3D hydrogel-based microcapsules as an in vitro model to study tumorigenicity, cell migration and drug resistance. - Ertekin, Özlem; Monavari, Mahshid; Krüger, René; Fuentes Chandia, Miguel Angel; Parma, Beatrice; Letort, Gaelle; Tripal, Philipp; Boccaccini, Aldo R.; Boßerhoff, Anja Katrin; Ceppi, Paolo; Kappelmann-Fenzl, Melanie; Leal-Egaña, Aldo (Acta Biomaterialia, 2022)
In this work, we analyzed the reliability of alginate-gelatin microcapsules as artificial tumor model. These tumor-like scaffolds are characterized by their composition and stiffness (∼25 kPa), and their capability to restrict -but not hinder- cell migration, proliferation and release from confinement. Hydrogel-based microcapsules were initially utilized to detect differences in mechano-sensitivity between MCF7 and MDA-MB-231 breast cancer cells, and the endothelial cell line EA.hy926. Additionally, we used RNA-seq and transcriptomic methods to determine how the culture strategy (i.e. 2D v/s 3D) may pre-set the expression of genes involved in multidrug resistance, being then validated by performing cytotoxicological tests and assays of cell morphology. Our results show that both breast cancer cells can generate elongated multicellular spheroids inside the microcapsules, prior being released (mimicking intravasation stages), a behavior which was not observed in endothelial cells. Further, we demonstrate that cells isolated from 3D scaffolds show resistance to cisplatin, a process which seems to be strongly influenced by mechanical stress, instead of hypoxia. We finally discuss the role played by aneuploidy in malignancy and resistance to anticancer drugs, based on the increased number of polynucleated cells found within these microcapsules. Overall, our outcomes demonstrate that alginate-gelatin microcapsules represent a simple, yet very accurate tumor-like model, enabling us to mimic the most relevant malignant hints described in vivo, suggesting that confinement and mechanical stress need to be considered when studying pathogenicity and drug resistance of cancer cells in vitro. STATEMENT OF SIGNIFICANCE: In this work, we analyzed the reliability of alginate-gelatin microcapsules as an artificial tumor model. These scaffolds are characterized by their composition, elastic properties, and their ability to restrict cell migration, proliferation, and release from confinement. Our results demonstrate four novel outcomes: (i) studying cell migration and proliferation in 3D enabled discrimination between malignant and non-pathogenic cells, (ii) studying the cell morphology of cancer aggregates entrapped in alginate-gelatin microcapsules enabled determination of malignancy degree in vitro, (iii) determination that confinement and mechanical stress, instead of hypoxia, are required to generate clones resistant to anticancer drugs (i.e. cisplatin), and (iv) evidence that resistance to anticancer drugs could be due to the presence of polynucleated cells localized inside polymer-based artificial tumors.

67-year-old woman with exercise-induced angina pectoris - Mitschke, M.; Gattenloehner, S.; Achenbach, Susanne (Deutsche Medizinische Wochenschrift, 2014)
Was sehen Sie? Abb.1 Invasive Koronarangiografie des linken Koronararteriensystems. Eine 67-jahrige Patientin stellte sich mit belastungsabhangiger Angina pectoris vor. Eine dilatative Kardiomyopathie war bekannt. 5 Jahre zuvor war invasiv eine koronare Herzerkrankung ausgeschlossen worden. Die invasive Koronarangiografie des linken Koronararteriensystems zeigt einen Befund. Welcher ist das? Erlaubt dieser Befund eine Diagnose? Wenn ja, welche? Sind Differenzialdiagnosen moglich? Wenn ja, welche?
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AB0-Locus influences the Clot Structure Comment - Hackstein, Holger (Transfusionsmedizin, 2021)
CRIS-Team WoS Importer:2021-03-26

Absolute quantification of DcR3 and GDF15 from human serum by LC-ESI MS - Lancrajan, Ioana Maria; Schneider-Stock, Regine; Naschberger, Elisabeth; Schellerer, Vera; Stürzl, Michael; Enz, Ralf (Journal of Cellular and Molecular Medicine, 2015)
Biomarkers are widely used in clinical diagnosis, prognosis and therapy monitoring. Here, we developed a protocol for the efficient and selective enrichment of small and low concentrated biomarkers from human serum, involving a 95% effective depletion of high-abundant serum proteins by partial denaturation and enrichment of low-abundant biomarkers by size exclusion chromatography. The recovery of low-abundance biomarkers was above 97%. Using this protocol, we quantified the tumour markers DcR3 and growth/differentiation factor (GDF)15 from 100 ?l human serum by isotope dilution mass spectrometry, using (15) N metabolically labelled and concatamerized fingerprint peptides for the both proteins. Analysis of three different fingerprint peptides for each protein by liquid chromatography electrospray ionization mass spectrometry resulted in comparable concentrations in three healthy human serum samples (DcR3: 27.23 ± 2.49 fmol/ml; GDF15: 98.11 ± 0.49 fmol/ml). In contrast, serum levels were significantly elevated in tumour patients for DcR3 (116.94 ± 57.37 fmol/ml) and GDF15 (164.44 ± 79.31 fmol/ml). Obtained data were in good agreement with ELISA and qPCR measurements, as well as with literature data. In summary, our protocol allows the reliable quantification of biomarkers, shows a higher resolution at low biomarker concentrations than antibody-based strategies, and offers the possibility of multiplexing. Our proof-of-principle studies in patient sera encourage the future analysis of the prognostic value of DcR3 and GDF15 for colon cancer patients in larger patient cohorts.
EVALuna2:4708

A comparative observational study on intrasphincteric injections with Botulinum toxin vs. enteral neuromodulation in chronic refractory constipation - Walther, Mona; Müller, Hanna; Weiß, Christel; Carbon, Roman; Diez, Sonja; Besendörfer, Manuel (BMC Pediatrics, 2023)
Purpose: Botulinum toxin injections in the anal sphincter apparatus (Botox) and enteral neuromodulation (ENM) are options for treatment of refractory chronic constipation. We present a retrospective comparative observational study. Patients and methods: From 2014 to 2022, pediatric patients with chronic constipation were either treated with Botox or ENM with continuation of conservative treatment. Comparison was conducted regarding the primary outcome variables defecation frequency, stool consistency, and abdominal pain. Secondary outcomes were fecal incontinence, enuresis, change of medication and safety of treatment. Results: 19 Botox patients (10 boys, 9 girls, 12 patients with Hirschsprung disease (HD), 7 patients with functional constipation (FC)) were compared to 24 ENM patients (18 boys, 6 girls, 12 HD patients, 7 FC patients). Groups differed significantly in age (5.0 years (Botulinum toxin) and 6.5 years (ENM), mean values, p-value 0.008). Improvement of constipation was seen in 68% (n = 13/19) of Botox and 88% (n = 21/24) of ENM patients (p = 0.153). Influence of etiology on therapeutic effects was not observed. Complications were minor. Conclusions: Botox and ENM can be considered as valuable and effective treatment options in refractory chronic constipation. Prospective, large-population studies should be designed to enable improved evidence.
CRIS-Team Scopus Importer:2023-09-15
Keywords: Botulinum toxin; Chronic refractory constipation; Enteral neuromodulation; Fecal incontinence; Hirschsprung disease

