL, our data confirm that BGA devices are associated with different bias. Therefore, we suggest that hospitals assess their individual bias before implementing BGA as valid and stable supplement to CL. However, based on the finding that bias decreased with smaller Hb values, which in turn are used for transfusion decision, we expect no unnecessary or delayed RBC transfusion, and no major impact on the LIBERAL trial performance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240721PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598475PMC
December 2020

Comparison of Interim PET Response to Second-Line Versus First-Line Treatment in Classic Hodgkin Lymphoma: Contribution to the Development of Response Criteria for Relapsed or Progressive Disease.

J Nucl Med 2021 03 6;62(3):338-341. Epub 2020 Aug 6.

Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany.

In first-line treatment of Hodgkin lymphoma (HL), Deauville scores 1-3 define complete metabolic remission. Interim F-FDG PET is also used for relapse-treatment adaptation; however, PET response criteria are not validated for relapse treatment. We performed a pairwise comparative analysis of early response to first- and second-line treatments in 127 patients with classic HL who experienced relapse. The patients participated in the prospective, multicenter EuroNet-PHL-C1 study. Residual uptake was measured retrospectively using the qPET method, a validated semiautomatic quantitative extension of the Deauville score. Empiric cumulative distribution functions of the qPET values were used to systematically analyze the response to first- and second-line treatments. Individual patients responded variably to first- and second-line treatments. However, the empiric cumulative distribution functions of the qPET values from all patients were nearly superimposable. The findings support that first- and second-line treatments in HL do not require different response criteria.
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http://dx.doi.org/10.2967/jnumed.120.247924DOI Listing
March 2021

Interim PET Evaluation in Diffuse Large B-Cell Lymphoma Using Published Recommendations: Comparison of the Deauville 5-Point Scale and the ΔSUV Method.

J Nucl Med 2021 01 8;62(1):37-42. Epub 2020 May 8.

Klinik für Hämatologie, Universitätsklinikum, Essen, Germany.

The value of interim F-FDG PET/CT (iPET)-guided treatment decisions in patients with diffuse large B-cell lymphoma (DLBCL) has been the subject of much debate. This investigation focuses on a comparison of the Deauville score and the change-in-SUV (ΔSUV) approach-2 methods to assess early metabolic response to standard chemotherapy in DLBCL. Of 609 DLBCL patients participating in the PET-Guided Therapy of Aggressive Non-Hodgkin Lymphomas trial, iPET scans of 596 patients originally evaluated using the ΔSUV method were available for post hoc assessment of the Deauville score. A commonly used definition of an unfavorable iPET result according to the Deauville score is an uptake greater than that of the liver, whereas an unfavorable iPET scan with regard to the ΔSUV approach is characterized as a relative reduction of the SUV between baseline and iPET staging of less than or equal to 66%. We investigated the 2 methods' correlation and concordance by Spearman rank correlation coefficient and the agreement in classification, respectively. We further used Kaplan-Meier curves and Cox regression to assess differences in survival between patient subgroups defined by the prespecified cutoffs. Time-dependent receiver-operating-characteristic curve analysis provided information on the methods' respective discrimination performance. Deauville score and ΔSUV approach differed in their iPET-based prognosis. The ΔSUV approach outperformed the Deauville score in terms of discrimination performance-most likely because of a high number of false-positive decisions by the Deauville score. Cutoff-independent discrimination performance remained low for both methods, but cutoff-related analyses showed promising results. Both favored the ΔSUV approach, for example, for the segregation by iPET response, where the event-free survival hazard ratio was 3.14 (95% confidence interval, 2.22-4.46) for ΔSUV and 1.70 (95% confidence interval, 1.29-2.24) for the Deauville score. When considering treatment intensification, the currently used Deauville score cutoff of an uptake above that of the liver seems to be inappropriate and associated with potential harm for DLBCL patients. The ΔSUV criterion of a relative reduction in SUV of less than or equal to 66% should be considered as an alternative.
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http://dx.doi.org/10.2967/jnumed.120.244145DOI Listing
January 2021

Quantitative assessment of interim PET in Hodgkin lymphoma: An evaluation of the qPET method in adult patients in the RAPID trial.

PLoS One 2020 2;15(4):e0231027. Epub 2020 Apr 2.

King's College London and Guy's & St Thomas' PET Centre, School of Biomedical Engineering and Imaging Sciences, Kings College London, London, United Kingdom.

Aim: qPET is a quantitative method used to assess FDG-PET response in lymphoma. qPET was developed using 898 scans from children with Hodgkin Lymphoma (HL) in the EuroNet-PHL-C1 (C1) trial. The aim of this study was to determine if qPET could be applied as an alternative response method in adults in the RAPID trial.

Methods: PET-CT scans performed after 3 cycles of ABVD in RAPID were re-evaluated by an independent reader, blinded to PET results and outcome in RAPID. All initially involved regions were assessed visually and by qPET. The distribution of qPET measurements was compared for RAPID and C1 patients. Previously published qPET thresholds corresponding to visual DS (vDS) of 1-5 in C1 were used to derive quantitative DS (qDS) for RAPID patients.

Results: PET-CT scans were available for 450 patients from RAPID. vDS were 1 (171 scans), 2 (153 scans), 3 (72 scans), 4 (31 scans) and 5 (23 scans) respectively. The distribution of qPET values was similar to C1 patients, with a unimodal 'normal' distribution and a long tail to the right, suggestive of favorable response in the majority and less favorable response in the minority with outlying values. qPET thresholds from C1 applied in RAPID patients gave 86% concordance for vDS and qDS. There was 97% concordance for complete metabolic response (CMR; DS 1-3) vs. no-CMR using the Lugano classification.

Conclusion: qPET which was developed in pediatric patients receiving more intensive OEPA chemotherapy, was a suitable quantitative method for assessing response in adult patients treated with ABVD in a response-adapted setting in the RAPID trial.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231027PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117720PMC
July 2020

Risk and Response Adapted Treatment Guidelines for Managing First Relapsed and Refractory Classical Hodgkin Lymphoma in Children and Young People. Recommendations from the EuroNet Pediatric Hodgkin Lymphoma Group.

