University Medical Center Freiburg Research Articles

Treatment with proton pump inhibitors increases the risk for development of hepatic encephalopathy after implantation of transjugular intrahepatic portosystemic shunt (TIPS).

Treatment with proton pump inhibitors (PPIs) has been associated with development of hepatic encephalopathy (HE). As development of HE is a major complication after implantation of a transjugular intrahepatic portosystemic shunt (TIPS), we hypothesized that PPI treatment may be associated with a higher risk of post-TIPS HE. We analyzed data of 397 patients with liver cirrhosis who received de novo TIPS implantation at the University Medical Center Freiburg, Germany. We assessed whether PPI medication and other patient characteristics are predictive factors for the development of post-TIPS HE. Patients with PPI treatment at the time of TIPS implantation showed significantly higher rates of post-TIPS HE than those without PPI medication (30.4% vs 11.7%, p < 0.001). The rate of post-TIPS HE increased in a dose-dependent manner. However, PPI medication did not directly affect transplant-free survival. Remarkably, in 59.1% of patients who received PPIs there was no clear indication. PPI treatment may be an independent risk factor for the development of post-TIPS HE and the risk increases with PPI dose. Indication for PPI treatment should be assessed carefully prior to TIPS implantation in patients with liver cirrhosis.

Allogeneic transplantation of multiple myeloma patients may allow long-term survival in carefully selected patients with acceptable toxicity and preserved quality of life.

Despite significantly improved survival and response rates in patients diagnosed with multiple myeloma, it still remains an incurable disease with a poor outcome, especially in high-risk groups. Allogeneic stem cell transplantation offers a potentially curative option but remains controversial due to considerable treatment-related toxicity. We analyzed 109 consecutive myeloma patients who had received reduced-intensity conditioning allogeneic transplantation at the Freiburg University Medical Center between 2000 and 2016. Although most patients were heavily pre-treated in high-risk constellations, the overall response rate was high with 70%, the median overall survival (OS) 39.2%, and the median progression-free survival (PFS) 14.2 months, with a median follow up of 71.5 months. Survival was significantly better in patients with response to previous therapies than in those with progressive disease (median OS 65 vs. 11.5 months, P=0.003; median PFS 18.4 vs. 5.1 months, P=0.001). Moreover, survival of patients transplanted in first-line was significantly prolonged compared to relapsed/refractory disease (median OS not reached vs. 21.6 months, P<0.001; median PFS 47.7 vs. 9.6 months, P<0.001). The non-relapse mortality was relatively low with a cumulative incidence of 12.4% at ten years. Acute graft-versus-host disease (GvHD) grade II-IV was observed in 25%, and moderate or severe chronic GvHD in 24%. Quality of life (QoL) assessed with the revised Myeloma Comorbidity Index before and after transplantation remained unchanged. Our data suggest that allogeneic transplantation in the context of novel immunotherapeutic approaches may enable long-term survival and even a potential cure in a carefully selected subgroup of high-risk multiple myeloma patients with acceptable toxicity and preserved QoL.

Efficiency of SNPs for the Detection of 35DelG Mutation in 50 Cases with Nonsyndromic Hearing Loss

Congenital sensorineural hearing loss (SNHL) is recognized as a major public health burden. Mutations in the GJB2 gene are among the most frequent encountered etiological factors (approximately 50% of cases of autosomal recessive sensorineural non-syndromic hearing loss in the Caucasian population). Single nucleotide polymorphisms (SNPs) are important markers in studies that correlate the genotype with the phenotype. The main purpose of the study is to develop and validate a molecular-genetic screening algorithm based on the SNP rs80338939 for later use in laboratories in Romania and the Republic of Moldova. A prospective study was conducted on 50 randomly included subjects with profound congenital SNHL. The 35delG mutation was assessed by two methods: a reference method (University Medical Center Freiburg, Germany) and the method to validate: single nucleotide polymorphism (SNP) for the same mutation. We compared the results of the two methods to assess the specificity and sensitivity of the method used in the study. Results obtained indicate a sensitivity of 92% and 98% specificity for the studied method when compared with the reference method. The high sensitivity and specificity of the proposed method confirms that rs80338939 can be used as a biomarker in the assessment of the risk of autosomal recessive SNHL. In fact, we aim to optimize the technique to achieve 100% sensitivity and specificity. At the same time, we acknowledge that the screening of 35delG mutations does not replace the audiological screening tests, because the auditory function involves 1% of the human genes and mutations of any of these may lead to deafness.