A contemporary assessment of total neoadjuvant therapy (TNT) protocols for locally advanced rectal cancer: adoption and expert perspectives at German Cancer Society (DKG)-certified colorectal cancer centers - Langheinrich, Melanie; Paasch, Christoph; Mantke, René; Weber, Klaus; Benz, Stefan; Kersting, Stephan (Journal of Cancer Research and Clinical Oncology, 2023)
Purpose: The treatment paradigm for locally advanced rectal cancer (LARC) is shifting toward the total neoadjuvant therapy (TNT) concept, which administered systemic chemotherapy in the neoadjuvant setting, either before or after chemoradiotherapy (CRT) or short-course radiotherapy (SCRT). First results have shown higher pathologic complete response (pCR) rates and a favorable impact on disease-free survival (DFS). Our study aimed to evaluate the current clinical practice and expert opinion regarding TNT for locally advanced rectal cancer across DKG (German Cancer Society)-certified colorectal cancer centers. Methods: A comprehensive online questionnaire, constituted of 14 TNT-focused queries targeting patients with locally advanced rectal cancer, was conducted among DKG-certified colorectal cancer centers registered within the database of the Addz (Arbeitsgemeinschaft Deutscher Darmzentren) between December 2022 and January 2023. Results: A significant majority (68%) indicated that they treated between 0 and 10 patients using a TNT protocol. Only a third (36%) of these centers participated in patient enrollment for a TNT study. Despite this, 84% of centers reported treating patients in a manner analogous to a TNT study, with the RAPIDO regimen being the most prevalent approach, employed by 60% of the respondents. The decision to adopt a TNT approach was primarily influenced by factors, such as the lower third of the rectum (93% of centers), cT4 stage (86% of centers), and a positive circumferential resection margin (80% of centers). Regarding concerns, 65% of the survey respondents expressed no reservations about the TNT concept, while 35% had concerns. In particular, there appears to be disagreement and uncertainty in regard to a clinical complete response and the “Watch and Wait” approach. While some centers adopt the watch-and-wait approach (42%), others only utilize it when extirpation is otherwise necessary (39%), and a portion still proceeds with surgery as initially planned (19%). The survey also addressed unmet needs, which were elaborated in the free-text responses. Overall, there was high interest in participating in planned observational studies. Conclusions: This study presents an overview of current clinical practice and unmet needs within DKG-certified German colorectal cancer centers. It is noteworthy that total neoadjuvant therapy (TNT) is predominantly performed outside of clinical trials. Moreover, across the centers, there is significant heterogeneity in handling clinical complete response and adopting the “watch and wait” approach. Further research is needed to establish standardization in the care of locally advanced rectal cancer.
CRIS-Team Scopus Importer:2023-07-21
Keywords: DKG-certified colorectal cancer centers; Locally advanced rectal cancer; Rectal cancer; TNT; Total neoadjuvant therapy

Activation of liver X receptors inhibits experimental fibrosis by interfering with interleukin-6 release from macrophages - Beyer, Christian; Huang, Jingang; Beer, Juergen; Zhang, Yun; Palumbo-Zerr, Katrin; Zerr, Pawel; Distler, Alfiya; Dees, Clara; Maier, Christiane; Munoz, Louis; Krönke, Gerhard; Uderhardt, Stefan; et al. (Annals of the Rheumatic Diseases, 2015)
To investigate the role of liver X receptors (LXRs) in experimental skin fibrosis and evaluate their potential as novel antifibrotic targets.We studied the role of LXRs in bleomycin-induced skin fibrosis, in the model of sclerodermatous graft-versus-host disease (sclGvHD) and in tight skin-1 (Tsk-1) mice, reflecting different subtypes of fibrotic disease. We examined both LXR isoforms using LXR?-, LXR?- and LXR-?/?-double-knockout mice. Finally, we investigated the effects of LXRs on fibroblasts and macrophages to establish the antifibrotic mode of action of LXRs.LXR activation by the agonist T0901317 had antifibrotic effects in bleomycin-induced skin fibrosis, in the sclGvHD model and in Tsk-1 mice. The antifibrotic activity of LXRs was particularly prominent in the inflammation-driven bleomycin and sclGvHD models. LXR?-, LXR?- and LXR?/?-double-knockout mice showed a similar response to bleomycin as wildtype animals. Low levels of the LXR target gene ABCA-1 in the skin of bleomycin-challenged and control mice suggested a low baseline activation of the antifibrotic LXR signalling, which, however, could be specifically activated by T0901317. Fibroblasts were not the direct target cells of LXRs agonists, but LXR activation inhibited fibrosis by interfering with infiltration of macrophages and their release of the pro-fibrotic interleukin-6.We identified LXRs as novel targets for antifibrotic therapies, a yet unknown aspect of these nuclear receptors. Our data suggest that LXR activation might be particularly effective in patients with inflammatory disease subtypes. Activation of LXRs interfered with the release of interleukin-6 from macrophages and, thus, inhibited fibroblast activation and collagen release.
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Activation of matrix-metalloproteinase-2 and membrane-type-1-matrix-metalloproteinase in endothelial cells and induction of vascular permeability in vivo by human immunodeficiency virus-1 Tat protein and basic fibroblast growth factor. - Tosch, Elena; Barillari, Giovanni; Sgadari, Cecilia; Bacigalupo, Ilaria; Cereseto, Anna; Carlei, Davide; Palladino, Clelia; Zietz, Christian; Leone, Patrizia; Stürzl, Michael; Buttò, Stefano; Cafaro, Aurelio; et al. (Molecular Biology of the Cell, 2001)
Previous studies indicated that the Tat protein of human immunodeficiency virus type-1 (HIV-1) is a progression factor for Kaposi's sarcoma (KS). Specifically, extracellular Tat cooperates with basic fibroblast growth factor (bFGF) in promoting KS and endothelial cell growth and locomotion and in inducing KS-like lesions in vivo. Here we show that Tat and bFGF combined increase matrix-metalloproteinase-2 (MMP-2) secretion and activation in endothelial cells in an additive/synergistic manner. These effects are due to the activation of the membrane-type-1-matrix-metalloproteinase and to the induction of the membrane-bound tissue inhibitor of metalloproteinase-2 (TIMP-2) by Tat and bFGF combined, but also to Tat-mediated inhibition of both basal or bFGF-induced TIMP-1 and -2 secretion. Consistent with this, Tat and bFGF promote vascular permeability and edema in vivo that are blocked by a synthetic MMP inhibitor. Finally, high MMP-2 expression is detected in acquired immunodeficiency virus syndrome (AIDS)-KS lesions, and increased levels of MMP-2 are found in plasma from patients with AIDS-KS compared with HIV-uninfected individuals with classic KS, indicating that these mechanisms are operative in AIDS-KS. This suggests a novel pathway by which Tat can increase KS aggressiveness or induce vasculopathy in the setting of HIV-1 infection.