Hemasphere 2020 02 10;4(1):e329. Epub 2020 Jan 10.

University of Edinburgh and Department of Pediatrics, Royal Hospital for Sick Children, Edinburgh, Scotland, UK.

The objective of this guideline is to aid clinicians in making individual salvage treatment plans for pediatric and adolescent patients with first relapse or refractory (R/R) classical Hodgkin lymphoma (cHL). While salvage with standard dose chemotherapy followed by high dose chemotherapy and autologous stem cell transplant is often considered the standard of care in adult practice, pediatric practice adopts a more individualized risk stratified and response adapted approach to salvage treatment with greater use of non-transplant salvage. Here, we present on behalf of the EuroNet Pediatric Hodgkin Lymphoma group, evidence and consensus-based guidelines for standardized diagnostic, prognostic and response procedures to allocate children and adolescents with R/R cHL to stratified salvage treatments.
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http://dx.doi.org/10.1097/HS9.0000000000000329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000476PMC
February 2020

Prognostic role of body composition parameters in gastric/gastroesophageal junction cancer patients from the EXPAND trial.

J Cachexia Sarcopenia Muscle 2020 02 28;11(1):135-144. Epub 2019 Aug 28.

1st Medical Department, University Cancer Center Leipzig (UCCL), University Leipzig Medical Center, Leipzig, Germany.

Background: Body fat and/or muscle composition influences prognosis in several cancer types. For advanced gastric and gastroesophageal junction cancer, we investigated which body composition parameters carry prognostic information beyond well-established clinical parameters using robust model selection strategy such that parameters identified can be expected to generalize and to be reproducible beyond our particular data set. Then we modelled how differences in these parameters translate into survival outcomes.

Methods: Fat and muscle parameters were measured on baseline computed tomography scans in 761 patients with advanced gastric or gastroesophageal junction cancer from the phase III EXPAND trial, undergoing first-line chemotherapy. Cox regression analysis for overall survival (OS) and progression-free survival (PFS) included body composition parameters and clinical prognostic factors. All continuous variables were entered linearly into the model as there was no evidence of non-linear prognostic impact. For transferability, the final model included only parameters that were picked by Bayesian information criterion model selection followed by bootstrap analysis to identify the most robust model.

Results: Muscle and fat parameters formed correlation clusters without relevant between-cluster correlation. Mean muscle attenuation (MA) clusters with the fat parameters. In multivariate analysis, MA was prognostic for OS (P < 0.0001) but not for PFS, while skeletal muscle index was prognostic for PFS (P = 0.02) but not for OS. Worse performance status Eastern Cooperative Oncology Group (ECOG 1/0), younger age (on a linear scale), and the number of metastatic sites were strong negative clinical prognostic factors for both OS and PFS. MA remained in the model for OS (P = 0.0001) following Bayesian information criterion model selection in contrast to skeletal muscle index that remained prognostic for PFS (P = 0.009). Applying stricter criteria for transferability, MA represented the only prognostic body composition parameter for OS, selected in >80% of bootstrap replicates. Finally, Cox model-derived survival curves indicated that large differences in MA translate into only moderate differences in expected OS in this cohort.

Conclusions: Among body composition parameters, only MA has robust prognostic impact for OS. Data suggest that treatment approaches targeting muscle quality are unlikely to prolong OS noticeably on their own in advanced gastric cancer patients, indicating that multimodal approaches should be pursued in the future.
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http://dx.doi.org/10.1002/jcsm.12484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015239PMC
February 2020

Pseudoexfoliation syndrome: analysis of systemic comorbidities of 325 PEX-positive patients compared with 911 PEX-negative patients.

Graefes Arch Clin Exp Ophthalmol 2019 Nov 16;257(11):2471-2480. Epub 2019 Aug 16.

Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Härtelstrasse 16-18, 04107, Leipzig, Germany.

Purpose: Pseudoexfoliation syndrome (PEX) is an age-related systemic elastic fibrillopathy disorder featuring an excessive production and accumulation of elastic fibre components in the extracellular matrix and is associated with impaired protective mechanisms against oxidative and cellular stress. PEX is diagnosed solely by ophthalmologists; however, PEX deposits have been detected in the connective tissues of many extraocular organ systems. This large, retrospective case-control study investigates whether patients with PEX have an increased risk of extraocular comorbidities.

Methods: Cases and controls were drawn from consecutive patients over 50 years of age undergoing in-house ophthalmological operations under general anaesthesia or in standby preparedness for general anaesthesia. The participants were grouped based solely on PEX-positive (n = 325) or PEX-negative (n = 911) status. The same teams of ophthalmologists and anaesthesiologists uniformly documented every known systemic comorbidity of each patient through two independent rounds of standard anamnestic procedure and protocols in preparation for general anaesthesia. For the purpose of this study, every systemic comorbidity was registered from these forms and subsequently categorized into 17 disease groups based on the International Classification of Diseases (ICD-10) of the World Health Organization (WHO). Odds ratios (ORs) comparing comorbidities in cases and controls were adjusted for age and gender using logistic regression.

Results: After adjustment for multiple testing, patients with PEX had an increased odds ratio for respiratory OR 2.1 [1.4; 3.0], cardiac OR 2.5 [1.6; 4.2], vascular OR 2.0 [1.4; 2.8], and urogenital conditions OR 2.3 [1.4; 3.7]. Renal and psychiatric comorbidities were nominally significant. While no substantially higher frequency was found for hernias, aneurysms, aortic dissection, or varicose veins among PEX-positive patients, higher rates of cardiac valve disorders and benign prostate hyperplasia were found among the PEX-positive individuals.

Conclusion: In addition to confirming an increased risk of respiratory, cardiovascular, and urogenital comorbidities, our data found an increased risk of cardiac valve disorders and benign prostate hyperplasia among PEX-positive patients, which may be manifestations of the underlying systemic elastotic fibrillopathy and warrants further exploration, including future histological study.
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http://dx.doi.org/10.1007/s00417-019-04438-4DOI Listing
November 2019

High prevalence of severe hypovitaminosis D in patients with advanced gastric cancer treated with first-line chemotherapy with or without anti-EGFR-directed monoclonal antibody (EXPAND trial) showing no prognostic impact.