Hepatobiliary scintigraphy to evaluate liver function and short-term outcome for patients undergoing major liver resection

Introduction: While post hepatectomy liver failure (PHLF) was shown to be accurately predicted by liver volumetry based on computed tomography (CT), the role of 99mTc-mebrofenin hepatobiliary scintigraphy is not well assessed. Methods: Patients who underwent hepatectomy of ≥4 Couinaud's segments at the University Medical Center Freiburg in 2017 were analyzed. 99mTc-mebrofenin hepatobiliary scintigraphy and liver volumetry based on CT of the future liver remnant (FLR) were performed preoperatively. A FLR < 20% for healthy livers and < 30% for previously injured livers was determined insufficient to maintain an adequate liver function. The impact of estimated liver function vs CT volumetry on short-term outcome was analyzed. PHLF was defined acording to PeakBil >7 mg/dl, the “50:50 criteria” and ISGLS classification. Results: The study included 20 patients. One patient underwent ALLPS procedure due to an insufficient FLR and liver function. However, critical liver function (< 2.7 %/min/m2) was observed in 15 patients (75%). 5 patients (25%) developed ISGLS-defined PHLF (2 patients grade A, 3 patients grade B), including 4 patients (20%) with PeakBil >7 mg/dl. Of these, 3 patients showed critical preoperative liver function but only one had an insufficient FLR. Postoperative complications according to Dindo-Clavien ≥ IIIb occurred in 3 patients (15%), 30-day mortality was 0%. Conclusion: 99mTc-mebrofenin hepatobiliary scintigraphy may be a helpful tool to improve the estimation and accuracy of PHLF prediction, but the impact still remains unclear. Therefore further investigations are necessary.

Osteonecrosis of the jaw in patients transitioning from bisphosphonates to denosumab treatment for osteoporosis

Antiresorptive-related osteonecrosis of the jaw (ARONJ) is a rare but severe side effect of antiresorptive treatment with bisphosphonates or RANKL-antibody denosumab in patients with malignant diseases or osteoporosis. Whilst osteonecrosis of the jaw (ONJ) related to the administration of bisphosphonates (BPs) has been investigated for more than 1 decade now, only few data are available on denosumab-related ONJ, especially in patients with osteoporosis. From 2008 to 2016, 52 osteoporosis patients were treated with ARONJ in the Department of Oral and Maxillofacial Surgery, University Medical Center Freiburg, Germany. In all patients, a surgical regimen consisting of complete removal of necrotic bone, primary wound closure and perioperative i.v. antibiotic therapy was applied. Of the 52 patients, 38 developed ARONJ after BP monotherapy; in 11 patients, antiresorptive therapy had been transitioned from BPs to denosumab and 3 patients had received denosumab monotherapy. From July 2013, when the first patient with ONJ and transitioning therapy from BPs to denosumab presented to our department, to October 2016, we found recurrences in 17.6% of the patients with BP monotherapy and in 45.5% of the patients with transitioning therapy from BPs to denosumab. Transitioning antiresorptive therapy from BPs to denosumab may be an additional risk factor for developing ARONJ. In these patients, treatment of ARONJ-lesions seems to provoke more complications. An additional dental screening before transitioning should be initiated. Further studies are needed to evaluate if a first-line treatment with denosumab decreases the incidence of ARONJ in patients with osteoporosis and simplifies its treatment.

Reference Data for Polysomnography-Measured and Subjective Sleep in Healthy Adults.

Reference data for sleep are needed for the interpretation of clinical sleep parameters. This analysis aimed to provide polysomnography-measured, spectral analytic and subjective reference data based on a sample of healthy adults. In addition, effects of age and sex were investigated. The sample was selected from the archival database of the Sleep Center at the University Medical Center Freiburg and consisted of 206 healthy adults aged 19 to 73 years. For an adaptation and a second examination night, polysomnography parameters, spectral analytic data, and subjective sleep estimations are presented. With increasing age, sleep became shorter (less total sleep time, more wake time after sleep onset) and lighter (eg, more percentage of stage N1 sleep, increase in fast activity in the beta range). Sleep in females was deeper than sleep in males (eg, higher percentage of stage N3 sleep). Females had higher overall power density than males. Altogether, it is apparent that sleep parameters exhibit high standard deviations, suggesting a high variability within healthy adults and complicating the specification of reference values. Our data suggest that the informative value of sleep reference data in healthy individuals is limited because of high interindividual and intraindividual variation within sleep variables. More research, preferably in the form of meta-analyses and/or large international databases, is needed to further investigate the relevance of such reference data for mental and physical health. In the absence of such knowledge, giving patients feedback about deviations from the norm in their sleep profile may give rise to ill-founded concerns and worry.

Residual Tumor Volume as Best Outcome Predictor in Low Grade Glioma - A Nine-Years Near-Randomized Survey of Surgery vs. Biopsy.

