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Dieckhoff P.,University of Marburg | Runkel H.,University of Marburg | Daniel H.,Institute of Medical Biometry | Wiese D.,University of Marburg | And 8 more authors.
Digestion | Year: 2014

Background: Resection with curative intention is the cornerstone of treatment in patients with neuroendocrine tumors. A proportion of patients will relapse after R0 resection, but the factors predictive of recurrence are not well understood. Methods: A database established 1998 at the University Hospital Marburg was queried for all patients with documented R0 resection. Recurrence-free survival and overall survival were estimated using the Kaplan-Meier method. Uni- And multivariate analyses were performed. Results: 180 patients with a median age of 52 years entered the analysis. We observed 77 recurrences after a median time of 2.9 years. 24% of the recurrences occurred later than 5 years after operation. Median recurrence-free survival of the whole cohort was 101 months. In univariate analysis grade by Ki-67, stage, high lymph node ratio and microangioinvasion were significant predictors of recurrence. On multivariate analysis these parameters were confirmed as independent prognostic parameters with stage and microangioinvasion being the most important predictors. Conclusions: After R0 resection of neuroendocrine tumors, postoperative surveillance should be extended to at least 10 years. Patients with distant metastases and microangioinvasion are at high risk of recurrence. Clinical trials of adjuvant treatment protocols are indicated in these patients. © 2014 S. Karger AG, Basel.


PubMed | Institute of Pathology, Institute of Medical Biometry and University of Heidelberg
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

This study aimed to explore the ability of a minimal invasive biopsy to diagnose a pathological complete response (pCR=ypT0) in the breast.Ultrasound-guided, vacuum-assisted, minimal invasive biopsy (VAB) was performed in 50 patients after neoadjuvant chemotherapy and before breast surgery. Negative predictive values (NPV) and false negative rates (FNR) to predict a pCR in surgical specimen were the main outcome measures. To assess the possible sampling error, the representativeness of the sample was evaluated by the biopsy performing physician (subjectively based on the visibility in ultrasound), by radiography of the biopsy specimen, and by the pathologist (based on histopathology).The cohort (n=50) consisted of 15 (30%) triple negative breast cancers, 13 (26%) human epidermal growth factor receptor 2 (HER2) positiveand 22 (44%) hormone receptor positive/HER2 negativecancers. ypT0 was diagnosed in 23 (46%) cases. In the overall cohort (n=50), VAB yielded an NPV of 76.7% and an FNR of 25.9%. Given a representative VAB sample, according to the histopathological evaluation (n=38), the NPV was 94.4% (95% CI 87.1-100.0) and the FNR 4.8% (95% CI 0.0-11.6). Non-representative VABs were mainly due to bad visibility of the target lesion in ultrasound.A VAB can accurately diagnose a pCR, given a histopathologically representative sample.


PubMed | Hannover Medical School, University of Cologne, Charité - Medical University of Berlin, Childrens Hospital and 4 more.
Type: | Journal: Allergy | Year: 2016

Component-resolved diagnostics using specific IgE to 2 S albumins has shown to be a valuable new option in diagnostic procedure. Ana o 3 is a 2 S albumin from cashew. The aim of this study was to investigate the role of Ana o 3-specific serum IgE in the diagnosis of cashew allergy and to identify cut-off levels to replace oral food challenges. Moreover, the value of additional determination of total IgE has been investigated.In a multicentre study, we analysed specific IgE to cashew extract and Ana o 3 as well as total IgE in children with suspected cashew allergy using the ImmunoCAP-FEIA and a standardized diagnostic procedure including oral challenges where indicated.A total of 61 patients were included in the study. Forty-two were allergic to cashew, and 19 were tolerant. In receiver operating curves, Ana o 3 discriminates between allergic and tolerant children better than cashew-specific IgE with an area under the curve of 0.94 vs 0.78. The ratio of Ana o 3-specific IgE to total IgE did not further improve the diagnostic procedure. Probability curves for Ana o 3-specific IgE have been calculated, and a 95% probability could be estimated at 2.0 kU/l.Specific IgE to Ana o 3 is a valuable tool for the diagnosis of cashew allergy. Considering its positive predictive value, it might allow to make a considerable number of oral challenges superfluous.