Eur J Cancer 2019 07 10;116:107-113. Epub 2019 Jun 10.

1st Medical Department (Hematology, Cell Therapy, Medical Oncology and Hemostaseology), University Cancer Center Leipzig (UCCL), University Leipzig Medical Center, Germany. Electronic address:

Purpose: The goal of our analysis was to study pretherapeutic circulating 25-OHD plasma levels in patients with previously untreated advanced gastric cancer treated in the randomised controlled phase III Erbitux (cetuximab) in combination with Xeloda (capecitabine) and cisplatin in advanced esophago-gastric cancer (EXPAND) trial (NCT00678535) and to explore whether low 25-OHD plasma levels are associated with worse prognosis and may compromise the clinical efficacy of cetuximab.

Methods: Six hundred thirty patients with available pretherapeutic 25-OHD plasma levels and treated with chemotherapy based on capecitabine and cisplatin, or chemotherapy and cetuximab, were included. The Cox proportional hazard regression model was used to analyse the association between low 25-OHD and survival in both treatment arms.

Results: Majority of study patients were found to have severe vitamin D deficiency. No prognostic impact of 25-OHD plasma levels could be found in our patient cohort, and there was no indication of an interference of 25-OHD plasma levels and the efficacy of treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab.

Conclusions: Although majority of patients with advanced gastric cancer show hypovitaminosis D deficiency, there is no proof for a negative impact on survival or reduced treatment response. A prospective study is needed to investigate the potential benefit of vitamin D supplementation in this patient cohort during first-line chemotherapy.
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http://dx.doi.org/10.1016/j.ejca.2019.05.011DOI Listing
July 2019

Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients - the study design of the LIBERAL-Trial.

Trials 2019 Feb 4;20(1):101. Epub 2019 Feb 4.

Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Background: Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy.

Methods: The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9-10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5-9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect.

Discussion: The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery.

Trial Registration: ClinicalTrials.gov (identifier: NCT03369210 ).
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http://dx.doi.org/10.1186/s13063-019-3200-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360712PMC
February 2019

Genome-wide association study of myocardial infarction, atrial fibrillation, acute stroke, acute kidney injury and delirium after cardiac surgery - a sub-analysis of the RIPHeart-Study.

BMC Cardiovasc Disord 2019 01 24;19(1):26. Epub 2019 Jan 24.

Department of Anaesthesiology, University Hospital Wuerzburg, Wuerzburg, Germany.

Background: The aim of our study was the identification of genetic variants associated with postoperative complications after cardiac surgery.

Methods: We conducted a prospective, double-blind, multicenter, randomized trial (RIPHeart). We performed a genome-wide association study (GWAS) in 1170 patients of both genders (871 males, 299 females) from the RIPHeart-Study cohort. Patients undergoing non-emergent cardiac surgery were included. Primary endpoint comprises a binary composite complication rate covering atrial fibrillation, delirium, non-fatal myocardial infarction, acute renal failure and/or any new stroke until hospital discharge with a maximum of fourteen days after surgery.

Results: A total of 547,644 genotyped markers were available for analysis. Following quality control and adjustment for clinical covariate, one SNP reached genome-wide significance (PHLPP2, rs78064607, p = 3.77 × 10) and 139 (adjusted for all other outcomes) SNPs showed promising association with p < 1 × 10 from the GWAS.

Conclusions: We identified several potential loci, in particular PHLPP2, BBS9, RyR2, DUSP4 and HSPA8, associated with new-onset of atrial fibrillation, delirium, myocardial infarction, acute kidney injury and stroke after cardiac surgery.

Trial Registration: The study was registered with ClinicalTrials.gov NCT01067703, prospectively registered on 11 Feb 2010.
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http://dx.doi.org/10.1186/s12872-019-1002-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345037PMC
January 2019

Loss of paraspinal muscle mass is a gender-specific consequence of cirrhosis that predicts complications and death.

Aliment Pharmacol Ther 2018 12 11;48(11-12):1271-1281. Epub 2018 Nov 11.

Section Hepatology, Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.

Background: Loss of skeletal muscle mass is a recognised complication with a prognostic impact in patients with cirrhosis.

Aim: To explore in a retrospective analysis which muscle compartment most reliably predicts the occurrence of cirrhosis-associated complications and if there are gender-related differences.

Methods: 795 patients with cirrhosis listed for liver transplantation between 2001 and 2014 met the inclusion and exclusion criteria including an abdominal CT scan (±200). Controls were 109 patients who underwent a CT scan after polytrauma. The paraspinal muscles index (PSMI), the abdominal wall muscles index (AWMI) and its combination skeletal muscle index (SMI) were assessed at L3/L4, normalised to the height (cm /m ).

Results: 62.0% of patients with cirrhosis had alcoholic liver disease, and 70.6% were male. As compared to controls, a reduction in PSMI and SMI but not AWMI was associated with high model of end-stage liver disease (MELD) score, high Child-Pugh class, and the presence or history of cirrhosis-associated complications in males but not females. PSMI independently predicted the occurrence of bacterial infections (HR 0.932), spontaneous bacterial peritonitis (HR 0.901), hepatic encephalopathy (HR 0.961), and hepatorenal syndrome (HR 0.946) by multivariate Cox regression analysis in a gender-independent manner. Post-transplant survival was not associated with the PSMI; neither AWMI nor SMI predicted any clinical endpoints.

Conclusions: This study links muscle wasting in patients with cirrhosis predominantly to males. However, the presence of a low PSMI mass is a gender-independent predictor of developing cirrhosis-associated complications and death. Scores combining the MELD with muscle parameters should be re-validated by utilizing the PSMI.
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http://dx.doi.org/10.1111/apt.15026DOI Listing
December 2018

Rationale and design of a multicentre, randomized, placebo-controlled trial of mirabegron, a Beta3-adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3-left ventricular hypertrophy (Beta3-LVH).