Diffuse low grade gliomas (DLGG) are continuously progressive primary brain neoplasms that lead to neurological deficits and death. Treatment strategies are controversial. Randomized trials establishing the prognostic value of surgery do not exist. Here, we report the results of a nine-year near-randomized patient distribution between resection and biopsy. Until 2012, the Department of Neurosurgery and the Department of Stereotactic Neurosurgery at the University Medical Center Freiburg were organized as separate administrative units both coordinating DLGG patient treatment independently. All consecutive adult patients with a new diagnosis of DLGG by either stereotactic biopsy or resection were included. Pre- and post-operative tumor volumetry was performed. 126 patients, 87 men (69%), 39 women (31%), median age 41 years, were included. 77 (61%) were initially managed by biopsy, 49 (39%) by resection. A significant survival benefit was found for patients with an initial management by resection (5-year OS 82% vs. 54%). The survival benefit of patients with initial resection was reserved to patients with a residual tumor volume of less than 15 cm3. Maximum safe resection is the first therapy of choice in DLGG patients if a near-complete tumor removal can be achieved. Accurate prediction of the extent-of-resection is required for selection of surgical candidates.

Cystic lesions of the pancreas-is radical surgery really warranted?

The purpose of this study was to retrospectively evaluate diagnostic accuracy of cystic lesions of the pancreas in order to determine if less aggressive surgical treatment might be safe and therefore warranted. A retrospective cohort study was conducted in 232 patients with either observed or resected cystic lesions of the pancreas referred for evaluation and treatment to the University Medical Center Freiburg, Germany, between 2001 and 2011. Most patients had MRI or CT for preoperative imaging (90.6%). Preoperatively, benign pseudocysts (BPC) were diagnosed in 84 (36.2%) patients and intraductal papillary mucinous neoplasm (IPMN) in 59 (25.2%) patients, whereas serous cyst adenoma, mucinous cystic neoplasm (MCN), solid pseudopapillary tumors (SPPTs), and neuroendocrine tumors (NETs) were less common. In 43% of patients, the preoperative diagnosis concurred with the postoperative diagnosis. The preoperative diagnosis was accurate in BPC, less so in IPMN, and inaccurate in MCN, NET, and SPPT. However, prediction of tumor biology was accurate; only 11% of the lesions regarded as benign turned out to be malignant after resection, and no patient without resection developed malignancy at a median follow-up of 8months. Subsequently, 89% of diagnosed benign tumors had indeed benign pathology. The prediction of biology is often correct, whereas specific diagnosis is often wrong. A considerable amount of benign lesions are treated more aggressively than warranted if malignancy is suspected prior to surgery. Parenchyma-sparing techniques might be an option, but prospective multicenter studies need to follow. Experienced pancreatic radiologists can improve accuracy of preoperative biology.

Structured reporting ensures complete content and quick detection of essential data in pathology reports of oncological breast resection specimens.

There is increasing evidence that not only the way of data acquisition but also the design of data visualization (i.e., the format) has impact on the quality of pathology reports. Therefore, we investigated the correlation between the format of pathology reports and the amount as well as the detection time of transmitted data. All reports of oncological breast resection specimens referred to the Institute for Surgical Pathology, University Medical Center Freiburg, between 2003 and 2011 (n = 4181) were classified into descriptive reports (DR, n = 856), structured reports (SR, n = 2455), or template-based synoptic reports (TBSR, n = 870). The reports were screened regarding the content of nine organ-specific essential data. The amount of recorded essential data per report was summarized in an essential data score (EDS) and the format types were statistically compared regarding their EDS. Additionally, we measured the time a gynecologist needed to detect all nine essential data within a subset of reports and compared the format types regarding the detection times statistically. A full-score EDS of 9 was seen in 28.4 % of all reports, in 4 % of DRs, in 21.4 % of SRs, and in 72.3 % of TBSRs (p < 0.0001). Median EDS of DRs was 7, of SRs 8, and of TBSRs 9 (p < 0.0001). Data regarding tumor localization, tumor size, specific grading, angioinvasion, hormone receptor status, and additional findings were mentioned more frequently in TBSRs compared to other format type reports with a statistically highly significant difference (p < 0.0001). Mean data detection time decreased significantly from 26 to 20 and 14 s in DRs, SRs, and TBSRs, respectively. Our results clearly show that due to the use of TBSRs reporting of oncological breast resection specimens are improved regarding the content of essential data and the clarity of the data layout resulting in a rapid detection of essential data by clinicians.