Ezziddin S.,University of Bonn | Sabet A.,University of Bonn | Heinemann F.,University of Bonn | Yong-Hing C.J.,University of British Columbia | And 6 more authors.
Journal of Nuclear Medicine | Year: 2011

Peptide receptor radionuclide therapy (PRRT) is an efficient treatment for gastroenteropancreatic neuroendocrine tumors (GEP NETs), with outstanding overall response rates and survival. However, little is known about the particular efficacy regarding bone metastasis (BM). Methods: We retrospectively analyzed a consecutive subgroup of 42 patients with BM of GEP NETs treated with PRRT (177Lu-octreotate, 4 intended cycles at 3 monthly intervals [10-14 wk]; mean activity per cycle, 8.1 GBq). Availability of restaging and outcome data was required for patient inclusion. Baseline characteristics, including age, tumor origin, performance score, Ki-67 index, tumor load, tumor uptake, plasma chromogranin A, and neuron-specific enolase, were analyzed regarding impact on tumor regression (modified M.D. Anderson criteria) and time to progression. Survival analyses were performed using Kaplan-Meier curves, log-rank test at a significance level of P less than 0.05, and Cox proportional hazards model for uni- and multivariate analyses. Results: Median follow-up was 32 mo. The observed response of BMs consisted of complete remission in 2 (4.8%), partial remission in 14 (33.3%), minor response in 5 (11.9%), stable disease in 16 (38.1%), and progressive disease in 5 (11.9%) patients. Median progression-free survival and overall survival (OS) were 35 mo (26-44, 95% confidence interval) and 51 mo (37-65, 95% confidence interval), respectively. Patients with responding BMs (complete remission, partial remission, or minor response) exhibited a trend toward better OS (median OS not reached after 53 mo) when compared to nonresponding patients (39 mo, P 5 0.076). Only Ki-67 index (>10%) and chromogranin A level (>600 ng/mL) contributed to regression analysis. Conclusion: BM of GEP NETs is effectively controlled by PRRT, with long progression-free survival and OS. Poor patient condition and multifocality of BMs do not clearly affect treatment efficacy, possibly encouraging the use of PRRT in advanced bone metastatic disease. Larger studies are needed to assess predictors of treatment outcome in these patients. Copyright © 2011 by the Society of Nuclear Medicine, Inc.


Ezziddin S.,University of Bonn | Adler L.,University of Bonn | Sabet A.,University of Bonn | Poppel T.D.,University of Duisburg - Essen | And 7 more authors.
Journal of Nuclear Medicine | Year: 2014

The tumor proliferation marker, Ki-67 index, is a well-established prognostic marker in gastroenteropancreatic neuroendocrine neoplasms (NENs). Noninvasive molecular imaging allows whole-body metabolic characterization of metastatic disease. We investigated the prognostic impact of 18F-FDG PET in inoperable multifocal disease. Methods: Retrospective, dual-center analysis was performed on 89 patients with histologically confirmed, inoperable metastatic gastroenteropancreatic NENs undergoing 18F-FDG PET/CT within the staging routine. Metabolic (PET-based) grading was in accordance with the most prominent 18F-FDG uptake (reference tumor lesion): mG1, tumor-to-liver ratio of maximum standardized uptake value ≤ 1.0; mG2, 1.0-2.3; mG3, >2.3. Other potential variables influencing overall survival, including age, tumor origin, performance status, tumor burden, plasma chromogranin A (≥600 μg/L), neuron-specific enolase (≤25 μg/L), and classic grading (Ki-67-based) underwent univariate (log-rank test) and multivariate analysis (Cox proportional hazards model), with a P value of less than 0.05 considered significant. Results: The median follow-up period was 38 mo (95% confidence interval [CI], 27-49 mo); median overall survival of the 89 patients left for multivariate analysis was 29 mo (95% CI, 21-37 mo). According to metabolic grading, 9 patients (10.2%) had mG1 tumors, 22 (25.0%) mG2, and 57 (64.8%) mG3. On mul-tivariate analysis, markedly elevated plasma neuron-specific eno-lase (P = 0.016; hazard ratio, 2.9; 95% CI, 1.2-7.0) and high metabolic grade (P = 0.015; hazard ratio, 4.7; 95% CI, 1.2-7.0) were independent predictors of survival. Conclusion: This study demonstrated the feasibility of prognostic 3-grade stratification of meta-static gastroenteropancreatic NENs by whole-body molecular imaging using 18F-FDG PET. COPYRIGHT © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.