ESC Heart Fail 2018 10 22;5(5):830-841. Epub 2018 Jun 22.

Department of Medicine, Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Cliniques Universitaires Saint-Luc, Université catholique de Louvain, B1.53.09, 52 avenue Mounier, 1200, Brussels, Belgium.

Aims: Progressive left ventricular (LV) remodelling with cardiac myocyte hypertrophy, myocardial fibrosis, and endothelial dysfunction plays a key role in the onset and progression of heart failure with preserved ejection fraction. The Beta3-LVH trial will test the hypothesis that the β adrenergic receptor agonist mirabegron will improve LV hypertrophy and diastolic function in patients with hypertensive structural heart disease at high risk for developing heart failure with preserved ejection fraction.

Methods And Results: Beta3-LVH is a randomized, placebo-controlled, double-blind, two-armed, multicentre, European, parallel group study. A total of 296 patients will be randomly assigned to receive either mirabegron 50 mg daily or placebo over 12 months. The main inclusion criterion is the presence of LV hypertrophy, that is, increased LV mass index (LVMi) or increased wall thickening by echocardiography. The co-primary endpoints are a change in LVMi by cardiac magnetic resonance imaging and a change in LV diastolic function (assessed by the E/e' ratio). Secondary endpoints include mirabegron's effects on cardiac fibrosis, left atrial volume index, maximal exercise capacity, and laboratory markers. Two substudies will evaluate mirabegron's effect on endothelial function by pulse amplitude tonometry and brown fat activity by positron emission tomography using 17F-fluorodeoxyglucose. Morbidity and mortality as well as safety aspects will also be assessed.

Conclusions: Beta3-LVH is the first large-scale clinical trial to evaluate the effects of mirabegron on LVMi and diastolic function in patients with LVH. Beta3-LVH will provide important information about the clinical course of this condition and may have significant impact on treatment strategies and future trials in these patients.
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http://dx.doi.org/10.1002/ehf2.12306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165933PMC
October 2018

Antibody Concentrations Decrease 14-Fold in Children With Celiac Disease on a Gluten-Free Diet but Remain High at 3 Months.

Clin Gastroenterol Hepatol 2018 09 12;16(9):1442-1449.e5. Epub 2018 Apr 12.

Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Medical Faculty of the University, University Hospital, Leipzig, Germany.

Background & Aims: Celiac disease can be identified by a serologic test for IgA against tissue transglutaminase (IgA-TTG) in a large proportion of children. However, the increased concentrations of antibody rarely normalize within the months after children are placed on a gluten-free diet (GFD). Early serologic predictors of sufficient adherence to GFD are required for optimal treatment.

Methods: In a prospective study, we observed the response to a GFD in 345 pediatric patients (67% girls; mean age, 8.4 y) who underwent duodenal biopsy to confirm or refute celiac disease from October 2012 through December 2015. Baseline serum samples were tested centrally for IgA-TTG and IgG against deamidated gliadin. Follow-up serologic analyses of children on a GFD were performed about 3 months later.

Results: The geometric mean concentration of IgA-TTG decreased from 72.4-fold to 5.2-fold the upper limit of normal (ULN), or by a factor of 14.0 (95% CI, 12.0-16.4). A substantial response (defined as a larger change than the typical variation in patients not on a GFD) was observed in 80.6% of the children. Only 28.1% of patients had a substantial response in the concentration of IgG against deamidated gliadin. Concentration of IgA-TTG remained above 1-fold the ULN in 83.8% of patients, and above 10-fold the ULN in 26.6% of patients with a substantial response.

Conclusions: Serum concentration of IgA-TTG decreases substantially in most children with celiac disease within 3 months after they are placed on a GFD, but does not normalize in most. This information on changes in antibody concentrations can be used to assess patient response to the diet at short-term follow-up evaluations. Patients with a substantial response to a GFD often still have high antibody levels after 3 months. German Clinical Trials Registry no. DRKS00003854.
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http://dx.doi.org/10.1016/j.cgh.2018.04.008DOI Listing
September 2018

F-FDG PET Response of Skeletal (Bone Marrow and Bone) Involvement After Induction Chemotherapy in Pediatric Hodgkin Lymphoma: Are Specific Response Criteria Required?

J Nucl Med 2018 10 13;59(10):1524-1530. Epub 2018 Apr 13.

Department of Pediatric Oncology, Justus-Liebig-University, Giessen, Germany.

To determine whether the current F-FDG PET response criterion for skeletal involvement in Hodgkin lymphoma (HL) is suitable, we performed a systematic evaluation of the different types of skeletal involvement and their response on PET after 2 cycles of chemotherapy (PET-2). A secondary objective was to observe the influence of the initial uptake intensity (measured as qPET) and initial metabolic tumor volume (MTV) of skeletal lesions on the PET-2 response. The initial PET scans of 1,068 pediatric HL patients from the EuroNet-PHL-C1 trial were evaluated for skeletal involvement by central review. Three types of skeletal lesions were distinguished: PET-only lesions (those detected on PET only), bone marrow (BM) lesions (as confirmed by MRI or BM biopsy), and bone lesions. qPET and MTV were calculated for each skeletal lesion. All PET-2 scans were assessed for residual tumor activity. The rates of complete metabolic response for skeletal and nodal involvement on PET-2 were compared. Of the 1,068 patients, 139 (13%) showed skeletal involvement (44 PET-only, 32 BM, and 63 bone). Of the 139 patients with skeletal involvement, 101 (73%) became PET-2-negative in the skeleton and 94 (68%) became PET-2-negative in the lymph nodes. The highest number of PET-2-negative scans in the skeleton was 42 (95%) in the 44 PET-only patients, followed by 22 skeletal lesions (69%) in the 32 BM patients and 37 (59%) in the 63 bone patients. Lesions that became PET-2-negative showed a lower initial median qPET (2.74) and MTV (2 cm) than lesions that remained PET-2-positive (3.84 and 7 cm, respectively). In this study with pediatric HL patients, the complete response rate for skeletal involvement on PET-2 was similar to that for nodal involvement. Bone flare seemed to be irrelevant. Overall, the current skeletal PET response criterion-comparison with the local skeletal background-is well suited. The initial qPET and MTV of skeletal lesions were predictive of the PET-2 result. Higher values for both parameters were associated with a worse PET-2 response.
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http://dx.doi.org/10.2967/jnumed.117.205633DOI Listing
October 2018

RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study: Myocardial Dysfunction, Postoperative Neurocognitive Dysfunction, and 1 Year Follow-Up.

