Publications by authors named "Nisar Malek"

145 Publications

Annotation and initial evaluation of a large annotated German oncological corpus.

JAMIA Open 2021 Apr 19;4(2):ooab025. Epub 2021 Apr 19.

Knowledge Management for Bioinformatics, Humboldt Universität zu Berlin, Berlin, Germany.

Objective: We present the Berlin-Tübingen-Oncology corpus (BRONCO), a large and freely available corpus of shuffled sentences from German oncological discharge summaries annotated with diagnosis, treatments, medications, and further attributes including negation and speculation. The aim of BRONCO is to foster reproducible and openly available research on Information Extraction from German medical texts.

Materials And Methods: BRONCO consists of 200 manually deidentified discharge summaries of cancer patients. Annotation followed a structured and quality-controlled process involving 2 groups of medical experts to ensure consistency, comprehensiveness, and high quality of annotations. We present results of several state-of-the-art techniques for different IE tasks as baselines for subsequent research.

Results: The annotated corpus consists of 11 434 sentences and 89 942 tokens, annotated with 11 124 annotations for medical entities and 3118 annotations of related attributes. We publish 75% of the corpus as a set of shuffled sentences, and keep 25% as held-out data set for unbiased evaluation of future IE tools. On this held-out dataset, our baselines reach depending on the specific entity types F1-scores of 0.72-0.90 for named entity recognition, 0.10-0.68 for entity normalization, 0.55 for negation detection, and 0.33 for speculation detection.

Discussion: Medical corpus annotation is a complex and time-consuming task. This makes sharing of such resources even more important.

Conclusion: To our knowledge, BRONCO is the first sizable and freely available German medical corpus. Our baseline results show that more research efforts are necessary to lift the quality of information extraction in German medical texts to the level already possible for English.
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http://dx.doi.org/10.1093/jamiaopen/ooab025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054032PMC
April 2021

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Nature 2021 Apr 24;592(7854):450-456. Epub 2021 Mar 24.

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need. Here we report the progressive accumulation of exhausted, unconventionally activated CD8PD1 T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8PD1 T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8PD1CXCR6, TOX, and TNF T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 T cells or TNF neutralization, suggesting that CD8 T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8PD1 T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
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http://dx.doi.org/10.1038/s41586-021-03362-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046670PMC
April 2021

Mesenchymal Stem Cell Therapy for Severe COVID-19 ARDS.

J Intensive Care Med 2021 Mar 5:885066621997365. Epub 2021 Mar 5.

Department of Anaesthesiology and Intensive Care Medicine, University Hospital Tübingen, 9188Eberhard-Karls-University, Tübingen, Germany.

Background: The COVID-19 pandemic reached Germany in spring 2020. No proven treatment for SARS-CoV-2 was available at that time, especially for severe COVID-19-induced ARDS. We determined whether the infusion of mesenchymal stromal cells (MSCs) would help to improve pulmonary function and overall outcome in patients with severe COVID-19 ARDS. We offered MSC infusion as an extended indication to all critically ill COVID-19 patients with a Horovitz index <100. We treated 5 out of 23 patients with severe COVID-19 ARDS with an infusion of MSCs. One million MSCs/kg body weight was infused over 30 minutes, and the process was repeated in 3 patients twice and in 2 patients 3 times.

Result: Four out of 5 MSC-treated patients compared to 50% of control patients (9 out of 18) received ECMO support (80%). The MSC group showed a higher Murray score on admission than control patients, reflecting more severe pulmonary compromise (3.5 ± 0.2 versus 2.8 ± 0.3). MSC infusion was safe and well tolerated. The MSC group had a significantly higher Horovitz score on discharge than the control group. Compared to controls, patients with MSC treatment showed a significantly lower Murray score upon discharge than controls. In the MSC group, 4 out of 5 patients (80%) survived to discharge and exhibited good pulmonary function, whereas only 8 out of 18 patients (45%) in the control group survived to discharge.

Conclusion: MSC infusion is a safe treatment for COVID-19 ARDS that improves pulmonary function and overall outcome in this patient population.
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http://dx.doi.org/10.1177/0885066621997365DOI Listing
March 2021

Severe SARS-CoV-2 Infection Inhibits Fibrinolysis Leading to Changes in Viscoelastic Properties of Blood Clot: A Descriptive Study of Fibrinolysis in COVID-19.

Thromb Haemost 2021 Feb 25. Epub 2021 Feb 25.

Center for Clinical Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany.

Background:  Accumulating evidence indicates toward an association between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and procoagulatory state in blood. Thromboelastographic investigations are useful point-of-care devices to assess coagulation and fibrinolysis.

Objectives:  We investigated the hypothesis that the procoagulatory state in COVID-19 patients is associated with impaired fibrinolysis system.

Methods:  Altogether, 29 COVID-19 patients admitted to normal wards or to the intensive care unit (ICU) were included in this descriptive study. Whole blood samples were investigated by thromboelastography to assess coagulation and fibrinolysis. Additionally, standard routine coagulation testing and immunoassays for factors of fibrinolysis as plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), plasminogen activity and α2-antiplasmin (A2AP) were performed.

Results:  A significantly increased lysis resistance and a significantly longer time of lysis after adding tissue plasminogen activator were observed in blood samples from ICU COVID-19 patients compared with healthy controls (maximal lysis: 3.25 ± 0.56 vs. 6.20 ± 0.89%,  = 0.0127; lysis time: 365.7 ± 44.6 vs. 193.2 ± 16.3 seconds,  = 0.0014). PAI-1 activity was significantly higher in plasma samples of ICU COVID-19 patients (PAI-1: 4.92 ± 0.91 vs. 1.28 ± 0.33 U/mL,  = 0.001). A positive correlation between the activity of PAI-1 and lysis time of the formed clot ( = 0.70,  = 0.0006) was observed.

Conclusion:  Our data suggest that severe SARS-CoV-2 infection is associated with impaired fibrinolytic activity in blood, where fibrinolytic inhibitors are elevated leading to an increased resistance to clot lysis. Thromboelastography could offer a tool to investigate the contribution of the fibrinolytic status to the procoagulatory condition in COVID-19.
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http://dx.doi.org/10.1055/a-1400-6034DOI Listing
February 2021

Sonographic findings in coronavirus disease-19 associated liver damage.