Editorial introductions

Current Opinion in Anesthesiology was launched in 1988. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of anesthesiology is divided into 15 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Gernot MarxFigureDr Gernot Marx, MD, FRCA is full Professor of Anesthesiology and Critical Care Medicine and Chair at the University RWTH Aachen, Germany. He is Head of the Department of Intensive Care Medicine and Intermediate Care at the University Hospital RWTH Aachen. He is full board member of the German Society of Anaesthesia and Intensive Care and full board member of the interdisciplinary German Society of Intensive Care and Emergency Medicine. He graduated and took his residency at the Medizinische Hochschule Hannover in Germany. He was Senior Lecturer in Anaesthesia and Intensive Care Medicine at the University of Liverpool, UK and full Professor for Anaesthesiology, Intensive Care and Emergency Medicine at the Friedrich-Schiller-Universität Jena, Germany. He received the Fellowship by election of the Royal College of Anaesthetists. His research interest is focused on sepsis, fluid therapy and telemedicine. He is Editor of two books, Checklist Intensive Care Medicine and The Intensive Care Medicine. He is Editor of AINS (Anaesthesiologie Intensivmedizin Notfallmedizin Schmerztherapie) and Associate Editor of British Journal of Anaesthesia. Hartmut BürkleFigureHartmut Bürkle, MD, PhD is full Professor of Anesthesiology and Critical Care Medicine, and Chair of the Department of Anesthesiology and Intensive Care Medicine at the University Medical Center Freiburg, Germany. After his residency in Anesthesiology in Hamburg and a postdoctoral fellowship at the UCSD, San Diego (Prof T. L. Yaksh) he joined Prof Hugo Van Aken[Combining Acute Accent]s anesthesia and intensive care medicine group in Muenster, Germany. His research interests are centered on regional anesthesia techniques, perioperative pain therapy and perioperative rehabilitation, highlighting patient's outcome. During the last decade, he has also focused on the development of safe anesthesia strategies, the economical and ethical issues of modern health systems related to anesthesia and intensive care medicine, as well as on implementing peer reviewed quality care in anesthesiology and intensive care medicine. He has published more than 120 studies and acted as reviewer for most of the national and international journals of anesthesiology and intensive care medicine. Kai ZacharowskiFigureProfessor Kai Zacharowski holds the position of the Ordinarius and is the Director of the Department of Anesthesia, Intensive Care Medicine and Pain Therapy at the University Hospital Frankfurt. His research, teaching, and consulting interests are in both clinical and basic aspects of patient safety, transfusion and clotting, innate immunity, cardiovascular and critical care medicine. Professor Zacharowski received his MD from the German University of Mainz and his PhD from Queen Mary, University of London (where he was working with the Nobel laureate Prof Sir John Vane → discovered how aspirin works). His scientific contributions are published in peer-reviewed journals such as Nature Medicine, Lancet, NEJM and Proceedings of the National Academy of Science and were awarded with numerous awards for Innovative Clinical Research. He is serving as Editor-in-Chief for the Journal of Anesthesia & Intensive Care Medicine as well as an Editorial Board member of numerous journals in Critical Care Medicine, Emergency Medicine and Anesthesia. He obtained 2 clinical specializations (Anesthesia/Intensive Care Medicine and Clinical Pharmacology) and is practicing Anesthesia and Critical Care Medicine in Frankfurt.

Identification of hospital patients in need of palliative care--a predictive score.

BackgroundPalliative care was initially developed for patients with advanced cancer. Over the past years, however, palliative care has broadened its focus from terminal cancer patients to patients with other serious, life-limiting illnesses. Nevertheless, the identification of palliative care needs (PCNs) among hospital patients remains an insufficiently investigated topic of research. The aim of our study was to describe the characteristics of hospital patients with palliative care needs and to develop a score for their identification.MethodsWe conducted an epidemiological study. Data were collected prospectively from inpatients at the University Medical Center Freiburg, Germany. For each patient discharged from a hospital ward, the treating physician had to report whether the patient had PCNs or not. The response rate was 96 %, and data from 39,849 patients could be analyzed. A binary logistic regression analysis was performed in order to identify risk factors for developing PCNs and to develop a predictive score for the identification of patients with PCNs upon their admission to the hospital. In order to validate the risk prediction model, we used a bootstrap analysis.ResultsDuring the study period, 6.9 % (2757) of all patients had palliative care needs. Only 56 of them (2 %) received palliative treatment. Binary logistic regression analysis showed that older patients without relatives who suffered from metastatic cancer and/or liver cirrhosis had the highest risk of developing palliative care needs (PCN-score; sensitivity: 0.815; specificity: 0.640).ConclusionsGiven the aging population and associated increase in the number of patients requiring palliative care, it is crucial to detect palliative care needs in hospital patients with both cancerous and non-cancerous life-limiting diseases. Our predictive score contributes to the identification of palliative care needs in patients with life-limiting diseases, which allows physicians to take the appropriate therapeutic steps.