Activation of NF-κB by the Kaposi's sarcoma-associated herpesvirus K15 protein involves recruitment of the NF-κB-inducing kinase, IκB kinases, and phosphorylation of p65. - Havemeier, Anika; Gramolelli, Silvia; Pietrek, Marcel; Jochmann, Ramona; Stürzl, Michael; Schulz, Thomas F. (Journal of Virology, 2014)
Kaposi's sarcoma herpesvirus (KSHV) (or human herpesvirus 8) is the cause of Kaposi's sarcoma, primary effusion lymphoma (PEL), and the plasma cell variant of multicentric Castleman's disease (MCD). The transmembrane K15 protein, encoded by KSHV, has been shown to activate NF-κB and the mitogen-activated protein kinases (MAPKs) c-jun-N-terminal kinase (JNK) and extracellular signal-regulated kinase (Erk) as well as phospholipase C gamma (PLCγ) and to contribute to KSHV-induced angiogenesis. Here we investigate how the K15 protein activates the NF-κB pathway. We show that activation of NF-κB involves the recruitment of NF-κB-inducing kinase (NIK) and IKK α/β to result in the phosphorylation of p65/RelA on Ser536. A K15 mutant devoid in NIK/IKK recruitment fails to activate NF-κB but remains proficient in the stimulation of both NFAT- and AP1-dependent promoters, showing that the structural integrity of the mutant K15 protein has not been altered dramatically. Direct recruitment of NIK represents a novel way for a viral protein to activate and manipulate the NF-κB pathway. KSHV K15 is a viral protein involved in the activation of proinflammatory and angiogenic pathways. Previous studies reported that K15 can activate the NF-κB pathway. Here we show the molecular mechanism underlying the activation of this signaling pathway by K15, which involves direct recruitment of the NF-κB-inducing kinase NIK to K15 as well as NIK-mediated NF-κB p65 phosphorylation on Ser536. K15 is the first viral protein shown to activate NF-κB through direct recruitment of NIK. These results indicate a new mechanism whereby a viral protein can manipulate the NF-κB pathway. UNLABELLED IMPORTANCE
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Acute and chronic limb ischemia in endurance athletes - a serious diagnosis of exercise-induced lower limb pain - Regus, Susanne; Lang, Werner (Deutsche Medizinische Wochenschrift, 2016)
Lower extremity pain due to acute or chronic ischemia in high performance endurance athletes is an often forgotten differential diagnosis. A variety of symptoms constitues a multi-disciplinary challenge. Intermittent claudication or acute ischemia are clinical symptoms indicative of this vascular disease. The most important basic methods of investigation are anamnesis and clinical examination. Furthermore, the determination of the ankle-brachial index (ABI) and duplexsonography should be considered. In addition, modern cross-sectional imaging techniques such as computed tomography angiography (CTA) or magnetic resonance angiography (MRA) are recommended. In case of suspect findings, the digital substraction angiography (DSA) represents a high resolution image technique for illustration of the vessel lumen. If necessary, interventional therapy (balloon angioplasty or clot lysing) can be performed simultaneously. Surgical revision remains the gold-standard of therapy and the fastest way in which athletes regain maximum performance abilities. Correct diagnosis of lower limb ischemia affecting endurance athletes should be performed without delays. Determining the ankle-brachial index following maximal exertion represents the most important diagnostic tool. Surgical treatment techniques as decompression and revascularisation provide the best long-term results.
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Acute Hemolytic Transfusion Reaction by an Anti-s Due to Delayed Type and Screen Procedures Until Occurrence of a Hemorrhagic Shock - Zimmermann, Robert; Strasser, Erwin; Hackstein, Holger (Transfusionsmedizin, 2019)
In the past decade, profound changes in the clinical practice of haemotherapy have occurred in most industrial countries, including Germany. Red blood cell (RBC) order procedures are performed more and more cautious. The utilization of RBC concentrates is strongly declining. At the same time, the number of patients for whom the preoperative or pre-interventional provision of cross-matched blood is not carried out despite planned surgery or intervention is also increasing. We report on a 71-year-old multimorbid patient with dilated cardiomyopathy, severely reduced cardiac reserve, a few weeks after valve replacement surgery, ongoing anticoagulation with heparin and diagnosed anemia with hemoglobin values between 7 and 8 g/dl. In this patient, a haemorrhagic shock was induced by a Forrest-II b haemorrhage from a duodenal ulcer after several days of in-patient treatment. In the context of emergency care, it turned out that all pre-transfusion diagnostics had been missed. The patient received uncross-matched red blood cell concentrates of blood group 0 Rh negative which unexpectedly triggered an acute haemolytic transfusion reaction. The reason was an irregular antibody against the antigen s from the MNSs blood group system that had not been identified before the transfusion. Acute hemolytic transfusion reactions outside the AB0 system are a rare, but nevertheless always threatening complication of the transfusion of uncrossmatched erythrocyte concentrates in life- threatening bleeding emergencies. The case shows that the desire to follow a restrictive transfusion practice must not lead to overlooking constellations in individual cases which, of course, require the timely performance of a pre-transfusional diagnostic procedure with blood group typing, antibody screening and antibody identification. In our opinion, the frequency of comparable events is increasing to an extent that suggests that such errors in the clinical treatment process should not only be dealt within CIRS systems but also recorded in haemovigilance systems.
CRIS-Team WoS Importer:2019-09-20

Acute Paraplegia - a Paralysis without Trauma? The Anterior Spinal Artery Syndrome, a Case Report - Hackner, Danilo; Schneider, Kurt; Trumm, Christoph G. (Notarzt, 2021)
Zusammenfassung Schlaganfalle stehen als eine der fuhrenden Todesursache weltweit auf Platz zwei nach KHK/Herzinfarkt und gehoren zu den haufigsten Ursachen fur Invaliditat im hoheren Lebensalter. In der vorliegenden Kasuistik wird der Fall einer Patientin mit spinalem Schlaganfall aufgearbeitet. Bei plotzlich einsetzender Paraplegie mit dissoziierter Empfindungsstorung wurde ein arterioarteriell embolischer Arteria-spinalis-anterior-Infarkt diagnostiziert. Durch ein pra- sowie innerklinisch zielgerichtetes Vorgehen war es moglich, der Patientin in einem individuellen Heilversuch eine Lysetherapie anzubieten. Nach erfreulichem klinischem Verlauf war die Patientin 17 Tage nach dem Ereignis bereits auf kurzen Distanzen wieder gehfahig.
CRIS-Team WoS Importer:2021-04-16

Acyltransferase skinny hedgehog regulates TGFβ-dependent fibroblast activation in SSc - Liang, Ruifang; Kagwiria, Rosebeth; Zehender, Ariella; Dees, Clara; Bergmann, Christina; Krasowska, Dorota; Michalska-Jakubus, Małgorzata; Kreuter, Alexander; Kraner, Max; Schett, Georg; Distler, Jörg; Ramming, Andreas (Annals of the Rheumatic Diseases, 2019)
Objectives: Systemic sclerosis (SSc) is characterised by aberrant hedgehog signalling in fibrotic tissues. The hedgehog acyltransferase (HHAT) skinny hedgehog catalyses the attachment of palmitate onto sonic hedgehog (SHH). Palmitoylation of SHH is required for multimerisation of SHH proteins, which is thought to promote long-range, endocrine hedgehog signalling. The aim of this study was to evaluate the role of HHAT in the pathogenesis of SSc. Methods: Expression of HHAT was analysed by real-time polymerase chain reaction(RT-PCR), immunofluorescence and histomorphometry. The effects of HHAT knockdown were analysed by reporter assays, target gene studies and quantification of collagen release and myofibroblast differentiation in cultured human fibroblasts and in two mouse models. Results: The expression of HHAT was upregulated in dermal fibroblasts of patients with SSc in a transforming growth factor-β (TGFβ)/SMAD-dependent manner. Knockdown of HHAT reduced TGFβ-induced hedgehog signalling as well as myofibroblast differentiation and collagen release in human dermal fibroblasts. Knockdown of HHAT in the skin of mice ameliorated bleomycin-induced and topoisomerase-induced skin fibrosis. Conclusion: HHAT is regulated in SSc in a TGFβ-dependent manner and in turn stimulates TGFβ-induced long-range hedgehog signalling to promote fibroblast activation and tissue fibrosis. Targeting of HHAT might be a novel approach to more selectively interfere with the profibrotic effects of long-range hedgehog signalling.
CRIS-Team Scopus Importer:2019-06-21
Keywords: dermal fibrosis; hedgehog signaling; skinny hedgehog; systemic sclerosis; TGFβ

ADAR1 Is Required for Dendritic Cell Subset Homeostasis and Alveolar Macrophage Function - Baal, Nelli; Cunningham, Sarah; Obermann, Hannah-Lena; Thomas, Jenny; Lippitsch, Anne; Dietert, Kristina; Gruber, Achim D.; Kaufmann, Andreas; Michel, Gabriela; Nist, Andrea; Stiewe, Thorsten; Rupp, Oliver; et al. (Journal of Immunology, 2019)
RNA editing by adenosine deaminases acting on dsRNA (ADAR) has become of increasing medical relevance, particularly because aberrant ADAR1 activity has been associated with autoimmunity and malignancies. However, the role of ADAR1 in dendritic cells (DC), representing critical professional APCs, is unknown. We have established conditional murine CD11c Cre-mediated ADAR1 gene ablation, which did not induce general apoptosis in CD11c(+) cells but instead manifests in cell type-specific effects in DC subpopulations. Bone marrow-derived DC subset analysis revealed an incapacity to differentiate CD103 DC+ in both bulk bone marrow and purified pre-DC lineage progenitor assays. ADAR1 deficiency further resulted in a preferential systemic loss of CD8(+)/CD103(+) DCs, revealing critical dependency on ADAR1, whereas other DC subpopulations were moderately affected or unaffected. Additionally, alveolar macrophages were depleted and dysfunctional, resembling pulmonary alveolar proteinosis. These results reveal an unrecognized role of ADAR1 in DC subset homeostasis and unveils the cell type-specific effects of RNA editing.
CRIS-Team WoS Importer:2019-02-21