PLoS One 2021 19;16(2):e0244781. Epub 2021 Feb 19.

Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Tübingen, Germany.

Purpose: This study was conducted to evaluate the role of liver sonography in patients with coronavirus disease 2019 (COVID-19) and elevated liver enzymes.

Materials And Methods: In this retrospective study, patients tested positive for SARS-CoV-2 in our emergency ward between January 01 and April 24, 2020 and elevated liver enzymes were included (Cohort 1). Additionally, the local radiology information system was screened for sonographies in COVID-19 patients at the intensive care unit in the same period (Cohort 2). Liver sonographies and histologic specimen were reviewed and suspicious findings recorded. Medical records were reviewed for clinical data. Ultrasound findings and clinical data were correlated with severity of liver enzyme elevation.

Results: Cohort 1: 126 patients were evaluated, of which 47 (37.3%) had elevated liver enzymes. Severity of liver enzyme elevation was associated with death (p<0.001). 8 patients (6.3%) had suspicious ultrasound findings, including signs of acute hepatitis (n = 5, e.g. thickening of gall bladder wall, hepatomegaly, decreased echogenicity of liver parenchyma) and vascular complications (n = 4). Cohort 2: 39 patients were evaluated, of which 14 are also included in Cohort 1. 19 patients (48.7%) had suspicious ultrasound findings, of which 13 patients had signs of acute hepatitis and 6 had vascular complications. Pathology was performed in 6 patients. Predominant findings were severe cholestasis and macrophage activation.

Conclusion: For most hospitalized COVID-19 patients, elevated liver enzymes cause little concern as they are only mild to moderate. However, in severely ill patients bedside sonography is a powerful tool to reveal different patterns of vascular, cholestatic or inflammatory complications in the liver, which are associated with high mortality. In addition, macrophage activation as histopathologic correlate for a hyperinflammatory syndrome seems to be a frequent complication in COVID-19.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244781PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894893PMC
March 2021

Antibody-induced procoagulant platelets in severe COVID-19 infection.

Blood 2021 02;137(8):1061-1071

Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tuebingen, Tuebingen, Germany.

The pathophysiology of COVID-19-associated thrombosis seems to be multifactorial. We hypothesized that COVID-19 is accompanied by procoagulant platelets with subsequent alteration of the coagulation system. We investigated depolarization of mitochondrial inner transmembrane potential (ΔΨm), cytosolic calcium (Ca2+) concentration, and phosphatidylserine (PS) externalization. Platelets from COVID-19 patients in the intensive care unit (ICU; n = 21) showed higher ΔΨm depolarization, cytosolic Ca2+, and PS externalization compared with healthy controls (n = 18) and non-ICU COVID-19 patients (n = 4). Moreover, significant higher cytosolic Ca2+ and PS were observed compared with a septic ICU control group (ICU control; n = 5). In the ICU control group, cytosolic Ca2+ and PS externalization were comparable with healthy controls, with an increase in ΔΨm depolarization. Sera from COVID-19 patients in the ICU induced a significant increase in apoptosis markers (ΔΨm depolarization, cytosolic Ca2+, and PS externalization) compared with healthy volunteers and septic ICU controls. Interestingly, immunoglobulin G fractions from COVID-19 patients induced an Fcγ receptor IIA-dependent platelet apoptosis (ΔΨm depolarization, cytosolic Ca2+, and PS externalization). Enhanced PS externalization in platelets from COVID-19 patients in the ICU was associated with increased sequential organ failure assessment score (r = 0.5635) and D-dimer (r = 0.4473). Most importantly, patients with thrombosis had significantly higher PS externalization compared with those without. The strong correlations between markers for apoptosic and procoagulant platelets and D-dimer levels, as well as the incidence of thrombosis, may indicate that antibody-mediated procoagulant platelets potentially contributes to sustained increased thromboembolic risk in ICU COVID-19 patients.
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http://dx.doi.org/10.1182/blood.2020008762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791311PMC
February 2021

Curbing gastrointestinal infections by defensin fragment modifications without harming commensal microbiota.

Commun Biol 2021 Jan 8;4(1):47. Epub 2021 Jan 8.

Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.

The occurrence and spread of multidrug-resistant pathogens, especially bacteria from the ESKAPE panel, increases the risk to succumb to untreatable infections. We developed a novel antimicrobial peptide, Pam-3, with antibacterial and antibiofilm properties to counter this threat. The peptide is based on an eight-amino acid carboxyl-terminal fragment of human β-defensin 1. Pam-3 exhibited prominent antimicrobial activity against multidrug-resistant ESKAPE pathogens and additionally eradicated already established biofilms in vitro, primarily by disrupting membrane integrity of its target cell. Importantly, prolonged exposure did not result in drug-resistance to Pam-3. In mouse models, Pam-3 selectively reduced acute intestinal Salmonella and established Citrobacter infections, without compromising the core microbiota, hence displaying an added benefit to traditional broad-spectrum antibiotics. In conclusion, our data support the development of defensin-derived antimicrobial agents as a novel approach to fight multidrug-resistant bacteria, where Pam-3 appears as a particularly promising microbiota-preserving candidate.
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http://dx.doi.org/10.1038/s42003-020-01582-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794397PMC
January 2021

Clinical and Genetic Tumor Characteristics of Responding and Non-Responding Patients to PD-1 Inhibition in Hepatocellular Carcinoma.

Cancers (Basel) 2020 Dec 18;12(12). Epub 2020 Dec 18.

Department Internal Medicine I, Eberhard-Karls University, 72076 Tuebingen, Germany.