J Am Heart Assoc 2018 03 26;7(7). Epub 2018 Mar 26.

Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.

Background: Remote ischemic preconditioning (RIPC) has been suggested to protect against certain forms of organ injury after cardiac surgery. Previously, we reported the main results of RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study, a multicenter trial randomizing 1403 cardiac surgery patients receiving either RIPC or sham-RIPC.

Methods And Results: In this follow-up paper, we present 1-year follow-up of the composite primary end point and its individual components (all-cause mortality, myocardial infarction, stroke and acute renal failure), in a sub-group of patients, intraoperative myocardial dysfunction assessed by transesophageal echocardiography and the incidence of postoperative neurocognitive dysfunction 5 to 7 days and 3 months after surgery. RIPC neither showed any beneficial effect on the 1-year composite primary end point (RIPC versus sham-RIPC 16.4% versus 16.9%) and its individual components (all-cause mortality [3.4% versus 2.5%], myocardial infarction [7.0% versus 9.4%], stroke [2.2% versus 3.1%], acute renal failure [7.0% versus 5.7%]) nor improved intraoperative myocardial dysfunction or incidence of postoperative neurocognitive dysfunction 5 to 7 days (67 [47.5%] versus 71 [53.8%] patients) and 3 months after surgery (17 [27.9%] versus 18 [27.7%] patients), respectively.

Conclusions: Similar to our main study, RIPC had no effect on intraoperative myocardial dysfunction, neurocognitive function and long-term outcome in cardiac surgery patients undergoing propofol anesthesia.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01067703.
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http://dx.doi.org/10.1161/JAHA.117.008077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907591PMC
March 2018

EFFECT of daily antiseptic body wash with octenidine on nosocomial primary bacteraemia and nosocomial multidrug-resistant organisms in intensive care units: design of a multicentre, cluster-randomised, double-blind, cross-over study.

BMJ Open 2017 Nov 8;7(11):e016251. Epub 2017 Nov 8.

Institute of Hygiene/Hospital Epidemiology, Medical Faculty of the University of Leipzig, Leipzig, Saxony, Germany.

Introduction: Nosocomial infections are serious complications that increase morbidity, mortality and costs and could potentially be avoidable. Antiseptic body wash is an approach to reduce dermal micro-organisms as potential pathogens on the skin. Large-scale trials with chlorhexidine as the antiseptic agent suggest a reduction of nosocomial infection rates. Octenidine is a promising alternative agent which could be more effective against Gram-negative organisms. We hypothesise that daily antiseptic body wash with octenidine reduces the risk of intensive care unit (ICU)-acquired primary bacteraemia and ICU-acquired multidrug-resistant organisms (MDRO) in a standard care setting.

Methods And Analysis: EFFECT is a controlled, cluster-randomised, double-blind study. The experimental intervention consists in using octenidine-impregnated wash mitts for the daily routine washing procedure of the patients. This will be compared with using placebo wash mitts. Replacing existing washing methods is the only interference into clinical routine.Participating ICUs are randomised in an AB/BA cross-over design. There are two 15-month periods, each consisting of a 3-month wash-out period followed by a 12-month intervention and observation period. Randomisation determines only the sequence in which octenidine-impregnated or placebo wash mitts are used. ICUs are left unaware of what mitts packages they are using.The two coprimary endpoints are ICU-acquired primary bacteraemia and ICU-acquired MDRO. Endpoints are defined based on individual ward-movement history and microbiological test results taken from the hospital information systems without need for extra documentation. Data on clinical symptoms of infection are not collected. EFFECT aims at recruiting about 45 ICUs with about 225 000 patient-days per year.

Ethics And Dissemination: The study was approved by the ethics committee of the University of Leipzig (number 340/16-ek) in November 2016. Findings will be published in peer-reviewed journals.

Trial Registration Number: DRKS-ID: DRKS00011282.
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http://dx.doi.org/10.1136/bmjopen-2017-016251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695441PMC
November 2017

Reply to: Laffon and Marthan "FDG PET for therapy monitoring in Hodgkin's and non-Hodgkin's lymphomas: qPET versus rPET".

Eur J Nucl Med Mol Imaging 2017 12 22;44(13):2331-2332. Epub 2017 Sep 22.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Härtelstrasse 16-18, 04107, Leipzig, Germany.

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http://dx.doi.org/10.1007/s00259-017-3826-xDOI Listing
December 2017

Risk-adapted monitoring is not inferior to extensive on-site monitoring: Results of the ADAMON cluster-randomised study.

Clin Trials 2017 Dec 8;14(6):584-596. Epub 2017 Aug 8.

5 Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany.