A detailed examination of platelet function inhibition by nitric oxide in platelet-rich plasma and whole blood - Zimmermann, Robert; Krüger, Julia; Filipovic, Milos; Ivanovic-Burmazovic, Ivana; Calatzis, Andreas; Eckstein, Reinhold; Weiss, Dominik R. (Clinical Laboratory, 2013)
Background: The question of whether novel instruments such as multiple electrode aggregometry (MEA) can be used for measurement of the effects of nitric oxide (NO) on platelets (PLTs) has not been examined. Methods: Therefore, we compared the effects of NO concentrations (1, 10, and 100 μM) on the PLT aggregation response to ADP, arachidonic acid (AA), collagen, ristocetin, and thrombin receptor-activating peptide 6 (TRAP-6) using light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) and examined the effects of NO using the platelet function analyzer (PFA)-100™. Results: The response of PLTs to ADP and AA was strongly inhibited by all NO concentrations in LTA and MEA. The inhibition of the responses to ristocetin and collagen was detectable in MEA at lower NO concentrations than in LTA. However, the typically increasing lag phase between collagen addition and the aggregation response in the presence of NO was more obvious in LTA. TRAP caused a reproducible early response in the presence of NO in LTA which was followed by rapid PLT disaggregation, whereas even 100 μM NO did not inhibit the response to TRAP in MEA. Finally, NO prolonged the in-vitro bleeding time remarkably more in the PFA-100 collagen-epinephrin cartridge than in the collagen-ADP cartridge. Conclusions: Whole blood versus PLT rich plasma, citrate versus hirudin, and high versus low shear influenced the effects of NO. This shows that a careful selection of models and potentially a combination of different methods is appropriate for a differentiated evaluation of pharmacological or physiological mechanisms of NO-donors or of NO-inhibitors.

Adjvant HIPEC in gastric cancer patients with high risk of peritoneal carcinomatosis - Aladashvili, A.; Croner, R.; Pantsulaia, I. (2017)
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A European snapshot of psychosocial characteristics and patients’ perspectives of faecal incontinence—do they correlate with current scoring systems? - Creamer, Felicity; Orlando, Alessandra; Brunner, Maximilian; Buntzen, Steen; Dennis, Alexander; Gómez-Fernández, Laura; Handtrack, Claudia; Hanly, Ann; Matzel, Klaus E.; Duyos, Arantxa Muñoz; Meurette, Guillaume; O’Connell, P. Ronan; et al. (International Journal of Colorectal Disease, 2021)
Purpose: To compare the current clinical scoring systems used to quantify the severity of symptoms of faecal incontinence (FI) to patients’ subjective scoring of parameters of psychosocial well-being. Methods: Patients referred to six European centres for investigation or treatment of symptoms of FI between June 2017 and September 2019 completed a questionnaire that captured patient demographics, incontinence symptoms using St. Mark’s Incontinence score (SMIS) and ICIQ-B, psychological well-being (HADS, Hospital Anxiety and Depression Scale), and social interaction (a three-item loneliness scale). Results: Three hundred eighteen patients completed questionnaires (62 men, mean age 58.7). Sixty percent of the respondents were aged under 65. Median SMIS was 15 (11–18), ICIQ-B bowel pattern was 8 (6–11) and bowel control was 17 (13–22), similar across all demographic groups; however, younger patients were more likely to experience symptoms of depression and anxiety (HADS score > 10, 65.2% of patients age < 65 vs 54.9% of those ages > = 65, p = 0.03) with lower quality of life (ICIQ-B QoL, median score 19 (14–23)) vs age > = 65 (16 (11–21) (p < 0.005)). On loneliness score 25.5% reported often feeling isolated from others. One of the most significant concerns by patients was the fear and embarrassment related to unpredictable episodes of incontinence. Conclusion: The SMIS remains a useful tool for quantifying incontinence symptoms but may underestimate the psychosocial morbidity associated with unpredictable episodes of incontinence. Interventions aimed at decreasing anxiety and to address feelings of disgust may be helpful for a significant number of patients requiring treatment for FI.
CRIS-Team Scopus Importer:2021-01-22
Keywords: Anxiety; Faecal incontinence; Psychosocial; Score

A faecal microbiota signature with high specificity for pancreatic cancer - Kartal, Ece; Schmidt, Thomas S. B.; Molina-Montes, Esther; Rodriguez-Perales, Sandra; Wirbel, Jakob; Maistrenko, Oleksandr M.; Akanni, Wasiu A.; Alhamwe, Bilal Alashkar; Alves, Renato J.; Carrato, Alfredo; Erasmus, Hans-Peter; Estudillo, Lidia; et al. (Gut, 2022)
Background Recent evidence suggests a role for the microbiome in pancreatic ductal adenocarcinoma (PDAC) aetiology and progression. Objective To explore the faecal and salivary microbiota as potential diagnostic biomarkers. Methods We applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case-control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case-control study (n=76), in the validation phase. Results Faecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19-9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation. Conclusion Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible.
CRIS-Team WoS Importer:2022-03-25

A falciform ligament flap surface sealing technique for laparoscopic and robotic-assisted liver surgery - Rahimli, M.; Perrakis, A.; Schellerer, Vera; Andric, M.; Stockheim, J.; Lorenz, E.; Franz, M.; Arend, J.; Croner, R. S. (Scientific Reports, 2020)
Whether sealing the hepatic resection surface after liver surgery decreases morbidity is still unclear. Nevertheless, various methods and materials are currently in use for this procedure. Here, we describe our experience with a simple technique using a mobilized falciform ligament flap in minimally invasive liver surgery (MILS). We retrospectively analyzed the charts from 46 patients who received minor MILS between 2011 and 2019 from the same surgical team in a university hospital setting in Germany. Twenty-four patients underwent laparoscopic liver resection, and 22 patients received robotic-assisted liver resection. Sixteen patients in the laparoscopic group and fourteen in the robotic group received a falciform ligament flap (FLF) to cover the resection surface after liver surgery. Our cohort was thus divided into two groups: laparoscopic and robotic patients with (MILS + FLF) and without an FLF (MILS−FLF). Twenty-eight patients (60.9%) in our cohort were male. The overall mean age was 56.8 years (SD 16.8). The mean operating time was 249 min in the MILS + FLF group vs. 235 min in the MILS−FLF group (p = 0.682). The mean blood loss was 301 ml in the MILS + FLF group vs. 318 ml in the MILS−FLF group (p = 0.859). Overall morbidity was 3.3% in the MILS + FLF group vs. 18.8% in the MILS−FLF group (p = 0.114). One patient in the MILS−FLF group (overall 2.2%), who underwent robotic liver surgery, developed bile leakage, but this did not occur in the MILS + FLF group. Covering the resection surface of the liver after minor minimally invasive liver resection with an FLF is a simple and cost-effective technique that does not prolong surgical time or negatively affect other perioperative parameters. In fact, it is a safe add-on step during MILS that may reduce postoperative morbidity. Further studies with larger cohorts will be needed to substantiate our proof of concept and results.
CRIS-Team Scopus Importer:2020-07-31