Immune checkpoint inhibitors (ICIs) belong to the therapeutic armamentarium in advanced hepatocellular carcinoma (HCC). However, only a minority of patients benefit from immunotherapy. Therefore, we aimed to identify indicators of therapy response. This multicenter analysis included 99 HCC patients. Progression-free (PFS) and overall survival (OS) were studied by Kaplan-Meier analyses for clinical parameters using weighted log-rank testing. Next-generation sequencing (NGS) was performed in a subset of 15 patients. The objective response (OR) rate was 19% median OS (mOS)16.7 months. Forty-one percent reached a PFS > 6 months; these patients had a significantly longer mOS (32.0 vs. 8.5 months). Child-Pugh (CP) A and B patients showed a mOS of 22.1 and 12.1 months, respectively. Ten of thirty CP-B patients reached PFS > 6 months, including 3 patients with an OR. Tumor mutational burden (TMB) could not predict responders. Of note, antibiotic treatment within 30 days around ICI initiation was associated with significantly shorter mOS (8.5 vs. 17.4 months). Taken together, this study shows favorable outcomes for OS with low AFP, OR, and PFS > 6 months. No specific genetic pattern, including TMB, could identify responders. Antibiotics around treatment initiation were associated with worse outcome, suggesting an influence of the host microbiome on therapy success.
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http://dx.doi.org/10.3390/cancers12123830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766321PMC
December 2020

Evaluation of bowel wall thickness by ultrasound as early diagnostic tool for therapeutic response in Crohn's disease patients treated with ustekinumab.

Z Gastroenterol 2020 Nov 24. Epub 2020 Nov 24.

Medizinische Klinik I, Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Uniklinik Tübingen, Germany.

Background:  Ustekinumab was approved for the treatment of patients with moderate to severe CD 2. Development of predictors for selecting patients responding to ustekinumab has to be the next step. US offers a noninvasive method with great sensitivity in detecting CD activity 11.

Aim:  To evaluate BWT by BS as early diagnostic tool for treatment response in CD patients treated with ustekinumab at week 8.

Methods:  This is a prospective monocentric study. Twenty-three CD patients had BS at the time of first and second application. BS was performed by one of 2 experienced DEGUM certificated sonographers, with evaluation by both independently and blindly. Primary endpoint was substantial sonographic response defined as decrease of BWT ≥ 1 mm. Secondary endpoint was concordance between sonographic and clinical response, defined as decrease of CDAI ≥ 70 points and sonographic and biochemical response defined as decrease of CRP ≥ 0.5 mg/dl.

Results:  At week 8, BS detected in 10 of 23 patients a substantial decrease of BWT ≥ 1 mm; in 7, a decrease < 1 mm. Compared to baseline, all 17 patients showed generally improved blood data and 16/17 generally improved clinical data. Of those with a decrease of BWT ≥ 1 mm, we observed a substantial decrease of CDAI ≥ 70 points in 9/10 patients and a substantial decrease of CRP ≥ 0.5 mg/dl in 8/10 patients.

Conclusion:  Our study suggests that sonographic measurement of BWT can be a helpful parameter for selecting patients responding early to ustekinumab and for providing assistance in terms of further treatment interval at week 8.
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http://dx.doi.org/10.1055/a-1283-6550DOI Listing
November 2020

Impact of the COVID-19 pandemic on an interdisciplinary endoscopy unit in a German "hotspot" area: a single center experience.

Surg Endosc 2020 Nov 2. Epub 2020 Nov 2.

Department of Gastroenterology, Hepatology, Gastrointestinal Oncology, Geriatrics and Infectious Diseases, University Hospital Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.

Background And Study Aims: Since December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of coronavirus disease 2019 (COVID-19), has posed a pandemic threat to global health and has challenged health care system in all affected countries.

Patients And Methods: This is a combined study including a descriptive part about the changes in the daily work routine of an Interdisciplinary Endoscopic Unit (IEU) and a prospective analysis of patients tested positive for SARS-CoV-2 who required endoscopic interventions. Conclusively, we present the finding of a point-prevalence analysis in the staff of the IEU.

Results: We present effects of the COVID-19-related restructuring of processes in our interdisciplinary endoscopy unit (IEU) with respect to cancelation of examinations, relocation of staff to other departments, impact of SARS-CoV-2 on medical staff of the IEU, and supply of protective clothing. Additionally, we analyzed the cohort of COVID-19 patients: Sixteen endoscopic interventions were done in ten patients. In all patients with confirmed infection with SARS-CoV-2, emergency endoscopies were required for relevant bleeding situations. Re-endoscopies were required only in critically ill COVID-19 patients.

Conclusions: The restructuring of processes in the IEU was feasible in short time, effective, and can also be applied broadly at least in developed countries [Garbe et al. in Gastroenterology 159:778-780, 2020; Repici A, Pace F, Gabbiadini R, Colombo M, Hassan C, Dinelli M, Group IG-CW, Maselli R, Spadaccini M, Mutignani M, Gabbrielli A, Signorelli C, Spada C, Leoni P, Fabbri C, Segato S, Gaffuri N, Mangiavillano B, Radaelli F, Salerno R, Bargiggia S, Maroni L, Benedetti A, Occhipinti P, De Grazia F, Ferraris L, Cengia G, Greco S, Alvisi C, Scarcelli A, De Luca L, Cereatti F, Testoni PA, Mingotto R, Aragona G, Manes G, Beretta P, Amvrosiadis G, Cennamo V, Lella F, Missale G, Lagoussis P, Triossi O, Giovanardi M, De Roberto G, Cantu P, Buscarini E, Anderloni A, Carrara S, Fugazza A, Galtieri PA, Pellegatta G, Antonelli G, Rosch T, Sharma P (2020) Endoscopy units and the COVID-19 Outbreak: a Multi-Center Experience from Italy. Gastroenterology;]. The endoscopy-related rate of SARS-CoV-2 infection of staff is low, but supply of protective equipment is crucial for this. Endoscopic procedures in COVID-19 patients were not directly related to SARS-CoV-2 infection, but to other underlying diseases or typical complications of long-term ICU treatment.
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http://dx.doi.org/10.1007/s00464-020-08119-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605334PMC
November 2020

Human β-defensin-2 suppresses key features of asthma in murine models of allergic airways disease.

Clin Exp Allergy 2021 Jan 11;51(1):120-131. Epub 2020 Nov 11.

Priority Research Centre for Healthy Lungs, University of Newcastle, & Hunter Medical Research Institute, Newcastle, NSW, Australia.

Background: Asthma is an airway inflammatory disease and a major health problem worldwide. Anti-inflammatory steroids and bronchodilators are the gold-standard therapy for asthma. However, they do not prevent the development of the disease, and critically, a subset of asthmatics are resistant to steroid therapy.

Objective: To elucidate the therapeutic potential of human β-defensins (hBD), such as hBD2 mild to moderate and severe asthma.