Dose Intensification with Rituximab, MTX and CHOP Results in Superior Results for Young High Risk DLBCL Patients Than Primary Autologous Transplantation

Despite treatment of diffuse large B cell lymphoma has improved the last decade by incorporating rituximab to CHOP therapy, outcome in young high risk patients (aaIPI 2-3) remains poor with a substantial percentage of pts achieving only a short EFS and OS. In recent years primary autologous transplantation seemed to improve results. We designed an upfront treatment schedule consisting of 6 cycles CHOP-14 as backbone, incorporating dose dense rituximab as suggested by data from Pfreundschuh at al. and high dose MTX as CNS directed approach and compared results with own controls using primary autologous transplantation. All pts aged <65 y presenting with high risk DLBCL at Freiburg University Medical Center since 2012 were treated with 6 cycles CHOP-14 and dose dense rituximab (375 mg/m²) on days 0, 1, 4, 8, 15, 22, 29, 47, 61 and 75. HD MTX (3.0 g/m²) was administered on days 30 and 76 right before standard CHOP. We reviewed all pts treated according to the protocol in an intention to treat analysis identifying 18 patients meeting the criteria. 3 pts presenting with the diagnosis of DLBCL were not treated according to the protocol. 1 pt with a double hit lymphoma was primarily intensified with HD chemotherapy and subsequent ASCT. 1 pt with a prior history of kidney transplantation received 6 cycles R-CHOP and 1 pt was however primarily intensified. Response was evaluated using PET-CT according to revised criteria for response assessment by Cheson et al. 2014. Of 18 pts, histology included DLBCL (n=17, 95 %) and follicular lymphoma grade IIIb (n=1, 5 %). Median age at diagnosis was 52 y (range 23-68 y), with 50 % female. Stage I/II vs. III/IV: 22 % vs. 78 %; Of stage I/II pts, 2 had a bulky disease, 1 pt had a testicular lymphoma and 1 pt had orbital involvement; B-symptoms: 44 %; LDH was elevated in all pts; ECOG > 1: 33 %; Extranodal site ≥ 2: 61 %; According to IPI and aaIPI 16 pts (89 %) had an intermediate high and high risk score. Median follow-up was 15.6 month (range 0.4 - 35.9). 16 pts (89 %) completed the protocol. No treatment related deaths were observed. Toxicities were as expected and manageable; one pt could not receive 6th cycle CHOP due to severe infection. One early death was observed 4 days after 1st R-CHOP due to lymphoma infiltration of the heart and consecutive arrhythmia. All pts responded, 13 pts achieving a CR (72 %) and 4 pts a PR (22 %). Of 4 pts in PR by PET criteria 3 pts underwent second biopsy. 2 pts were lymphoma negative and 1 pt positive. The lymphoma positive pt underwent radiation of residual lymphoma masses, achieving a CR. The other pts did not receive any further treatment and are retrospectively in CR with a prior false positive PET-CT Scan. For all pts estimated 18m-OS was 94.5% and 2y-PFS was 94.5%. No CNS events occurred. This data compared favourable to own historic controls using an R-CHOP based induction followed by R-VCPE intensification and autologous transpplantation after BEAM in 133 high-risk patients with 3y-OS of 68%. Dose intensification with rituximab, CHOP and MTX is feasible for high risk DLBCL pts <65 y, showing promising results regarding ORR, progression-free and overall survival. In our cohort no CNS relapse was yet observed. Longer follow-up and larger cohort is required to confirm our results. DisclosuresNo relevant conflicts of interest to declare.

The Final Oral/Practical State Examination at Freiburg Medical Faculty in 2012--Analysis of grading to test quality assurance.

Aim: The aim of this study is to analyze the grades given for the oral/practical part of the German State Examination at the Medical Faculty of Freiburg. We examined whether or not the grades given for the written and the oral/practical examinations correlated and if differences in grading between the Freiburg University Medical Center (UMC) and the other teaching hospitals could be found.In order to improve the quality of the state examination, the medical school has been offering standardized training for examiners for several years. We evaluated whether or not trained and untrained examiners differed in their grading of the exam and how these differences have changed over time.Methods: The results of the 2012 spring and fall exams were analyzed (N=315). The relevant data set was made available to us by the Baden-Württemberg Examination Office (Landesprüfungsamt). The data were analyzed by means of descriptive and inferential statistics.Results: We observed a correlation of ρ=0.460** between the grades for the written and the oral/practical exams. The UMC and the teaching hospitals did not differ significantly in their grade distributions. Compared to untrained examiners, trained ones assigned the grade of “very good” less often. Furthermore, they displayed a significantly higher variance in the grades given (p=0.007, phi=0.165). This effect is stronger when concentrating specifically on those examiners who took part in the training less than a year before.Conclusion: The results of this study suggest that the standardized training for examiners at the Medical Faculty of Freiburg is effective for quality assurance. As a consequence, more examiners should be motivated to take part in the training.