Age Distribution and Concomitant Injuries in Pulmonary Contusion: An Analysis Based on Routine Data - Finkbeiner, Rebekka; Krinner, Sebastian; Langenbach, Andreas; Besendörfer, Manuel; Schulz-Drost, Stefan (Thoracic and Cardiovascular Surgeon, 2018)
BACKGROUND: As the population ages, low-energy thoracic injuries are becoming increasingly relevant in individual injuries, particularly pulmonary contusions (PCs) and their common concomitant injuries. The objective of this study was to determine the prevalence and age distribution of thoracic trauma, especially PC, to make conclusions about common secondary diagnoses and developments in management. METHODS: A retrospective analysis of 209,820 cases, based on German routine data from the years 2009 to 2015, with a main diagnosis (MD) or secondary diagnosis (SD) of thoracic trauma (S27 according to ICD-10) was performed. The entire patient collective with a MD of S27 was examined as well as those with PCs (S27.31). RESULTS: In all 61,016 patients with a MD of S27, 7,558 (12.4%) had a MD of PC and among the 148,804 patients with a SD of S27, 58,247 patients (39.1%) had a SD of PC. PC occurs mostly in the age groups of 20 to 25, 45 to 50, and 70 to 75 years. The proportion of older people tends to be increasing. The most concomitant thoracic injuries were serial rib fractures (27.1%), pneumothorax (11.9%), and sternum fractures (6.2%). Computed tomography scan is the most common diagnostic tool in PC (MD >80%, SD >60%). Therapeutically, intensive care (>50%) and chest drainage are most important (MD: 12.5%, SD: 60.1%), while operative measures are rare (≤ 4%). CONCLUSION: PC shows a marked increase in the incidence, especially in older patients and as a companion diagnosis in thoracic injuries. It should be diagnosed early as well as its concomitant injuries to avoid complications.
EVALuna2:35788

Aggregates in platelet concentrates - Van Der Meer, P. F.; Dumont, L. J.; Lozano, Miguel; Bondar, N.; Wong, J.; Ismay, S.; Pink, J.; Nussbaumer, W.; Coene, J.; Feys, H. B.; Compernolle, V.; Devine, D. V.; et al. (Vox Sanguinis, 2015)
EVALuna2:15991

Agonistic autoantibodies against ß2-adrenergic receptor influence retinal microcirculation in glaucoma suspects and patients - Hohberger, Bettina; Hosari, Sami; Wallukat, Gerd; Kunze, Rudolf; Krebs, Johann Ferdinand; Müller, Magdalena; Hennig, Till; Lämmer, Robert; Horn, Folkert; Garcia Munoz, Luis Enrique; Herrmann, Martin; Mardin, Christian (PLoS ONE, 2021)
PURPOSE: Agonistic β2-adrenergic receptor autoantibodies (β2-agAAb) have been observed in sera of patients with ocular hypertension and open-angle glaucoma (OAG). They target the β2-receptors on trabecular meshwork, ciliary body and pericytes (Junemann et al. 2018; Hohberger et al. 2019). In addition to their influence on the intraocular pressure, an association to retinal microcirculation is discussed. This study aimed to investigate foveal avascular zone (FAZ) characteristics by en face OCT angiography (OCT-A) in glaucoma suspects and its relationship to β2-agAAb status in patients with OAG. MATERIAL AND METHODS: Thirty-four patients (28 OAG, 6 glaucoma suspects) underwent standardized, clinical examination including sensory testing as white-on-white perimetry (Octopus G1, mean defect, MD) and structural measures as retinal nerve fibre layer (RNFL) thickness, neuroretinal rim width (BMO-MRW), retinal ganglion cell layer (RGCL) thickness, and inner nuclear layer (INL) thickness with high-resolution OCT. FAZ characteristics were measured by OCT-A scans of superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). FAZ-R was calculated (area FAZ (SVP)/area FAZ (ICP)). Using cardiomyocyte bioassays we analysed serum samples for the presence of β2-agAAb. RESULTS: (I) Total mean FAZ area [mm2]: 0.34±0.16 (SVP), 0.24±0.12 (ICP), and 0.49±0.24 (DCP); mean FAZ-R 1.58±0.94. No correlation was seen for FAZ-R with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (II) ß2-agAAb have been observed in 91% patients and showed no correlation with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (III) FAZ-R correlated significantly with the β2-agAAb-induced increase of the beat rate of cardiomyocyte (p = 0.028). CONCLUSION: FAZ characteristics did not correlate with any glaucoma associated functional and morphometric follow-up parameter in the present cohort. However, level of β2-agAAb showed a significantly correlation with FAZ-ratio. We conclude that β2-agAAb might be a novel biomarker in glaucoma pathogenesis showing association to FAZ-ratio with OCT-A.
CRIS-Team Scopus Importer:2021-05-21

A health insurance claims analysis on the effect of female sex on long-term outcomes after peripheral endovascular interventions for symptomatic peripheral arterial occlusive disease - Heidemann, Franziska; Kuchenbecker, Jenny; Peters, Frederik; Kotov, Artur; Marschall, Ursula; L'Hoest, Helmut; Acar, Laura; Ramkumar, Niveditta; Goodney, Philip; Debus, Eike Sebastian; Rother, Ulrich; Behrendt, Christian Alexander (Journal of Vascular Surgery, 2021)
Objective: Several reports have addressed sex disparities in peripheral arterial occlusive disease (PAOD) treatment with inconclusive or even conflicting results. However, most previous studies have neither been sufficiently stratified nor used matching or weighting methods to address severe confounding. In the present study, we aimed to determine the disparities between sexes after percutaneous endovascular revascularization (ER) for symptomatic PAOD. Methods: Health insurance claims data from the second-largest insurance fund in Germany, BARMER, were used. A large cohort of patients who had undergone index percutaneous ER of symptomatic PAOD from January 1, 2010 to December 31, 2018 were included in the present study. The study cohort was stratified by the presence of intermittent claudication, ischemic rest pain, and wound healing disorders. Propensity score matching was used to adjust for confounding through differences in age, treated vessel region, comorbidities, and pharmacologic treatment. Sex-related differences regarding cardiovascular event-free survival, amputation-free survival, and overall survival within 5 years of surgery were determined using Kaplan-Meier time-to-event curves, log-rank test, and Cox regression analysis. Results: In the present study, 50,051 patients (47.2% women) were identified and used to compose a matched cohort of 35,232 patients. Among all strata, female patients exhibited lower mortality (hazard ratio [HR], 0.69-0.90), fewer amputations or death (HR, 0.70-0.89), and fewer cardiovascular events or death (HR, 0.78-0.91). The association between female sex and improved long-term outcomes was most pronounced for the patients with intermittent claudication. Conclusions: In the present propensity score-matched analysis of health insurance claims, we observed superior cardiovascular event-free survival, amputation-free survival, and overall survival during 5 years of follow-up after percutaneous ER in women with symptomatic PAOD. Future studies should address sex disparities in the open surgical treatment of PAOD to illuminate whether the conflicting data from previous reports might have resulted from insufficient stratification of the studies.
CRIS-Team Scopus Importer:2021-04-16
Keywords: Endovascular techniques; Health services research; Outcomes; Peripheral arterial disease; Sex

A hundred patients with vertical rectus abdominis myocutaneous (VRAM) flap for pelvic reconstruction after total pelvic exenteration - Horch, Raymund E.; Hohenberger, Werner; Eweida, A.; Kneser, U.; Weber, K.; Arkudas, Andreas; Merkel, Susanne; Göhl, Jonas; Beier, Justus (International Journal of Colorectal Disease, 2014)
We analysed the outcomes of a series of 100 consecutive patients with anorectal cancer with neoadjuvant radiochemotherapy and abdominoperineal exstirpation or total pelvic exenteration, who received a transpelvic vertical rectus abdominis myocutaneous (VRAM) flap for pelvic, vaginal and/or perineal reconstruction and compare a cohort to patients without VRAM flaps.Within a 10-year period (2003-2013) in our institution 924 patients with rectal cancer stage y0 to y IV were surgically treated. Data of those 100 consecutive patients who received a transpelvic VRAM flap were collected and compared to patients without flaps.In 100 consecutive patients with transpelvic VRAM flaps, major donor site complications occurred in 6 %, VRAM-specific perineal wound complications were observed in 11 % of the patients and overall 30-day mortality was 2 %.The VRAM flap is a reliable and safe method for pelvic reconstruction in patients with advanced disease requiring pelvic exenteration and irradiation, with a relatively low rate of donor and recipient site complications. In this first study, to compare a large number of patients with VRAM flap reconstruction to patients without pelvic VRAM flap reconstruction, a clear advantage of simultaneous pelvic reconstruction is demonstrated.
EVALuna2:15167