Methods: We investigated the role of hBD2 in a steroid-sensitive, house dust mite-induced allergic airways disease (AAD) model and a steroid-insensitive model combining ovalbumin-induced AAD with C muridarum (Cmu) respiratory infection.

Results: In both models, we demonstrated that therapeutic intranasal application of hBD2 significantly reduced the influx of inflammatory cells into the bronchoalveolar lavage fluid. Furthermore, key type 2 asthma-related cytokines IL-9 and IL-13, as well as additional immunomodulating cytokines, were significantly decreased after administration of hBD2 in the steroid-sensitive model. The suppression of inflammation was associated with improvements in airway physiology and treatment also suppressed airway hyper-responsiveness (AHR) in terms of airway resistance and compliance to methacholine challenge.

Conclusions And Clinical Relevance: These data indicate that hBD2 reduces the hallmark features and has potential as a new therapeutic agent in allergic and especially steroid-resistant asthma.
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http://dx.doi.org/10.1111/cea.13766DOI Listing
January 2021

Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer.

Cell Death Dis 2020 10 17;11(10):875. Epub 2020 Oct 17.

Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.

Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC. Consistently, pharmacologic and genetic inhibition of BCL-XL induced apoptosis in human CRC cell lines. In a combined treatment approach, targeting BCL-XL augmented the efficacy of chemotherapy in vitro, in a murine CRC model, and in human ex vivo derived CRC tissue cultures. Collectively, these data show that targeting of BCL-XL is efficient and safe in preclinical CRC models, observations that pave the way for clinical translation.
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http://dx.doi.org/10.1038/s41419-020-03092-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568722PMC
October 2020

Next-Generation Sequencing of Advanced GI Tumors Reveals Individual Treatment Options.

JCO Precis Oncol 2020 30;4. Epub 2020 Mar 30.

Department of Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany.

Purpose: Precision oncology connects highly complex diagnostic procedures with patient histories to identify individualized treatment options in interdisciplinary molecular tumor boards (MTBs). Detailed data on MTB-guided treatments and outcome with a focus on advanced GI cancers have not been reported yet.

Patients And Methods: Next-generation sequencing of tumor and normal tissue pairs was performed between April 2016 and February 2018. After identification of relevant molecular alterations, available clinical studies or in-label, off-label, or matched experimental treatment options were recommended. Follow-up data and a response assessment that was based on radiologic imaging were recorded.

Results: Ninety-six patients were presented to the MTB of Tuebingen University Hospital. Sixteen (17%) showed "pathogenic" or "likely pathogenic" germline variants. Recommendations on the basis of molecular alterations or tumor mutational burden were given for 41 patients (43%). Twenty-five received the suggested drug, and 20 were evaluable for best response assessment. Three patients (15%) reached a partial response (PR), and 6 (30%), stable disease (SD), whereas 11 (55%) had tumor progression (progressive disease). Median progression-free survival (PFS) for all treated and evaluable patients was 2.8 months (range, 1.0-9.0 months), and median overall survival (OS) of all treated patients was 5.2 months (range, 0.1 months to not reached). Patients with SD for ≥ 3 months or PR compared with progressive disease showed both a statistically significant longer median PFS (7.8 months [95% CI, 4.2 to 11.4 months] 2.2 months [95% CI, 1.5 to 2.8 months], < .0001) and median OS (18.0 months [95% CI, 10.4 to 25.6 months] 3.8 months [95% CI, 2.3 to 5.4 months], < .0001).

Conclusion: Next-generation sequencing diagnostics of advanced GI cancers identified a substantial number of pathogenic or likely pathogenic germline variants and unique individual treatment options. Patients with PR or SD in the course of MTB-recommended treatments seemed to benefit with respect to PFS and OS.
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http://dx.doi.org/10.1200/PO.19.00359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446530PMC
March 2020

Depatux-M and temozolomide in advanced high-grade glioma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa063. Epub 2020 Jun 6.

Department of Neurology and Interdisciplinary Neuro-Oncology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany.

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http://dx.doi.org/10.1093/noajnl/vdaa063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367419PMC
June 2020

Test and treat COVID 65 plus - Hydroxychloroquine versus placebo in early ambulatory diagnosis and treatment of older patients with COVID19: A structured summary of a study protocol for a randomised controlled trial.

Trials 2020 Jul 10;21(1):635. Epub 2020 Jul 10.

Department of Internal Medicine 1, University Hospital Tübingen, Tübingen, Germany.

Objectives: The aim of this trial is to identify the effect of ambulatory treatment in early COVID-19 disease with hydroxychloroquine on the rate of hospitalization or death in older patients above the age of 64.

Trial Design: Parallel, 2:1 randomization, double blind, placebo-controlled, multi-center trial.

Participants: Male and female patients above the age of 64 (i.e. ≥65 years of age) with COVID-19 diagnosis confirmed by SARS-CoV2 positive throat swab (PCR). Patients can only be included within 3 days of symptom onset in ambulatory care if they consent to the study procedure and are able to adhere to the study visit schedule and protocol requirements (including telephone visits concerning symptoms and side effects). Severity of disease at inclusion is mild to moderate defined as not requiring hospital admission: SpO2 >94%, respiratory rate <20, mental state alert, no signs of septic shock. Cardiac risk is minimised by requiring a Tisdale score ≤ 6. Patients are recruited in the two german cities of Ulm and Tübingen in various ambulatory care settings.

Intervention And Comparator: Each patient will be given a first dose of 600 mg Hydroxychloroquine or the equivalent number of placebo capsules (3 capsules) at the day of inclusion. From the 2 day on, each patient will get 200 mg or the equivalent number of placebo capsules twice a day (400mg/day) until day 7 (6 more does of 400 mg); a cumulative dose of 3 g.

Main Outcomes: Rate of hospitalization or death at day 7 after study inclusion RANDOMISATION: All consenting adult patients having confirmed COVID-19 are randomly and blindly allocated in a 2:1 ratio to either IMP or placebo. The biostatistical center produced a randomization list (block randomization) with varying block length and stratified for the study center. This list is provided for packaging to the pharmaceutical unit which is providing encapsulated placebo and IMP. Only the pharmaceutical unit is aware of group allocation according to the randomization list.