Wieland A.,Institute of Medical Biometry | Wieland A.,University of Bonn | Trageser D.,Institute of Medical Biometry | Trageser D.,University of Bonn | And 28 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Glioblastoma is a highly malignant, invariably fatal brain tumor for which effective pharmacotherapy remains an unmet medical need. Experimental Design: Screening of a compound library of 160 synthetic and natural toxic substances identified the antihelmintic niclosamide as a previously unrecognized candidate for clinical development. Considering the cellular and interindividual heterogeneity of glioblastoma, a portfolio of short-term expanded primary human glioblastoma cells (pGBM; n = 21), common glioma lines (n = 5), and noncancer human control cells (n = 3) was applied as a discovery platform and for preclinical validation. Pharmacodynamic analysis, study of cell-cycle progression, apoptosis, cell migration, proliferation, and on the frequency of multipotent/self-renewing pGBM cells were conducted in vitro, and orthotopic xenotransplantation was used to confirm anticancer effects in vivo. Results: Niclosamide led to cytostatic, cytotoxic, and antimigratory effects, strongly reduced the frequencies of multipotent/self-renewing cells in vitro, and after exposure significantly diminished the pGBMs' malignant potential in vivo. Mechanism of action analysis revealed that niclosamide simultaneously inhibited intracellular WNT/CTNNB1-, NOTCH-, mTOR-, and NF-kB signaling cascades. Furthermore, combinatorial drug testing established that a heterozygous deletion of the NFKBIA locus in glioblastoma samples could serve as a genomic biomarker for predicting a synergistic activity of niclosamide with temozolomide, the current standard in glioblastoma therapy. Conclusions: Together, our data advocate the use of pGBMs for exploration of compound libraries to reveal unexpected leads, for example, niclosamide that might be suited for further development toward personalized clinical application. © 2013 American Association for Cancer Research.


Trapp C.,University of Bonn | Schiller W.,University of Bonn | Mellert F.,University of Bonn | Halbe M.,University of Zürich | And 3 more authors.
Thoracic and Cardiovascular Surgeon | Year: 2015

Background During the last decades many efforts have been made to reduce transfusion requirements and adverse clinical effects during cardiopulmonary bypass (CPB). The minimal extracorporeal circulation (MECC) system and the technique of retrograde autologous priming (RAP) of a conventional CPB circuit have been associated with decreased hemodilution. Our study aimed to compare conventional CPB (cCPB), RAP, and the ROCsafe MECC (Terumo Europe N.V., Leuven, Belgium) system in elective coronary artery bypass patients. Patients and MethodsData were retrospectively collected on three cohorts of 30 adult CPB patients. Patients were operated using cCPB, RAP, and the ROCsafe MECC system. ResultsThe three groups were comparable in demographic data. The priming volume in the ROCsafe and RAP group was significantly less compared with the conventional priming group (p <0.05). The mean time of extracorporeal circulation and aortic cross-clamp time (p <0.05) were significantly shorter in the ROCsafe group. The levels of hemoglobin (Hb) and hematocrit (Hct) during CPB and postoperatively showed significant differences between the three groups (p〈0.05) and resulted in significantly higher blood transfusion requirements (p〈0.05). Lactate, serum creatinine, troponin, and creatine kinase-myocardial band (CK-MB) levels did not differ significantly among the three groups (p >0.05). There was also no statistically significant difference in ventilation time, intensive care unit (ICU) stay, overall hospital stay, and postoperative complications (p >0.05). ConclusionIn conclusion, RAP is compared with cCPB and MECC a safe and low-cost technique in reducing the priming volume of the CPB system, causes less hemodilution, and reduces the need for intra- and postoperative blood transfusion. © 2015 Georg Thieme Verlag KG Stuttgart.


Aicher D.,Institute of Medical Biometry | Kunihara T.,Institute of Medical Biometry | Abou Issa O.,Institute of Medical Biometry | Brittner B.,Institute of Medical Biometry | And 2 more authors.
Circulation | Year: 2011

Background-: Reconstruction of the regurgitant bicuspid aortic valve has been performed for >10 years, but there is limited information on long-term results. We analyzed our results to determine the predictors of suboptimal outcome. Methods and results-: Between November 1995 and December 2008, 316 patients (age, 49±14 years; male, 268) underwent reconstruction of a regurgitant bicuspid aortic valve. Intraoperative assessment included extent of fusion, root dimensions, circumferential orientation of the 2 normal commissures (>160°, ≤160°), and effective height after repair. Cusp pathology was treated by central plication (n=277), triangular resection (n=138), or pericardial patch (n=94). Root dilatation was treated by subcommissural plication (n=100), root remodeling (n=122), or valve reimplantation (n=2). All patients were followed up echocardiographically (cumulative follow-up, 1253 years; mean, 4±3.1 years). Clinical and morphological parameters were analyzed for correlation with 10-year freedom from reoperation with the Cox proportional hazards model. Hospital mortality was 0.63%; survival was 92% at 10 years. Freedom from reoperation at 5 and 10 years was 88% and 81%; freedom from valve replacement, 95% and 84%. By univariable analysis, statistically significant predictors of reoperation were age (hazard ratio [HR]=0.97), aortoventricular diameter (HR=1.24), effective height (HR=0.76), commissural orientation (HR=0.95), use of a pericardial patch (HR=7.63), no root replacement (HR=3.80), subcommissural plication (HR=2.07), and preoperative aortic regurgitation grade 3 or greater. By multivariable analysis, statistically significant predictors for reoperation were age (HR=0.96), aortoventricular diameter (HR=1.30), effective height (HR=0.74), commissural orientation (HR=0.96), and use of a pericardial patch (HR=5.16). Conclusions-: Reconstruction of bicuspid aortic valve can be performed reproducibly with good early results. Recurrence and progression of regurgitation, however, may occur, depending primarily on anatomic features of the valve. Copyright © 2011 American Heart Association. All rights reserved.