Conditional survival analysis of Multiple Myeloma patients: experience of the Comprehensive Cancer Center Freiburg (CCCF) University Medical Center Freiburg

The high-level production of antibody molecules by multiple myeloma (MM) cells makes them susceptible to killing by bortezomib and other proteosome inhibitors, but may also make normal plasma cells (PC, responsible for sustaining protective antibody titers elicited by vaccination or infection) susceptible to these agents. This in turn may make bortezomib-treated patients susceptible to reinfection and would necessitate re-immunization. However, it has not been determined if bortezomib treatment actually affects normal PC and compromises vaccine-induced antibody titers in patients. The primary objective of our study is to determine whether bortezomib treatment affects the antibody titers against common viral and vaccine antigens. 25 newly diagnosed MM patients patients (to date) treated with bortezomib + dexamethasone (with the later addition of lenalidomide in some patients) were assayed for antibody titers against mumps (IgG), rubella (IgG), Epstein Barr (IgG), varicella zoster, tetanus and diptheria prior to treatment, and then after 1, 3, 6 cycles of treatment and 4 months after completion. Unexpectedly, we found that bortezomib treatment either had no effect, or significantly increased some (but not all) antibody titers in individual patients (Fig. 1). 52% of the patients had increases in titers against EBV, 48% against mumps, 40% against varicella, 32% against rubella, 12% against diphtheria and 8% against tetanus. Since normal PC do not proliferate, this reconstitution of antibody titers in patients that were not re-vaccinated suggests previously unrecognized and novel plasma cell biology. PO-168 Conditional survival analysis of Multiple Myeloma patients: experience of the Comprehensive Cancer Center Freiburg (CCCF) University Medical Center Freiburg J.M. Waldschmidt, I. Promny, S. Hieke, M. Schinke, G. Ihorst, M. Pantic, J. Duyster, R. Wasch, M. Schumacher, M. Engelhardt University of Freiburg Medical Center, Department of Hematology, Oncology and Stem Cell Transplantation; Institute of Medical Biometry and Medical Informatics, University Medical Center Freiburg; Clinical Trials Unit, University of Freiburg Medical Center, Freiburg, Germany

The Effect Of Bortezomib Treatment On Antibody Titers Against Common Viral And Vaccine Antigens

The high-level production of antibody molecules by multiple myeloma (MM) cells makes them susceptible to killing by bortezomib and other proteosome inhibitors, but may also make normal plasma cells (PC, responsible for sustaining protective antibody titers elicited by vaccination or infection) susceptible to these agents. This in turn may make bortezomib-treated patients susceptible to reinfection and would necessitate re-immunization. However, it has not been determined if bortezomib treatment actually affects normal PC and compromises vaccine-induced antibody titers in patients. The primary objective of our study is to determine whether bortezomib treatment affects the antibody titers against common viral and vaccine antigens. 25 newly diagnosed MM patients patients (to date) treated with bortezomib + dexamethasone (with the later addition of lenalidomide in some patients) were assayed for antibody titers against mumps (IgG), rubella (IgG), Epstein Barr (IgG), varicella zoster, tetanus and diptheria prior to treatment, and then after 1, 3, 6 cycles of treatment and 4 months after completion. Unexpectedly, we found that bortezomib treatment either had no effect, or significantly increased some (but not all) antibody titers in individual patients (Fig. 1). 52% of the patients had increases in titers against EBV, 48% against mumps, 40% against varicella, 32% against rubella, 12% against diphtheria and 8% against tetanus. Since normal PC do not proliferate, this reconstitution of antibody titers in patients that were not re-vaccinated suggests previously unrecognized and novel plasma cell biology. PO-168 Conditional survival analysis of Multiple Myeloma patients: experience of the Comprehensive Cancer Center Freiburg (CCCF) University Medical Center Freiburg J.M. Waldschmidt, I. Promny, S. Hieke, M. Schinke, G. Ihorst, M. Pantic, J. Duyster, R. Wasch, M. Schumacher, M. Engelhardt University of Freiburg Medical Center, Department of Hematology, Oncology and Stem Cell Transplantation; Institute of Medical Biometry and Medical Informatics, University Medical Center Freiburg; Clinical Trials Unit, University of Freiburg Medical Center, Freiburg, Germany