Blinding (masking): Patients and investigators, as well as treating physicians are blinded to the treatment- allocation.

Numbers To Be Randomised (sample Size): In the first stage of an adaptive design 120 patients in a 2:1 ration: 72 Verum and 36 Placebo, plus an increase for 10% drop outs. After interim analysis, the total sample size will be calculated based on the effect seen in the first stage. Total sample size is estimated approximately n = 300-400 patients.

Trial Status: Protocol version number: V3, 19.05.2020 Recruitment not yet started but is anticipated to begin by June 2020 and be complete by December 2020 TRIAL REGISTRATION: ClinicalTrials.gov: NCT04351516 , date: 17 April 2020 EudraCT: 2020-001482-37, date: 30 March 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-020-04556-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348125PMC
July 2020

Fragmentation of Human Neutrophil α-Defensin 4 to Combat Multidrug Resistant Bacteria.

Front Microbiol 2020 3;11:1147. Epub 2020 Jun 3.

Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, Human Genomics and Metagenomics in Metabolism, University of Copenhagen, Copenhagen, Denmark.

The occurrence and spread of multidrug-resistant bacteria is a prominent health concern. To curb this urgent threat, new innovative strategies pursuing novel antimicrobial agents are of the utmost importance. Here, we unleashed the antimicrobial activity of human neutrophil peptide-4 (HNP-4) by tryptic digestion. We identified a single 11 amino acid long fragment (HNP-4) with remarkable antimicrobial potential, exceeding that of the full length peptide on both mass and molar levels. Importantly, HNP-4 was equally bactericidal against multidrug-resistant and non-resistant strains; a potency that was further enhanced by N- and C-terminus modifications (acetylation and amidation, respectively). These observations, combined with negligible cytotoxicity not exceeding that of the full length peptide, presents proteolytic digestion of innate host-defense-peptides as a novel strategy to overcome the current health crisis related to antibiotic-resistant bacteria.
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http://dx.doi.org/10.3389/fmicb.2020.01147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286198PMC
June 2020

Impact of implementing a non-restrictive antibiotic stewardship program in an emergency department: a four-year quasi-experimental prospective study.

Sci Rep 2020 05 18;10(1):8194. Epub 2020 May 18.

Division of Infectious Diseases, Department of Internal Medicine I, German Center for Infection Research, University of Tübingen, Otfried Müller Straße 12, 72074, Tübingen, Germany.

Antibiotic resistance is increasing worldwide. The implementation of antibiotic stewardship programmes (ASPs) is of utmost importance to optimize antibiotic use in order to prevent resistance development without harming patients. The emergency department (ED), cornerstone between hospital and community, represents a crucial setting for addressing ASP implementation; however, evidence data on ASP in ED are poor. In this study, a 4-year, non-restrictive, multi-faceted ASP was implemented in a general ED with the aim to evaluate its impact on antibiotic use and costs. Secondly, the study focused on assessing the impact on length of hospital stay (LOS), Clostridioides difficile infection (CDI) incidence rate, and mortality in the patients' group admitted from ED to medical wards. The ASP implementation was associated with a reduction of antibiotic use and costs. A mild but sustained LOS decrease in all medical wards and a significant downward trend of CDI incidence rate were observed, while mortality did not significantly change. In conclusion, the implementation of our ED-based ASP has demonstrated to be feasible and safe and might clinically benefit the hospital admitted patients' group. Further research is needed to identify the most suitable ASP design for ED and the key outcome measures to reliably assess its effectiveness.
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http://dx.doi.org/10.1038/s41598-020-65222-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235006PMC
May 2020

Dysregulation of Carnosine Metabolism in Progression of Diseases.

Curr Med Chem 2020;27(11):1713

Department of Internal Medicine I, Faculty of Medicine, Tubingen University, Otfried-Müller-Strasse 10, 72076 Tubingen, Germany.

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http://dx.doi.org/10.2174/092986732711200423112140DOI Listing
July 2020

Quality of life in inflammatory bowel diseases: it is not all about the bowel.

Intest Res 2021 Jan 27;19(1):45-52. Epub 2020 Feb 27.

Division of Gastroenterology, Hepatology, Infectious Diseases, Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.

Background/aims: The inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) are chronic diseases mostly affecting young patients. As they are diseases accompanying patients for their entire life, and the quality of life (QUOL) interacts with disease activity, improving QUOL should be one of the main goals of therapy. This study aims to identify factors contributing to good or impaired QUOL.

Methods: Questionnaires addressing health-related QUOL and other psychological and social features were positioned on our institutions' webpage and on the webpage of the largest self-help group for IBD in Germany. Patients were subdivided according to their QUOL score with a cutoff of <60. We used the Short Inflammatory Bowel Disease Questionnaire, the Assessment of the Demand for Additional Psychological Treatment, and the Fear of Progression Questionnaire Short Form.

Results: High numbers of patients in both subgroups showed an impaired QUOL (87.34% in UC, 91.08% in CD). Active extraintestinal manifestations, smoking, high fear of progression and high demand for psychotherapy were associated with reduced QUOL. In addition, polypharmacological interventions did not result in a good QUOL, but ostomies are linked to improved QUOL especially in CD patients.

Conclusions: Scores used in clinical day-to-day-practice mainly focusing on somatic factors do not sufficiently address important aspects concerning QUOL. Most importantly, extraintestinal manifestations show a hitherto underestimated impact on QUOL.
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http://dx.doi.org/10.5217/ir.2019.00135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873402PMC
January 2021

Human β-Defensin 2 Mediated Immune Modulation as Treatment for Experimental Colitis.

Front Immunol 2020 31;11:93. Epub 2020 Jan 31.

Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.