A large cohort of patients with hepatocellular carcinoma in a single European centre: aetiology and prognosis now and in a historical cohort - Ganslmayer, Marion; Hagel, Alexander; Dauth, Wolfgang; Zopf, Steffen; Strobel, Deike; Mueller, Volker; Uder, Michael; Neurath, Markus; Siebler, Jürgen (Swiss Medical Weekly, 2014)
The incidence of hepatocellular carcinoma is rising. However, this is occurring not only in developing nations, but in industrial countries as well. Surveillance programmes, classification systems and therapeutic options have improved, but there is a lack of data regarding their impact on the prognosis of this difficult-to-treat cancer.We evaluated 484 patients and reported on disease stage, therapeutic procedures and survival time. Data were compared with a historical cohort treated in the same centre 10 years before.In this cohort, the main reason for liver disease was alcoholism, although hepatitis B remains the leading cause of hepatocellular carcinoma worldwide. Now, most patients have compensated liver function and hepatocellular carcinoma is diagnosed in the early tumour stages (it was diagnosed in the advanced disease stages in the previous cohort). Overall, median survival time was 62.4 weeks, 1-year survival was 58.6% and 3-year survival was 23.2%. Survival time correlated with the stage of liver disease, tumour stage and with therapeutic options.Surveillance programmes lead to diagnosis in earlier tumour stages. Differentiated classification systems allow individualised therapeutic approaches. Earlier cancer stage and compensated liver function allow combination or sequential therapy, which was nearly impossible some years ago but is an option for most now. Primary liver cancer remains a difficult-to-treat malignancy, but the prognosis has improved remarkably, at least in the western world.
EVALuna2:1851

Alpha interferon inhibits human herpesvirus 8 (HHV-8) reactivation in primary effusion lymphoma cells and reduces HHV-8 load in cultured peripheral blood mononuclear cells. - Monini, Paolo; Carlini, Francesca; Stürzl, Michael; Rimessi, Paola; Superti, Fabiana; Franco, Marina; Melucci-Vigo, Gianna; Cafaro, Aurelio; Goletti, Delia; Sgadari, Cecilia; Buttò, Stefano; Leone, Patrizia; et al. (Journal of Virology, 1999)
Infection by human herpesvirus 8 (HHV-8) is associated with the development of Kaposi's sarcoma (KS). Since regression of KS can be achieved by treatment of the patients with alpha interferon (IFN-alpha), we analyzed the effects of IFN-alpha or anti-IFN-alpha antibodies (Ab) on HHV-8 latently infected primary effusion lymphoma-derived cell lines (BCBL-1 and BC-1) and on peripheral blood mononuclear cells (PBMC) from patients with all forms of KS and from at-risk subjects. IFN-alpha inhibited in a dose-dependent manner the amplification of HHV-8 DNA in BCBL-1 cells induced to lytic infection with tetradecanoyl phorbol acetate (TPA). This effect was associated with the inhibition of the expression of HHV-8 nut-1 and kaposin genes that are induced early and several hours, respectively, after TPA treatment. In addition, IFN-alpha inhibited virus production and/or release from BCBL-1 cells. Inhibition of nut-1 and kaposin genes by IFN-alpha was also observed in BC-1 cells induced with n-butyrate. Conversely, the addition of anti-IFN-alpha Ab to TPA-induced BCBL-1 cells resulted in a larger number of mature enveloped particles and in a more extensive cytopathic effect due to the neutralization of the endogenous IFN produced by these cells. IFN was also produced by cultured PBMC from HHV-8-infected individuals, and this was associated with a loss of viral DNA during culture. However, the addition of anti-IFN-alpha Ab or anti-type I IFN receptor Ab promoted the maintenance of HHV-8 DNA in these cells that was associated with the detection of the latency-associated kaposin RNA. Finally, the addition of IFN-alpha reduced the HHV-8 load in PBMC. Thus, IFN-alpha appears to have inhibitory effects on HHV-8 persistent infection of PBMC. These results suggest that, in addition to inhibiting the expression of angiogenic factors that are key to KS development, IFN-alpha may induce KS regression by reducing the HHV-8 load and/or inhibiting virus reactivation.

Altered Diversity and Composition of the Microbiome in Patients with Primary Untreated Colorectal Cancer - Langheinrich, Melanie; Wirtz, Stefan; Weber, Klaus; Grützmann, Robert; Kersting, Stephan (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

A microfluidic-based PDAC organoid system reveals the impact of hypoxia in response to treatment - Geyer, Marlene; Schreyer, Daniel; Gaul, Lisa Marie; Pfeffer, Sina; Pilarsky, Christian; Queiroz, Karla (Cell Death Discovery, 2023)
Pancreatic Ductal Adenocarcinoma (PDAC) is estimated to become the second leading cause of cancer-related deaths by 2030 with mortality rates of up to 93%. Standard of care chemotherapeutic treatment only prolongs the survival of patients for a short timeframe. Therefore, it is important to understand events driving treatment failure in PDAC as well as identify potential more effective treatment opportunities. PDAC is characterized by a high-density stroma, high interstitial pressure and very low oxygen tension. The aim of this study was to establish a PDAC platform that supported the understanding of treatment response of PDAC organoids in mono-, and co-culture with pancreatic stellate cells (PSCs) under hypoxic and normoxic conditions. Cultures were exposed to Gemcitabine in combination with molecules targeting relevant molecular programs that could explain treatment specific responses under different oxygen pressure conditions. Two groups of treatment responses were identified, showing either a better effect in monoculture or co-culture. Moreover, treatment response also differed between normoxia and hypoxia. Modulation of response to Gemcitabine was also observed in presence of a Hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) inhibitor and HIF inhibitors. Altogether this highlights the importance of adjusting experimental conditions to include relevant oxygen levels in drug response studies in PDAC.
CRIS-Team Scopus Importer:2023-02-03

Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation - Gingras, Marie-Claude; Covington, Kyle R.; Chang, David K.; Donehower, Lawrence A.; Gill, Anthony J.; Ittmann, Michael M.; Creighton, Chad J.; Johns, Amber L.; Shinbrot, Eve; Dewal, Ninad; Fisher, William E.; Pilarsky, Christian; et al. (Cell Reports, 2016)
The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of ?-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.
EVALuna2:15250

Analysis of DNA Hypermethylation in Pancreatic Cancer Using Methylation-Specific PCR and Bisulfite Sequencing - Liu, Bin; Pilarsky, Christian (Methods in Molecular Biology, 2018)
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor and the fourth common cause of cancer death in the Western world. The lack of effective therapeutic strategies is attributed to the late diagnosis of this disease. Methylation markers could improve early detection and help in the surveillance of PDAC after treatment. Analysis of hypermethylation in the tumor tissue and tumor-derived exosomes might help to identify new therapeutic strategies and aid in the understanding of the pathophysiological changes occurring in pancreatic cancer. There are several methods for the detection of methylation events. Whereas methylation-specific PCR (MSP-PCR) is the method of choice, the cost reductions in DNA sequencing enables researchers to add bisulfite sequencing (BSS) to their repertoire if a small number of genes will be tested in a larger set of patients' samples. During the last years, several techniques to isolate and analyze DNA methylation have been proposed, but DNA modification using sodium bisulfite is still the gold standard.
CRIS-Team WoS Importer:2019-02-27