Background According to Good Clinical Practice, clinical trials must protect rights and safety of patients and make sure that the trial results are valid and interpretable. Monitoring on-site has an important role in achieving these objectives; it controls trial conduct at trial sites and informs the sponsor on systematic problems. In the past, extensive on-site monitoring with a particular focus on formal source data verification often lost sight of systematic problems in study procedures that endanger Good Clinical Practice objectives. ADAMON is a prospective, stratified, cluster-randomised, controlled study comparing extensive on-site monitoring with risk-adapted monitoring according to a previously published approach. Methods In all, 213 sites from 11 academic trials were cluster-randomised between extensive on-site monitoring (104) and risk-adapted monitoring (109). Independent post-trial audits using structured manuals were performed to determine the frequency of major Good Clinical Practice findings at the patient level. The primary outcome measure is the proportion of audited patients with at least one major audit finding. Analysis relies on logistic regression incorporating trial and monitoring arm as fixed effects and site as random effect. The hypothesis was that risk-adapted monitoring is non-inferior to extensive on-site monitoring with a non-inferiority margin of 0.60 (logit scale). Results Average number of monitoring visits and time spent on-site was 2.1 and 2.7 times higher in extensive on-site monitoring than in risk-adapted monitoring, respectively. A total of 156 (extensive on-site monitoring: 76; risk-adapted monitoring: 80) sites were audited. In 996 of 1618 audited patients, a total of 2456 major audit findings were documented. Depending on the trial, findings were identified in 18%-99% of the audited patients, with no marked monitoring effect in any of the trials. The estimated monitoring effect is -0.04 on the logit scale with two-sided 95% confidence interval (-0.40; 0.33), demonstrating that risk-adapted monitoring is non-inferior to extensive on-site monitoring. At most, extensive on-site monitoring could reduce the frequency of major Good Clinical Practice findings by 8.2% compared with risk-adapted monitoring. Conclusion Compared with risk-adapted monitoring, the potential benefit of extensive on-site monitoring is small relative to overall finding rates, although risk-adapted monitoring requires less than 50% of extensive on-site monitoring resources. Clusters of findings within trials suggest that complicated, overly specific or not properly justified protocol requirements contributed to the overall frequency of findings. Risk-adapted monitoring in only a sample of patients appears sufficient to identify systematic problems in the conduct of clinical trials. Risk-adapted monitoring has a part to play in quality control. However, no monitoring strategy can remedy defects in quality of design. Monitoring should be embedded in a comprehensive quality management approach covering the entire trial lifecycle.
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http://dx.doi.org/10.1177/1740774517724165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718334PMC
December 2017

Remote ischaemic preconditioning for coronary artery bypass grafting (with or without valve surgery).

Cochrane Database Syst Rev 2017 05 5;5:CD011719. Epub 2017 May 5.

Department of Cardiothoracic Surgery, University Hospital Aachen, Pauwelsstrasse 30, Aachen, North Rhine Westphalia, Germany, 52074.

Background: Despite substantial improvements in myocardial preservation strategies, coronary artery bypass grafting (CABG) is still associated with severe complications. It has been reported that remote ischaemic preconditioning (RIPC) reduces reperfusion injury in people undergoing cardiac surgery and improves clinical outcome. However, there is a lack of synthesised information and a need to review the current evidence from randomised controlled trials (RCTs).

Objectives: To assess the benefits and harms of remote ischaemic preconditioning in people undergoing coronary artery bypass grafting, with or without valve surgery.

Search Methods: In May 2016 we searched CENTRAL, MEDLINE, Embase and Web of Science. We also conducted a search of ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP). We also checked reference lists of included studies. We did not apply any language restrictions.

Selection Criteria: We included RCTs in which people scheduled for CABG (with or without valve surgery) were randomly assigned to receive RIPC or sham intervention before surgery.

Data Collection And Analysis: Two review authors independently assessed trials for inclusion, extracted data and checked them for accuracy. We calculated mean differences (MDs), standardised mean differences (SMDs) and risk ratios (RR) using a random-effects model. We assessed quality of the trial evidence for all primary outcomes using the GRADE methodology. We completed a 'Risk of bias' assessment for all studies and performed sensitivity analysis by excluding studies judged at high or unclear risk of bias for sequence generation, allocation concealment and incomplete outcome data. We contacted authors for missing data. Our primary endpoints were 1) composite endpoint (including all-cause mortality, non-fatal myocardial infarction or any new stroke, or both) assessed at 30 days after surgery, 2) cardiac troponin T (cTnT, ng/L) at 48 hours and 72 hours, and as area under the curve (AUC) 72 hours (µg/L) after surgery, and 3) cardiac troponin I (cTnI, ng/L) at 48 hours, 72 hours, and as area under the curve (AUC) 72 hours (µg/L) after surgery.

Main Results: We included 29 studies involving 5392 participants (mean age = 64 years, age range 23 to 86 years, 82% male). However, few studies contributed data to meta-analyses due to inconsistency in outcome definition and reporting. In general, risk of bias varied from low to high risk of bias across included studies, and insufficient detail was provided to inform judgement in several cases. The quality of the evidence of key outcomes ranged from moderate to low quality due to the presence of moderate or high statistical heterogeneity, imprecision of results or due to limitations in the design of individual studies.Compared with no RIPC, we found that RIPC has no treatment effect on the rate of the composite endpoint with RR 0.99 (95% confidence interval (CI) 0.78 to 1.25); 2 studies; 2463 participants; moderate-quality evidence. Participants randomised to RIPC showed an equivalent or better effect regarding the amount of cTnT release measured at 72 hours after surgery with SMD -0.32 (95% CI -0.65 to 0.00); 3 studies; 1120 participants; moderate-quality evidence; and expressed as AUC 72 hours with SMD -0.49 (95% CI -0.96 to -0.02); 3 studies; 830 participants; moderate-quality evidence. We found the same result in favour of RIPC for the cTnI release measured at 48 hours with SMD -0.21 (95% CI -0.40 to -0.02); 5 studies; 745 participants; moderate-quality evidence; and measured at 72 hours after surgery with SMD -0.37 (95% CI -0.59 to -0.15); 2 studies; 459 participants; moderate-quality evidence. All other primary outcomes showed no differences between groups (cTnT release measured at 48 hours with SMD -0.14, 95% CI -0.33 to 0.06; 4 studies; 1792 participants; low-quality evidence and cTnI release measured as AUC 72 hours with SMD -0.17, 95% CI -0.48 to 0.14; 2 studies; 159 participants; moderate-quality evidence).We also found no differences between groups for all-cause mortality after 30 days, non-fatal myocardial infarction after 30 days, any new stroke after 30 days, acute renal failure after 30 days, length of stay on the intensive care unit (days), any complications and adverse effects related to ischaemic preconditioning. We did not assess many patient-centred/salutogenic-focused outcomes.