Defensins represents an integral part of the innate immune system serving to ward off potential pathogens and to protect the intestinal barrier from microbial encroachment. In addition to their antimicrobial activities, defensins in general, and human β-defensin 2 (hBD2) in particular, also exhibit immunomodulatory capabilities. In this report, we assessed the therapeutic efficacy of systemically administered recombinant hBD2 to ameliorate intestinal inflammation in three distinct animal models of inflammatory bowel disease; i.e., chemically induced mucosal injury (DSS), loss of mucosal tolerance (TNBS), and T-cell transfer into immunodeficient recipient mice. Treatment efficacy was confirmed in all tested models, where systemically administered hBD2 mitigated inflammation, improved disease activity index, and hindered colitis-induced body weight loss on par with anti-TNF-α and steroids. Treatment of lipopolysaccharide (LPS)-activated human peripheral blood mononuclear cells with rhBD2 confirmed the immunomodulatory capacity in the circulatory compartment. Subsequent analyzes revealed dendritic cells (DCs) as the main target population. Suppression of LPS-induced inflammation was dependent on chemokine receptor 2 (CCR2) expression. Mechanistically, hBD2 engaged with CCR2 on its DC target cell to decrease NF-κB, and increase CREB phosphorylation, hence curbing inflammation. To our knowledge, this is the first study showing efficacy of a systemically administered defensin in experimental disease.
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http://dx.doi.org/10.3389/fimmu.2020.00093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006816PMC
April 2021

Platelets in chronic liver disease, from bench to bedside.

JHEP Rep 2019 Dec 25;1(6):448-459. Epub 2019 Oct 25.

Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.

In the last decade, numerous studies revealed physiologic and pathophysiologic roles of platelets beyond haemostasis, a process to prevent and stop bleeding. These include the activation of the immune system and the promotion of inflammation, infection and cancer. Hence, the emerging view on the role of platelets has shifted - platelets are now seen as alert "sentinels" of the immune compartment, rather than passive bystanders. Herein, we review well-established and newly discovered features of platelets that define their natural role in maintaining blood haemostasis, but also their functional relationship with other cells of the immune system. We focus on recent studies underlining functional involvement of platelets in chronic liver diseases and cancer, as well as the effects of anti-platelet therapy in these contexts. Finally, we illustrate the potential of platelets as possible diagnostic and therapeutic tools in liver disease based on recently developed methodologies.
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http://dx.doi.org/10.1016/j.jhepr.2019.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005648PMC
December 2019

Infodemiology of Crohn's disease and Ulcerative colitis using Google Trends - an approach to investigate patient needs.

Z Gastroenterol 2020 Mar 4;58(3):224-233. Epub 2020 Feb 4.

Department of Internal Medicine I (Gastroenterology, Hepatology, Infectious Diseases), University Hospital Tübingen, Tübingen, Germany.

Introduction:  Inflammatory bowel diseases (IBD) highly affect quality of life. The course of disease and success of treatment are variable. These factors result in a high number of psychiatric comorbidities with patients requiring extensive medical consultation or additional psychotherapy. Unfortunately, time is often limited in daily clinical care, which leaves patients not feeling sufficiently informed about their disease. Patients often compensate by searching the internet, with possibly harmful information. We aim to identify information gaps to allow a more complete education of patients.

Methods:  We analyzed the internet search behavior using the key words [Morbus Crohn] (CD) and [Colitis ulcerosa] (UC) using Google Trends. In addition, we investigated which websites are the first hits on Google, as those are most likely visited by patients.

Results:  Symptoms, nutrition and therapy are central topics for persons interested in IBD. The searches concerning symptoms or therapies do not match the actual incidence or prevalence of comorbidities as well as the more commonly used therapies or established nutritional recommendations. We found a distinct impact of well-known personalities on disease related searches. The first suggested websites on google showed great heterogeneity of responsible publishers, often with possible conflict of interests. In line with those observations, quality of website content is highly heterogeneous.

Conclusion:  This study showed a need of information concerning symptoms, nutrition and therapy that should be considered during patient education. Since time in physician patient dialogue is short it may be helpful to further evaluate websites independently in order to give recommendations of websites offering reliable information.
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http://dx.doi.org/10.1055/a-1068-2877DOI Listing
March 2020

Three different ways of training ultrasound student-tutors yield significant gains in tutee's scanning-skills.

GMS J Med Educ 2019 15;36(6):Doc77. Epub 2019 Nov 15.

University Hospital Tübingen, Department of Internal Medicine I, Tübingen, Germany.

Many medical universities rely these days on trained student tutors to enable faculty-wide undergraduate ultrasound training. However, there is neither consensus on an optimal method nor any developed and agreed standard in the training of these student tutors. Usually internships and courses are employed which have both a specific set of advantages and disadvantages. We conducted a prospective quasi-randomized study of assess the effects of three types of tutor training on the resulting improvement in scanning skills of their tutees. Three batches of student tutors were trained by a course only (C-group), by an internship only (I-group) or by a course and an internship (CI-group). The respective gains in ultrasound scanning skills of the tutees were measured prospectively. A total 75 of the 124 5 year medical students (60.5%) who attended the mandatory ultrasound course completed both pre- and post-exams on a voluntary basis. Within a limit of eight minutes and three images, they were asked to depict and label a maximum of 14 anatomical structures. Two blinded raters independently awarded two points for each label with an identifiable structure and one point for each label with a possibly identifiable structure. In all three groups, the tutees improved significantly by more than doubling their pre-score results and comparably (Gains: C-group 9.19±5.73 points, p<.0001, I-group 9.77±4.81 points, p<.0001, CI-group 8.97±5.49 points, p<.0001). Student tutors, who were trained with a course or an internship or a course and an internship could teach scanning skills to 5th year medical students very effectively and with similar success.
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http://dx.doi.org/10.3205/zma001285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905374PMC
May 2020

[Gastrointestinal complications of the new immune checkpoint inhibitor therapies].

Dtsch Med Wochenschr 2019 12 2;144(24):1731-1736. Epub 2019 Dec 2.

Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Dept. für Innere Medizin, Universitätsklinik Tübingen.