Characterization of a novel genetic defect causing plasma cell deficiency

Event Abstract Back to Event Characterization of a novel genetic defect causing plasma cell deficiency Desirée Schubert1, 2*, Janine Kemming1, Sarah Hassdenteufel3, Marie-Christine Klein3, Johannes Kühn1, Manfred Fliegauf1, Sandra Winzer1, Alejandro Schäffer4, Jennifer Puck5, Robert Hostoffer6, Anna Köttgen7, Marta Rizzi8, Hermann Eibel1, Richard Zimmermann3 and Bodo Grimbacher1 1 Center for Chronic Immunodeficiency, University Medical Center Freiburg, Germany 2 Spemann Graduate School of Biology and Medicine, Freiburg University, Germany 3 Medical Biochemistry & Molecular Biology, Saarland University, Homburg, Germany 4 National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States 5 Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, United States 6 University Hospitals Case Medical Center, Cleveland, Ohio, United States 7 Department of Medicine, Division of Nephrology, University Medical Center Freiburg, Germany 8 Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Germany Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency in humans. It is characterized by hypogammaglobulinemia, absent vaccination responses and recurrent infections. We are working on the identification of the genetic defect in a family with autosomal dominant CVID. The clinical phenotype is mostly restricted to severe recurrent infections of the upper and lower respiratory tract. Flow cytometric analysis revealed that the patients have normal B and T cell populations in the periphery. However, in in vitro activation assays, the patient’s B cells were less capable of generating CD27+CD38++ plasmablasts and secreting IgG. By the combination of linkage analysis and whole exome sequencing, we identified two novel mutations in the linkage region, one of them in a protein involved in the immune response. The segregation of this mutation with the disease phenotype in the family was verified by Sanger Sequencing. Multiple myeloma cells did not survive the overexpression of the mutated gene while they tolerated the wild type protein. Overexpression of the mutant variant in other cells like B cells, T cells, monocytes and Hek293T cells did not affect their survival, indicating that the detrimental effects of this mutant are restricted to plasma cells. The underlying pathomechanism might reveal novel insights into plasma cell homeostasis and support the development of therapeutic strategies to treat CVID patients with an infection-only phenotype. Keywords: immunodeficiency, Clinical Immunology, B cells, Plasma Cells, hypogammaglobulinemia, Mutation Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Oral Presentation Topic: Immunodeficiencies Citation: Schubert D, Kemming J, Hassdenteufel S, Klein M, Kühn J, Fliegauf M, Winzer S, Schäffer A, Puck J, Hostoffer R, Köttgen A, Rizzi M, Eibel H, Zimmermann R and Grimbacher B (2015). Characterization of a novel genetic defect causing plasma cell deficiency. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00350 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 May 2015; Published Online: 15 Sep 2015. * Correspondence: Ms. Desirée Schubert, Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freibug, Germany, desiree.schubert@uniklinik-freiburg.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Desirée Schubert Janine Kemming Sarah Hassdenteufel Marie-Christine Klein Johannes Kühn Manfred Fliegauf Sandra Winzer Alejandro Schäffer Jennifer Puck Robert Hostoffer Anna Köttgen Marta Rizzi Hermann Eibel Richard Zimmermann Bodo Grimbacher Google Desirée Schubert Janine Kemming Sarah Hassdenteufel Marie-Christine Klein Johannes Kühn Manfred Fliegauf Sandra Winzer Alejandro Schäffer Jennifer Puck Robert Hostoffer Anna Köttgen Marta Rizzi Hermann Eibel Richard Zimmermann Bodo Grimbacher Google Scholar Desirée Schubert Janine Kemming Sarah Hassdenteufel Marie-Christine Klein Johannes Kühn Manfred Fliegauf Sandra Winzer Alejandro Schäffer Jennifer Puck Robert Hostoffer Anna Köttgen Marta Rizzi Hermann Eibel Richard Zimmermann Bodo Grimbacher PubMed Desirée Schubert Janine Kemming Sarah Hassdenteufel Marie-Christine Klein Johannes Kühn Manfred Fliegauf Sandra Winzer Alejandro Schäffer Jennifer Puck Robert Hostoffer Anna Köttgen Marta Rizzi Hermann Eibel Richard Zimmermann Bodo Grimbacher Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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Decompressive Craniectomy after Severe Traumatic Brain Injury in Children: Complications and Outcome

Decompressive craniectomy (DC) is a controversially discussed neurosurgical procedure to reduce elevated intracranial pressure after severe traumatic brain injury (TBI). In contrast to adults, several studies could show a benefit for the pediatric population, but still DC is considered as an emergency procedure only. The aim of our study was to identify secondary complications and long-term sequelae of the procedure. All children presenting to the University Medical Center Freiburg between 2005 and 2013 who underwent DC after severe TBI were retrospectively reviewed with respect to complications and outcome. Twelve children were included with a mean Glasgow Coma Scale of 4.5 ± 1.7. The most frequent complications after TBI and DC were formation of hygroma (83%), aseptic bone resorption of the reimplanted bone flap (50%), posttraumatic hydrocephalus (42%), secondary infection or dysfunction of ventriculoperitoneal shunt (25%) or cranioplasty (33%), and epilepsy (33%). Because of these complications, 75% of patients required further surgery in addition to cranioplasty with up to eight interventions. At follow-up, mean Glasgow Outcome Scale was 3.3 ± 1.2. Within our patient population, we demonstrated high incidence of complications after DC, leading to further surgical procedures and longer hospitalization. These potential complications have to be considered in any decision about DC as an emergency procedure.