Analysis of GPRC6A variants in different pancreatitis etiologies - Kaune, Tom; Ruffert, Claudia; Hesselbarth, Nico; Damm, Marko; Krug, Sebastian; Cardinal von Widdern, Julian; Masson, Emmanuelle; Chen, Jian Min; Rebours, Vinciane; Buscail, Louis; Férec, Claude; Grützmann, Robert; et al. (Pancreatology, 2020)
Background: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies. Methods: We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis. Results: We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65–0.89, p = 8 × 10−5) and a Chinese cohort (OR 0.78, 95% CI 0.64–0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99–1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis. Conclusions: Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.
CRIS-Team Scopus Importer:2020-09-04
Keywords: Calcium; G-Protein coupled receptor; Genetics; Inflammation; Pancreatitis

Analysis of Intraoperative Frozen Pancreatic Resection Margin and Prediction of Postoperative Pancreatic Fistula Risk During Pancreatoduodenectomy - Brunner, Maximilian; Kovacevic, Jasna; Krautz, Christian; Merkel, Susanne; Hartmann, Arndt; Grützmann, Robert; Haller, Florian; Weber, Georg (Journal of the American College of Surgeons, 2022)
BACKGROUND: Pancreatic duct diameter and pancreatic texture are important predictive factors for a postoperative pancreatic fistula (POPF) and are assessed intraoperatively by the surgeon. However, surgical evaluation is arbitrary and difficult to objectify, especially in minimally invasive approaches in pancreatic surgery. STUDY DESIGN: We conducted a retrospective analysis of 275 patients that underwent pancreatoduodenectomy from 2012 to 2019 at our institution. Pancreatic duct diameter and pancreatic fibrosis were assessed by histopathologic examination of the pancreatic resection margin using intraoperative frozen sections and correlated with the occurrence of POPF and clinically relevant POPF (CR-POPF). RESULTS: The POPF and CR-POPF rates were 27% and 19%, respectively. Univariate analysis indicated that the indication for surgery, the surgically determined pancreatic duct diameter, and pancreatic texture, as well as the histopathologically determined pancreatic duct diameter and pancreatic fibrosis were significant predictive factors for POPF and CR-POPF. A multivariate analysis revealed histopathologically determined pancreatic duct diameter and pancreatic fibrosis as independent risk factors for POPF (OR [odds ratio] 2.3 [1.1 to 4.5], p = 0.022 and OR 2.4 [1.1 to 5.1], p = 0.023, respectively) and CR-POPF (OR 2.2 [1.1 to 4.8], p = 0.037 and OR 2.6 [1.1 to 6.1], p = 0.036). CONCLUSIONS: Histopathologically determined pancreatic duct diameter and pancreatic fibrosis are quantitatively measurable independent risk factors for POPF and CR-POPF. An intraoperative objective histopathologic evaluation of these parameters using frozen sections could support the surgical assessment of the pancreatic duct diameter and the pancreatic texture.
CRIS-Team Scopus Importer:2022-04-29

Analysis of the interferon-γ-induced secretome of intestinal endothelial cells: putative impact on epithelial barrier dysfunction in IBD - Naschberger, Elisabeth; Flierl, Christian; Huang, Jinghao; Erkert, Lena; Gámez Belmonte, Maria de los Reyes; Gonzalez Acera, Miguel; Bober, Magdalena; Mehnert, Martin; Becker, Christoph; Schellerer, Vera S.; Britzen-Laurent, Nathalie; Stürzl, Michael (Frontiers in Cell and Developmental Biology, 2023)
The development of inflammatory bowel diseases (IBD) involves the breakdown of two barriers: the epithelial barrier and the gut-vascular barrier (GVB). The destabilization of each barrier can promote initiation and progression of the disease. Interestingly, first evidence is available that both barriers are communicating through secreted factors that may accordingly serve as targets for therapeutic modulation of barrier functions. Interferon (IFN)-γ is among the major pathogenesis factors in IBD and can severely impair both barriers. In order to identify factors transmitting signals from the GVB to the epithelial cell barrier, we analyzed the secretome of IFN-γ-treated human intestinal endothelial cells (HIEC). To this goal, HIEC were isolated in high purity from normal colon tissues. HIEC were either untreated or stimulated with IFN-γ (10 U/mL). After 48 h, conditioned media (CM) were harvested and subjected to comparative hyper reaction monitoring mass spectrometry (HRM™ MS). In total, 1,084 human proteins were detected in the HIEC-CM. Among these, 43 proteins were present in significantly different concentrations between the CM of IFN-γ- and control-stimulated HIEC. Several of these proteins were also differentially expressed in various murine colitis models as compared to healthy animals supporting the relevance of these proteins secreted by inflammatory activated HIEC in the inter-barrier communication in IBD. The angiocrine pathogenic impact of these differentially secreted HIEC proteins on the epithelial cell barrier and their perspectives as targets to treat IBD by modulation of trans-barrier communication is discussed in detail.
CRIS-Team Scopus Importer:2023-09-08
Keywords: angiocrine; barrier; cytokines; endothelial; IBD-inflammatory bowel disease; interferon; paracrine; secretion

Anatomy of the Transverse Colon and Possible Pathways of Aberrant Lymphatic Tumour Spread in Complete Mesocolic Excision for Colon Cancer - Stelzner, S.; Hohenberger, Werner; Weber, K.; West, N. P.; Witzigmann, H.; Wedel, T. (2016)
EVALuna2:15246

Anatomy of the transverse colon revisited with respect to complete mesocolic excision and possible pathways of aberrant lymphatic tumor spread - Stelzner, Sigmar; Hohenberger, Werner; Weber, Klaus; West, Nicholas P.; Witzigmann, Helmut; Wedel, Thilo (International Journal of Colorectal Disease, 2016)
Although lymph node metastases to pancreatic and gastroepiploic lymph node stations in transverse colon cancer have been described, the mode of lymphatic spread in this area remains unclear. This study was undertaken to describe possible pathways of aberrant lymphatic spread in the complex anatomic area of the proximal superior mesenteric artery and vein, the greater omentum, and the lower pancreatic border.Abdominal specimens obtained from four cadaveric donors were dissected according to the principles of complete mesocolic excision. The vascular architecture of the transverse colon was scrutinized in search of possible pathways of lymphatic spread to the pancreatic and gastroepiploic lymph nodes.Vascular connections between the transverse colon and the greater omentum at the level of both the hepatic and the splenic flexures could be identified. In addition, small vessels running from the transverse mesocolon to the lower pancreatic border in the area between the middle colic artery and the inferior mesenteric vein were demonstrated. Moreover, venous tributaries to the gastrocolic trunk could be exposed to highlight its surgical importance as a guiding structure for complete mesocolic excision.The technical feasibility to clearly separate embryologic compartments by predefined tissue planes in complete mesocolic excision was confirmed. However, the vicinity of all three endodermal intestinal segments (foregut, midgut, and hindgut) obviously gives way to vascular connections that might serve as potential pathways for lymphatic metastatic spread of transverse colon cancer.
EVALuna2:15210

An Exploratory Study Using Next-Generation Sequencing to Identify Prothrombotic Variants in Patients with Cerebral Vein Thrombosis. - Kramer, Robert Anton; Zimmermann, Robert; Strobel, Julian; Achenbach, Susanne; Stroebel, Armin; Hackstein, Holger; Messerer, David Alexander Christian; Schneider, Sabine (International Journal of Molecular Sciences, 2023)
Prothrombotic hereditary risk factors for cerebral vein thrombosis (CVT) are of clinical interest to better understand the underlying pathophysiology and stratify patients for the risk of recurrence. This study explores prothrombotic risk factors in CVT patients. An initial screening in patients of the outpatient clinic of the Department of Transfusion Medicine and Hemostaseology of the University Hospital Erlangen, Germany, revealed 183 patients with a history of CVT. An initial screening identified a number of common prothrombic risk factors, including Factor V Leiden (rs6025) and Prothrombin G20210A (rs1799963). All patients without relevant findings (58 individuals) were invited to participate in a subsequent genetic analysis of 55 relevant genes using next-generation sequencing (NGS). Three intron variants (ADAMTS13: rs28446901, FN1: rs56380797, rs35343655) were identified to occur with a significantly higher frequency in the CVT patient cohort compared to the general European population. Furthermore, the combined prevalence of at least two of four potentially prothrombic variants (FGA (rs6050), F13A1 (rs5985), ITGB3 (rs5918), and PROCR (rs867186)) was significantly higher in the CVT subjects. The possible impact of the identified variants on CVT is discussed.
EVALuna2:535884