In recent years, immune checkpoint inhibitors (ICPI) have become established as an integral part of drug tumor therapy. They belong to a group of monoclonal antibodies that promote anti-cancer cell immune response. Inhibitory signaling pathways are interrupted by binding to CTLA-4 and PD-1 or PD-L1, which increases the activity of cytotoxic T lymphocytes and reduces the immunological tolerance to tumor cells.Diarrhea - a symptom of enterocolitis - is the most common side effect of ICPI therapy after dermatological phenomena. A combined CTLA-4 and PD-1 blockade may affect up to 44 % of patients. The symptoms of ICPI-associated colitis are similar to the clinical appearance of inflammatory bowel disease.The treatment of affected patients should follow a standardized approach. Both the European and American Oncology Societies offer specific recommendations for the diagnosis and treatment of ICPI-associated adverse reactions. Rapid immunosuppressant treatments, to include steroids and biologics, are necessary to reduce morbidity once differential diagnoses are excluded. It may then be possible to subsequently resume ICPI therapy.Immune-mediated hepatitis is a potential side effect which occurs about 6 to 14 weeks after initiation of therapy. It is usually asymptomatic and characterized by an increase in serum transaminases. Lipasemia, without clinical signs of acute pancreatitis, is a common laboratory finding, which usually has no therapeutic consequence.
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http://dx.doi.org/10.1055/a-0848-9965DOI Listing
December 2019

Navigating Through Electronic Health Records: Survey Study on Medical Students' Perspectives in General and With Regard to a Specific Training.

JMIR Med Inform 2019 Nov 12;7(4):e12648. Epub 2019 Nov 12.

Department of Gastroenterology, Hepatology and Infectious Diseases, Internal Medicine, University Hospital Tübingen, Tübingen, Germany.

Background: An electronic health record (EHR) is the state-of-the-art method for ensuring all data concerning a given patient are up to date for use by multidisciplinary hospital teams. Therefore, medical students need to be trained to use health information technologies within this environment from the early stages of their education.

Objective: As little is known about the effects of specific training within the medical curriculum, this study aimed to develop a course module and evaluate it to offer best practice teaching for today's students. Moreover, we looked at the acceptance of new technologies such as EHRs.

Methods: Fifth-year medical students (N=104) at the University of Tübingen took part in a standardized two-day training procedure about the advantages and risks of EHR use. After the training, students performed their own EHR entries on hypothetical patient cases in a safe practice environment. In addition, questionnaires-standardized and with open-ended questions-were administered to assess students' experiences with a new teaching module, a newly developed EHR simulator, the acceptance of the health technology, and their attitudes toward it before and after training.

Results: After the teaching, students rated the benefit of EHR training for medical knowledge significantly higher than before the session (mean 3.74, SD 1.05). However, they also had doubts about the long-term benefit of EHRs for multidisciplinary coworking after training (mean 1.96, SD 0.65). The special training with simulation software was rated as helpful for preparing students (88/102, 86.2%), but they still did not feel safe in all aspects of EHR.

Conclusions: A specific simulated training on using EHRs helped students improve their knowledge and become more aware of the risks and challenges of such a system. Overall, students welcomed the new training module and supported the integration of EHR teaching into the medical curriculum. Further studies are needed to optimize training modules and make use of long-term feedback opportunities a simulated system offers.
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http://dx.doi.org/10.2196/12648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913756PMC
November 2019

Hypoxia induced Sonic Hedgehog signaling regulates cancer stemness, epithelial-to-mesenchymal transition and invasion in cholangiocarcinoma.

Exp Cell Res 2019 12 18;385(2):111671. Epub 2019 Oct 18.

Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany; Department of Internal Medicine II, Bremen-Nord Hospital, Bremen, Germany. Electronic address:

Aberrant activation of Sonic Hedgehog (SHH) pathway has been implicated in a variety of cancers including cholangiocarcinoma (CC); however, the influencing factors are still unknown. Additionally, intratumoral hypoxia is known to contribute towards therapeutic resistance through modulatory effects on various pathways. In this study, we investigated the relationship between hypoxia and SHH pathway activation and the effect of this interplay on cancer stemness and epithelial-to- mesenchymal transition (EMT) during cholangiocarcinogenesis. Hypoxia promoted SHH pathway activation, evidenced by upregulated SHH and SMO levels, and enhanced glioma-associated oncogene homolog 1 (GLI1) nuclear translocation; whereas silencing of HIF-1α impaired SHH upregulation. Hypoxia also enhanced the expression of cancer stem cell (CSC) transcription factors (NANOG, Oct4, SOX2), CD133 and EMT markers (N-cadherin, Vimentin), thereby supporting invasion. Cyclopamine treatment suppressed hypoxia induced SHH pathway activation, consequently reducing invasiveness by downregulating the expression of CSC transcription factors, CD133 and EMT. Cyclopamine induced apoptosis in CC cells under hypoxia, suggesting that hypoxia induced activation of SHH pathway has modulatory effects on CC progression. Therefore, SHH signaling is proposed as a target for CC treatment, which is refractory to standard chemotherapy.
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http://dx.doi.org/10.1016/j.yexcr.2019.111671DOI Listing
December 2019

Chemovirotherapy for pancreatic cancer: Gemcitabine plus oncolytic measles vaccine virus.

Oncol Lett 2019 Nov 20;18(5):5534-5542. Epub 2019 Sep 20.

Department of Internal Medicine VIII (Medical Oncology and Pneumology), University Hospital Tuebingen, D-72076 Tuebingen, Germany.

Oncolytic virotherapy with vaccine viruses employs replicative vectors, which quite selectively infect tumor cells leading to massive virus replication followed by subsequent profound tumor cell death (oncolysis). Measles vaccine virus (MeV) has already shown great oncolytic activity against different types of cancers, including pancreatic cancer. Gemcitabine is a first line chemotherapeutic drug used for pancreatic cancer in palliative treatment plans. Furthermore, this drug can be used to induce senescence, a permanent cell cycle arrest, in tumor cells. In our preclinical work, three well-characterized immortalized human pancreatic cancer cell lines were used to investigate the combinatorial effect of MeV-based virotherapy together with the chemotherapeutic compound gemcitabine. Viability assays revealed that the combination of only small amounts of MeV together with subtherapeutic concentrations of gemcitabine resulted in a tumor cell mass reduction of >50%. To further investigate the replication of the oncolytic MeV vectors under these distinct combinatorial conditions, viral growth curves were generated. As a result, viral replication was found to be only slightly diminished in the presence of gemcitabine. As gemcitabine induces senescence, the effect of MeV on that phenomenon was explored using a senescence-associated β-galactosidase assay. Notably, gemcitabine-induced tumor cell senescence was not impaired by MeV. Accordingly, the chemovirotherapeutic combination of gemcitabine plus oncolytic MeV constitutes a novel therapeutic option for advanced pancreatic carcinoma that is characterized by the mutual improvement of the effectiveness of each therapeutic component.
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http://dx.doi.org/10.3892/ol.2019.10901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781561PMC
November 2019

Electronic Patient-Reported Outcome Measures in Radiation Oncology: Initial Experience After Workflow Implementation.