Construction and Clinical Validation of a Questionnaire-based Risk Score to Identify Patients Suffering from Immunodeficiency or Systemic Autoimmunity

Aims: A self-reporting tool for identifying adults at risk for immune-based diseases was designed and termed immune system assessment questionnaire (ISAQ). It was the aim of this study to validate this novel questionnaire in groups of patients with defined immunodeficiency or autoimmune diseases in comparison to normal adults. Study Design: Non-randomised, cross-sectional observational study in groups of Original Research Article British Journal of Medicine & Medical Research, 4(29): 4751-4769, 2014 4752 patients and normal adults. Place and Duration of Study: Department of Rheumatology and Clinical Immunology and Clinical Epidemiology Group, Institute of Medical Biometry and Medical Informatics University Medical Center Freiburg, Germany. Questionnaires from patients and controls were collected between March 2005 and November 2010. Methodology: Two experienced clinical immunologists selected 17 informative topics including frequency and duration of infections, previous surgery on immunological organs, recent polytrauma, vaccination history, allergies, co-morbidities, use of antibiotics and immunomodulating agents. The ensuing questions were differently weighted based on published evidence and assumed relevance for immunological dysfunction. The questionnaire was distributed to 539 cases suffering from chronic immunodeficiency (n=322) or autoimmunity (n=217) and to 1020 healthy controls. An ISAQ score was calculated for each participant based on the sum of the weighted items. Results: The median ISAQ-score was 39.5 for cases and 30.4 for controls. 93.7% of all controls scored lower than the median of the cases, which resulted in an AUC of the ROC curve of 0.838 (95%CI: 0.817-0.859). Items with highest predictive value were frequency and duration of infections, use of antibiotics, corticosteroids, immunosuppressants, sinus-mucosa resection, chronic disease of kidney, lungs, gut and hematopoietic system. Although the results indicate that neither the item selection nor the weighting of single items were optimal, several sub-scores with reduced item number could not substitute for the whole ISAQ. Conclusion: The ISAQ can discriminate between healthy individuals and persons suffering from immune-based disease. The ISAQ performs better for chronic immunodeficiency than for chronic rheumatic diseases; the highest values were obtained for common variable immunodeficiency (CVID) and systemic vasculitides. Future studies are needed to refine item selection and validate the score for predicting immune dysfunction.

Terminally Ill Patients as Customers: The Patient's Perspective

Consumerism in health care defines patients as self-determined, rational customers. Yet, it is questionable whether vulnerable patients, such as the terminally ill, also fulfill these criteria. Vulnerable contexts and the patient's perspective on being a customer remain relatively unexplored. The present study addresses this research gap by analyzing terminally ill patients' views on being customers. To explore the ways in which patients in palliative care refer to themselves as patients/customers, and how the patients' concepts of self-determination are related to their attitudes toward the patient/customer role. Qualitative interviews were conducted. Data were analyzed in three steps: narrative analysis, thematic content analysis, and typology construction. Researchers recruited 25 patients via the Department of Palliative Care, University Medical Center Freiburg, Germany. In many ways, palliative patients contradict the image of a self-determined customer. The palliative patient role is characterized by the concept of relational self-determination rather than an unrestricted self-determination. Self-attribution as a customer still occurs when positively associated with a person-centered, individualized treatment. Thus, the customer and patient role overlap within the palliative care setting because of the focus on the individual. The idealized customer role cannot be arbitrarily applied to all medical fields. Palliative patients are dependent on the physician, regardless of whether the customer or patient role is preferred. Hence, self-determination must be understood in relational terms, and physicians must recognize their crucial role in promoting patients' self-determination in the context of shared decision-making.

Game-Based E-Learning Is More Effective than a Conventional Instructional Method: A Randomized Controlled Trial with Third-Year Medical Students

BackgroundWhen compared with more traditional instructional methods, Game-based e-learning (GbEl) promises a higher motivation of learners by presenting contents in an interactive, rule-based and competitive way. Most recent systematic reviews and meta-analysis of studies on Game-based learning and GbEl in the medical professions have shown limited effects of these instructional methods.ObjectivesTo compare the effectiveness on the learning outcome of a Game-based e-learning (GbEl) instruction with a conventional script-based instruction in the teaching of phase contrast microscopy urinalysis under routine training conditions of undergraduate medical students.MethodsA randomized controlled trial was conducted with 145 medical students in their third year of training in the Department of Urology at the University Medical Center Freiburg, Germany. 82 subjects where allocated for training with an educational adventure-game (GbEl group) and 69 subjects for conventional training with a written script-based approach (script group). Learning outcome was measured with a 34 item single choice test. Students' attitudes were collected by a questionnaire regarding fun with the training, motivation to continue the training and self-assessment of acquired knowledge.ResultsThe students in the GbEl group achieved significantly better results in the cognitive knowledge test than the students in the script group: the mean score was 28.6 for the GbEl group and 26.0 for the script group of a total of 34.0 points with a Cohen's d effect size of 0.71 (ITT analysis). Attitudes towards the recent learning experience were significantly more positive with GbEl. Students reported to have more fun while learning with the game when compared to the script-based approach.ConclusionsGame-based e-learning is more effective than a script-based approach for the training of urinalysis in regard to cognitive learning outcome and has a high positive motivational impact on learning. Game-based e-learning can be used as an effective teaching method for self-instruction.