Authors' Conclusions: We found no evidence that RIPC has a treatment effect on clinical outcomes (measured as a composite endpoint including all-cause mortality, non-fatal myocardial infarction or any new stroke, or both, assessed at 30 days after surgery). There is moderate-quality evidence that RIPC has no treatment effect on the rate of the composite endpoint including all-cause mortality, non-fatal myocardial infarction or any new stroke assessed at 30 days after surgery, or both. We found moderate-quality evidence that RIPC reduces the cTnT release measured at 72 hours after surgery and expressed as AUC (72 hours). There is moderate-quality evidence that RIPC reduces the amount of cTnI release measured at 48 hours, and measured 72 hours after surgery. Adequately-designed studies, especially focusing on influencing factors, e.g. with regard to anaesthetic management, are encouraged and should systematically analyse the commonly used medications of people with cardiovascular diseases.
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http://dx.doi.org/10.1002/14651858.CD011719.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481544PMC
May 2017

Validation of Antibody-Based Strategies for Diagnosis of Pediatric Celiac Disease Without Biopsy.

Gastroenterology 2017 08 28;153(2):410-419.e17. Epub 2017 Apr 28.

Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Medical Faculty of the University and University Hospital, Leipzig, Germany. Electronic address:

Background & Aims: A diagnosis of celiac disease is made based on clinical, genetic, serologic, and duodenal morphology features. Recent pediatric guidelines, based largely on retrospective data, propose omitting biopsy analysis for patients with concentrations of IgA against tissue transglutaminase (IgA-TTG) >10-fold the upper limit of normal (ULN) and if further criteria are met. A retrospective study concluded that measurements of IgA-TTG and total IgA, or IgA-TTG and IgG against deamidated gliadin (IgG-DGL) could identify patients with and without celiac disease. Patients were assigned to categories of no celiac disease, celiac disease, or biopsy required, based entirely on antibody assays. We aimed to validate the positive and negative predictive values (PPV and NPV) of these diagnostic procedures.

Methods: We performed a prospective study of 898 children undergoing duodenal biopsy analysis to confirm or rule out celiac disease at 13 centers in Europe. We compared findings from serologic analysis with findings from biopsy analyses, follow-up data, and diagnoses made by the pediatric gastroenterologists (celiac disease, no celiac disease, or no final diagnosis). Assays to measure IgA-TTG, IgG-DGL, and endomysium antibodies were performed by blinded researchers, and tissue sections were analyzed by local and blinded reference pathologists. We validated 2 procedures for diagnosis: total-IgA and IgA-TTG (the TTG-IgA procedure), as well as IgG-DGL with IgA-TTG (TTG-DGL procedure). Patients were assigned to categories of no celiac disease if all assays found antibody concentrations <1-fold the ULN, or celiac disease if at least 1 assay measured antibody concentrations >10-fold the ULN. All other cases were considered to require biopsy analysis. ULN values were calculated using the cutoff levels suggested by the test kit manufacturers. HLA typing was performed for 449 participants. We used models that considered how specificity values change with prevalence to extrapolate the PPV and NPV to populations with lower prevalence of celiac disease.

Results: Of the participants, 592 were found to have celiac disease, 345 were found not to have celiac disease, and 24 had no final diagnosis. The TTG-IgA procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.934; the TTG-DGL procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.958. Based on our extrapolation model, we estimated that the PPV and NPV would remain >0.95 even at a disease prevalence as low as 4%. Tests for endomysium antibodies and HLA type did not increase the PPV of samples with levels of IgA-TTG ≥10-fold the ULN. Notably, 4.2% of pathologists disagreed in their analyses of duodenal morphology-a rate comparable to the error rate for serologic assays.

Conclusions: In a prospective study, we validated the TTG-IgA procedure and the TTG-DGL procedure in identification of pediatric patients with or without celiac disease, without biopsy. German Clinical Trials Registry no.: DRKS00003854.
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http://dx.doi.org/10.1053/j.gastro.2017.04.023DOI Listing
August 2017

Do paraneoplastic changes in diffuse FDG organ uptake predict relapse? - Wait for confirmation study : Reply to Jorgov et al. Eur J Nucl Med Mol Imaging. 2016 Jul;43(7):1220--30.

Eur J Nucl Med Mol Imaging 2017 Jan;44(1):170-171

Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Härtelstraße 16-18, 04107, Leipzig, Germany.

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http://dx.doi.org/10.1007/s00259-016-3534-yDOI Listing
January 2017

Modified BEAM with triple autologous stem cell transplantation for patients with relapsed aggressive non-Hodgkin lymphoma.

Ann Hematol 2016 Jun 11;95(7):1121-8. Epub 2016 May 11.

Department of Hematology, Oncology and Stem Cell Transplantation, Asklepios Klinik St. Georg, Hamburg, Germany.

Treatment of relapse and primary progression in aggressive lymphoma remains unsatisfactory; outcome is still poor. Better treatment strategies are much needed for this patient population. The R1 study is a prospective multi-center phase I/II study evaluating a dose finding approach with a triple transplant regimen in four BEAM dose levels in patients with relapsed aggressive non-Hodgkin lymphoma. The aim of the study was to determine feasibility, toxicity, and remission rate. In a total of 39 patients (pts.) enrolled in the study, 24 pts. were evaluated in the following analysis. Twenty pts. had aggressive B cell lymphoma, and two pts. had T cell lymphoma. All evaluated patients responded to DexaBEAM with a sufficient stem cell harvest. The phase I/II study was started with BEAM dose level II. Four patients were treated at dose level II, and 20 pts. were treated at dose level III. Due to the early termination of the study, dose levels I and IV were never administered. Sixteen pts. completed therapy according to protocol, and eight pts. (33.3 %) stopped treatment early. Infections (27 %) and stomatitis (13 %) were the most frequent grade III/IV non-hematologic toxicities. Thirteen percent of patients presented with severe grade III/IV lung toxicity during modified BEAM (m-BEAM). Fourteen pts. achieved a complete response (CR), one pt. achieved no change (NC), six pts. had progressive disease (PD), and two pts. died; for one pt., outcome is not known. One-year and 3-year event-free survival (EFS) was 38 and 33 %, respectively. Overall survival (OS) after 1 and 3 years was 50 and 38 %. In conclusion, dose escalation of standard BEAM is not feasible due to toxicity.
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http://dx.doi.org/10.1007/s00277-016-2671-5DOI Listing
June 2016

Inter-Reader Reliability of Early FDG-PET/CT Response Assessment Using the Deauville Scale after 2 Cycles of Intensive Chemotherapy (OEPA) in Hodgkin's Lymphoma.