JMIR Mhealth Uhealth 2019 07 24;7(7):e12345. Epub 2019 Jul 24.

University Hospital Tübingen, Department of Radiation Oncology, Tübingen, Germany.

Background: Mobile health (mHealth) technologies are increasingly used in various medical fields. However, the potential of mHealth to improve patient care in radiotherapy by acquiring electronic patient reported outcome measures (ePROMs) during treatment has been poorly studied so far.

Objective: The aim of this study was to develop and implement a novel Web app (PROMetheus) for patients undergoing radiotherapy. Herein, we have reported our experience with a focus on feasibility, patient acceptance, and a correlation of ePROMs with the clinical course of the patients.

Methods: In the period between January and June 2018, 21 patients used PROMetheus to score side effects, symptoms, and quality of life-related parameters during and after their treatment. Items of the Patient Reported Outcome version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) were chosen based on the primary site of disease, 27 items for head and neck tumors, 21 items for thoracic tumors, and 24 items for pelvic tumors.

Results: In total, 17 out of the 21 patients (81%) regularly submitted ePROMs and more than 2500 data points were acquired. An average of 5.2, 3.5, and 3.3 min was required to complete the head and neck, thorax, and pelvis questionnaires, respectively. ePROMS were able to detect the occurrence of both expected and unexpected side effects during the treatment. In addition, a gradual increase in the severity of side effects over the course the treatment and their remission afterward could be observed with ePROMs. In total, 9 out of the 17 patients (53%), mostly those with head and neck and thoracic cancers, reported PRO-CTCAE grade III or IV fatigue with severe impairments of activities of daily life.

Conclusions: This study shows the successful implementation of an ePROM system and a high patient acceptance. ePROMs have a great potential to improve patient care in radiotherapy by providing a comprehensive documentation of symptoms and side effects, especially of ones that are otherwise underreported.
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http://dx.doi.org/10.2196/12345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685133PMC
July 2019

Development and implementation of a comprehensive ultrasound curriculum for undergraduate medical students - a feasibility study.

BMC Med Educ 2019 May 28;19(1):170. Epub 2019 May 28.

Department of Internal Medicine I (Gastroenterology, Hepatology, Infectious Diseases), University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

Background: Ultrasound is one of the most important imaging techniques in clinical medicine with unique advantages. Skills in ultrasound imaging are very usefull for physicians including novices and thus also mandated by the Task Force "National Competence-Based Learning Objectives for Undergraduate Medical Education" (NKLM) in Germany and as well as by the German Ultrasound Society (Deutsche Gesellschaft für Ultraschall in der Medizin, DEGUM). Since ultrasound is best learned hands-on in very small supervised groups, we developed and implemented a comprehensive ultrasound-curriculum for all undergraduate medical students of our faculty using a peer-teaching concept.

Methods: We used Kern's six-step model of curricular development comprising (1) problem identification and general needs assessment, (2) needs assessment of the targeted learners, (3) goals and objectives, (4) educational stategies, (5) implementation, and (6) evaluation and feedback.

Results: The developed curriculum covers basic ultrasound of the abdomen and the throat, eFAST (Extended Focused Assessment with Sonography for Trauma), lung-ultrasound, FEEL (Focused Echocardiography in Emergency Life Support) and compression duplex sonography of the thigh deep vein system. All 5th year medical students receive a 90 min lecture on ultrasound basics by a faculty member and then a 12.5 h hands-on course divided into three sessions with one student tutor for every 4 students. The students are provided with a script (PDF-File) that covers all the learning goals, including example images of pathologies. The student tutors are trained during a 1 week ultrasound course and a 21-day rotation through seven different ultrasound laboratories. In addition, they undergo a standardized 1.5 day didactical training. Prior to the implementation for all students, the overall course was tested on 27 volunteer students. These students rated (on a 6-point Likert scale from 1 = excellent to 6 = very poor) the satisfaction with the student tutors and the faculty members as 1.4 ± .9 (mean ± stddev) and 1.3 ± .5 respectively.

Conclusion: A comprehensive ultrasound curriculum for all undergraduate medical students using a peer-teaching concept is feasible. Further studies are needed to evaluate in detail the learning outcomes for students and student tutors.
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http://dx.doi.org/10.1186/s12909-019-1611-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537195PMC
May 2019

Ustekinumab is effective in biological refractory Crohn's disease patients-regardless of approval study selection criteria.

Intest Res 2019 Jul 31;17(3):340-348. Epub 2019 May 31.

Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.

Background/aims: Ustekinumab is effective in active Crohn's disease. In a retrospective study we assessed the clinical outcome in nonresponders to anti-tumor necrosis factor therapy, and/or conventional therapy and/or the α4β7-integrin inhibitor vedolizumab. As approval study populations do not always reflect the average "real world" patient cohort, we assessed weather patients who would not have qualified for approval studies show similar outcomes.

Methods: Forty-one patients with mild to severe active Crohn's disease were treated with ustekinumab (intravenous 6 mg per kg/body weight) followed by subcutaneous ustekinumab (90 mg) at week 8. Depending on the clinical response maintenance therapy was chosen every 8 or 12 weeks. Clinical response was defined by Crohn's Disease Activity Index (CDAI) decline, decline of stool frequency or clinical improvement. Inclusion criteria for approval studies were assessed.

Results: The 58.5% (24/41) showed clinical response to ustekinumab. The 58.3% of this group (14/24) achieved clinical remission. Clinical response correlated significantly with drop of stool frequency and improvement of CDAI score. The 39 out of 41 patients had no side effects and we observed no serious infections. About a third of our patients would not have met ustekinumab approval study criteria. However, patients who did not meet study criteria showed clinical improvement numerically in the same range compared to patients who would have qualified for approval studies.

Conclusions: Ustekinumab is effective, safe and well tolerated in a highly therapy refractory patient cohort. Even though a reasonable number of patients did not meet ustekinumab approval study criteria, approval study results seem to be representative to the overall patient cohort.
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http://dx.doi.org/10.5217/ir.2019.00012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667371PMC
July 2019