Meyer S.,Saarland University | Sander J.,Saarland University | Graber S.,Institute of Medical Biometry | Gottschling S.,Saarland University | Gortner L.,Saarland University
Journal of Paediatrics and Child Health | Year: 2010

Purpose: Blood pressure constitutes an important parameter in the assessment of the cardiovascular status in preterm infants. Invasive arterial blood pressure (IBP) is considered the 'gold-standard', but non-invasive blood pressure (NIBP) is used frequently in preterm infants. The aim of this prospective study was to compare mean IBP and mean NIBP arterial blood pressure measurements in three subsets of preterm infants (>1500 g; 1000-1500 g, and <1000 g, and >31 weeks, 28-31 weeks, and <28 weeks of gestation). Methods: Prospective, simultaneous assessment of both IBP and NIBP measurements in 50 preterm neonates at 6, 12, 18, 24 h after birth in a tertiary University centre. Results: Mean gestational age was 26.7 ± 2.2 (24-32) in group I (n = 18), 29.6 ± 2.0 (27-34) in group II (n = 19) and 32.2 ± 1.9(30-36) weeks in group III (n = 13), respectively; mean birth weight was 777 ± 161 (495-995), 1251 ± 154 (1010-1490) and 2010 ± 332 (1590-2550) g. Mean IBP and mean NIBP increased significantly during the first 24 h of life in all three sub-groups (P < 0.01); IBP and NIBP measurements were significantly correlated, and showed good agreement, irrespective of birth weight and gestational age. Conclusions: Although IBP monitoring is considered the 'gold standard', NIBP values showed good agreement with those obtained invasively irrespective of gestational age and birth weight. We conclude that NIBP monitoring constitutes an important parameter in the assessment of the cardiovascular status even in extremely low birth weight infants. © 2010 Paediatrics and Child Health Division (Royal Australasian College of Physicians).


PubMed | University of Zürich, University of Bonn and Institute of Medical Biometry
Type: Comparative Study | Journal: The Thoracic and cardiovascular surgeon | Year: 2015

During the last decades many efforts have been made to reduce transfusion requirements and adverse clinical effects during cardiopulmonary bypass (CPB). The minimal extracorporeal circulation (MECC) system and the technique of retrograde autologous priming (RAP) of a conventional CPB circuit have been associated with decreased hemodilution. Our study aimed to compare conventional CPB (cCPB), RAP, and the ROCsafe MECC (Terumo Europe N.V., Leuven, Belgium) system in elective coronary artery bypass patients.Data were retrospectively collected on three cohorts of 30 adult CPB patients. Patients were operated using cCPB, RAP, and the ROCsafe MECC system.The three groups were comparable in demographic data. The priming volume in the ROCsafe and RAP group was significantly less compared with the conventional priming group (p <0.05). The mean time of extracorporeal circulation and aortic cross-clamp time (p <0.05) were significantly shorter in the ROCsafe group. The levels of hemoglobin (Hb) and hematocrit (Hct) during CPB and postoperatively showed significant differences between the three groups (p<0.05) and resulted in significantly higher blood transfusion requirements (p<0.05). Lactate, serum creatinine, troponin, and creatine kinase-myocardial band (CK-MB) levels did not differ significantly among the three groups (p >0.05). There was also no statistically significant difference in ventilation time, intensive care unit (ICU) stay, overall hospital stay, and postoperative complications (p >0.05).In conclusion, RAP is compared with cCPB and MECC a safe and low-cost technique in reducing the priming volume of the CPB system, causes less hemodilution, and reduces the need for intra- and postoperative blood transfusion.

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