PLoS One 2016 10;11(3):e0149072. Epub 2016 Mar 10.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

Purpose: The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised.

Methods: Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy (according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs.

Results: The probability that two random readers concord on the five point D score of a random case is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton.

Conclusion: Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149072PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786307PMC
August 2016

Modeling combined chemo- and immunotherapy of high-grade non-Hodgkin lymphoma.

Leuk Lymphoma 2016 07 15;57(7):1697-708. Epub 2015 Dec 15.

a Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig , Leipzig , Germany ;

Moderate, but not massive intensification of CHOP-21 improves outcome in aggressive non-Hodgkin lymphoma. Adding immunotherapy with Rituximab was a break-through, but levels differences in chemotherapy. Ongoing trials attempt to optimize R-CHOP type regimens. We present a mathematical model of chemo-immunotherapy to explain published and aiming at predicting future trials comparing R-CHOP variants. We hypothesize that, for cure, the immune system must dominate residual tumor cells at the end of treatment. Chemotherapy reduces both tumor and immune cells. Rituximab immunotherapy boosts the immune response. We translate this reasoning into a differential equations model. Model parameters are estimated using data of randomized clinical trials in elderly patients. The model explains observed hazard ratios between treatments. It explains why too intense chemotherapy could be detrimental. The model is validated predicting six published independent studies. As an application, we varied treatment schedules and predict that current R-CHOP variants have only limited optimization potential.
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http://dx.doi.org/10.3109/10428194.2015.1110746DOI Listing
July 2016

A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery.

N Engl J Med 2015 Oct 5;373(15):1397-407. Epub 2015 Oct 5.

From the Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt (P.M., U.S., C.R., K.Z.), the Departments of Anesthesiology and Intensive Care Medicine (P.M., B.B., M.G.) and Cardiovascular Surgery (J.C.), University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Clinical Trial Center (O.B.), the Department of Internal Medicine/Cardiology, University of Leipzig Heart Center (G.F.), and Institute for Medical Informatics, Statistics, and Epidemiology (D.H.), University of Leipzig, Leipzig, the Department of Anesthesiology, University Hospital Aachen, Aachen (C.S., M.C., G.S.), the Department of Cardiovascular Surgery, University of Giessen, Giessen (A.B., B.N.), Clinic of Anesthesiology and Intensive Care Medicine, University Hospital Rostock, Rostock (J.R., F.K.), the Department of Anesthesiology, Medical Center of Johannes Gutenberg University, Mainz (R.L.-F., M.F.), the Department of Anesthesiology and Intensive Care Medicine, University Hospital Göttingen, Göttingen (I.F.B., M.B.), the Department of Anesthesiology and Intensive Care Medicine and Center for Sepsis Control and Care, Jena University Hospital, Jena (S.N.S., A.K.), the Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn (M.W., G.B.), the Department of Anesthesiology and Intensive Care Medicine, University Hospital Düsseldorf, Düsseldorf (T.M.-T., P.K.), the Department of Anesthesiology and Intensive Care Medicine, University of Lübeck, Lübeck (M.H., J.S.), the Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin (M.S., S.T.), the Department of Anesthesiology, University Hospital Würzburg, Würzburg (T. Smul, E.W.), and the Department of Anesthesiology, University Hospital Magdeburg, Magdeburg (T. Schilling) - all in Germany.

Background: Remote ischemic preconditioning (RIPC) is reported to reduce biomarkers of ischemic and reperfusion injury in patients undergoing cardiac surgery, but uncertainty about clinical outcomes remains.

Methods: We conducted a prospective, double-blind, multicenter, randomized, controlled trial involving adults who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass under total anesthesia with intravenous propofol. The trial compared upper-limb RIPC with a sham intervention. The primary end point was a composite of death, myocardial infarction, stroke, or acute renal failure up to the time of hospital discharge. Secondary end points included the occurrence of any individual component of the primary end point by day 90.

Results: A total of 1403 patients underwent randomization. The full analysis set comprised 1385 patients (692 in the RIPC group and 693 in the sham-RIPC group). There was no significant between-group difference in the rate of the composite primary end point (99 patients [14.3%] in the RIPC group and 101 [14.6%] in the sham-RIPC group, P=0.89) or of any of the individual components: death (9 patients [1.3%] and 4 [0.6%], respectively; P=0.21), myocardial infarction (47 [6.8%] and 63 [9.1%], P=0.12), stroke (14 [2.0%] and 15 [2.2%], P=0.79), and acute renal failure (42 [6.1%] and 35 [5.1%], P=0.45). The results were similar in the per-protocol analysis. No treatment effect was found in any subgroup analysis. No significant differences between the RIPC group and the sham-RIPC group were seen in the level of troponin release, the duration of mechanical ventilation, the length of stay in the intensive care unit or the hospital, new onset of atrial fibrillation, and the incidence of postoperative delirium. No RIPC-related adverse events were observed.

Conclusions: Upper-limb RIPC performed while patients were under propofol-induced anesthesia did not show a relevant benefit among patients undergoing elective cardiac surgery. (Funded by the German Research Foundation; RIPHeart ClinicalTrials.gov number, NCT01067703.).
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http://dx.doi.org/10.1056/NEJMoa1413579DOI Listing
October 2015

The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.

Int J Cancer 2015 Dec 6;137(12):2846-57. Epub 2015 Jul 6.

LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.

Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.
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http://dx.doi.org/10.1002/ijc.29649DOI Listing
December 2015