Angiocrine Regulation of Epithelial Barrier Integrity in Inflammatory Bowel Disease - Stürzl, Michael; Kunz, Meik; Krug, Susanne M.; Naschberger, Elisabeth (Frontiers in Medicine, 2021)
Inflammatory bowel disease describes chronic inflammatory disorders. The incidence of the disease is rising. A major step in disease development is the breakdown of the epithelial cell barrier. Numerous blood vessels are directly located underneath this barrier. Diseased tissues are heavily vascularized and blood vessels significantly contribute to disease progression. The gut-vascular barrier (GVB) is an additional barrier controlling the entry of substances into the portal circulation and to the liver after passing the first epithelial barrier. The presence of the GVB rises the question, whether the vascular and endothelial barriers may communicate bi-directionally in the regulation of selective barrier permeability. Communication from epithelial to endothelial cells is well-accepted. In contrast, little is known on the respective backwards communication. Only recently, perfusion-independent angiocrine functions of endothelial cells were recognized in a way that endothelial cells release specific soluble factors that may directly act on the epithelial barrier. This review discusses the putative involvement of angiocrine inter-barrier communication in the pathogenesis of IBD.
CRIS-Team Scopus Importer:2021-08-27
Keywords: angiocrine; angiogenesis; barrier; endothelial; epithelial; inflammation; inflammatory bowel disease

Angioplasty in asymptomatic carotid artery stenosis vs. endarterectomy compared to best medical treatment: One-year interim results of SPACE-2 - Reiff, T.; Eckstein, H. H.; Mansmann, U.; Jansen, O.; Fraedrich, G.; Mudra, H.; Böckler, D.; Böhm, M.; Brückmann, H.; Debus, E. S.; Fiehler, J.; Lang, Werner; et al. (International Journal of Stroke, 2019)
Background: Treatment of individuals with asymptomatic carotid artery stenosis is still handled controversially. Recommendations for treatment of asymptomatic carotid stenosis with carotid endarterectomy (CEA) are based on trials having recruited patients more than 15 years ago. Registry data indicate that advances in best medical treatment (BMT) may lead to a markedly decreasing risk of stroke in asymptomatic carotid stenosis. The aim of the SPACE-2 trial (ISRCTN78592017) was to compare the stroke preventive effects of BMT alone with that of BMT in combination with CEA or carotid artery stenting (CAS), respectively, in patients with asymptomatic carotid artery stenosis of ≥70% European Carotid Surgery Trial (ECST) criteria. Methods: SPACE-2 is a randomized, controlled, multicenter, open study. A major secondary endpoint was the cumulative rate of any stroke (ischemic or hemorrhagic) or death from any cause within 30 days plus an ipsilateral ischemic stroke within one year of follow-up. Safety was assessed as the rate of any stroke and death from any cause within 30 days after CEA or CAS. Protocol changes had to be implemented. The results on the one-year period after treatment are reported. Findings: It was planned to enroll 3550 patients. Due to low recruitment, the enrollment of patients was stopped prematurely after randomization of 513 patients in 36 centers to CEA (n = 203), CAS (n = 197), or BMT (n = 113). The one-year rate of the major secondary endpoint did not significantly differ between groups (CEA 2.5%, CAS 3.0%, BMT 0.9%; p = 0.530) as well as rates of any stroke (CEA 3.9%, CAS 4.1%, BMT 0.9%; p = 0.256) and all-cause mortality (CEA 2.5%, CAS 1.0%, BMT 3.5%; p = 0.304). About half of all strokes occurred in the peri-interventional period. Higher albeit statistically non-significant rates of restenosis occurred in the stenting group (CEA 2.0% vs. CAS 5.6%; p = 0.068) without evidence of increased stroke rates. Interpretation: The low sample size of this prematurely stopped trial of 513 patients implies that its power is not sufficient to show that CEA or CAS is superior to a modern medical therapy (BMT) in the primary prevention of ischemic stroke in patients with an asymptomatic carotid stenosis up to one year after treatment. Also, no evidence for differences in safety between CAS and CEA during the first year after treatment could be derived. Follow-up will be performed up to five years. Data may be used for pooled analysis with ongoing trials.
CRIS-Team Scopus Importer:2019-05-28
Keywords: Asymptomatic carotid artery stenosis; best medical treatment; carotid artery stenting; carotid endarterectomy; disease-free survival; epidemiology; primary prevention; prospective study; stroke

Angiostatic immune reaction in colorectal carcinoma: Impact on survival and perspectives for antiangiogenic therapy - Naschberger, Elisabeth; Croner, Roland S.; Merkel, Susanne; Dimmler, Arno; Tripal, Philipp; Amann, Kerstin Ute; Kremmer, Elisabeth; Brueckl, Wolfgang M.; Papadopoulos, Thomas; Hohenadl, Christine; Hohenberger, Werner; Stürzl, Michael (International Journal of Cancer, 2008)
Angiogenesis and inflammation are the 2 major stroma reactions in colorectal carcinoma (CRC). Guanylate binding protein-1 (GBP-1) is a key mediator of angiostatic effects of inflammation. Therefore, we hypothesized that GBP-1 may be a biomarker of intrinsic angiostasis associated with an improved outcome in CRC patients. GBP-1 was strongly expressed in endothelial cells and immune cells in the desmoplastic stroma of 32% of CRC as determined by immunohistochemical investigation of 388 sporadic CRC. Cancer-related 5-year survival was highly significant (p < 0.001) increased (16.2%) in patients with GBP-1-positive CRC. Multivariate analysis showed that GBP-1 is an independent prognostic factor indicating a reduction of the relative risk of cancer-related death by the half (p = 0.032). A comparative transcriptome analysis (22,215 probe sets) of GBP-1-positive (n = 12) and -negative (n = 12) tumors showed that particularly IFN-γ-induced genes including the major antiangiogenic chemokines CXCL9, CXCL10 and CXCL11 were coexpressed with GBP-1. Altogether our findings indicated that GBP-1 may be a novel biomarker and an active component of a Th-1-like angiostatic immune reaction in CRC. This reaction may affect patient's response to antiangiogenic therapy and the identification of such tumors may provide a novel criterion for patient selection. Moreover, the induction of a Th-1-like angiostatic immune reaction may be a promising approach for the clinical treatment of CRC. © 2008 Wiley-Liss, Inc.
Created from Fastlane, Scopus look-up
Keywords: Angiogenesis; Colorectal carcinoma; Guanylate binding protein-1; Inflammation; Interferon-γ

An m5C methylation regulator-associated signature predicts prognosis and therapy response in pancreatic cancer - Yun, Duo; Yang, Zhirong; Zhang, Shuman; Yang, Hai; Liu, Dongxue; Grützmann, Robert; Pilarsky, Christian; Britzen-Laurent, Nathalie (Frontiers in Cell and Developmental Biology, 2022)
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive digestive malignancy due to frequent late-stage diagnosis, rapid progression and resistance to therapy. With increasing PDAC incidence worldwide, there is an urgent need for new prognostic biomarkers and therapy targets. Recently, RNA methylation has emerged as a new tumorigenic mechanism in different cancers. 5-methylcytosine (m5C) is one of the most frequent RNA modifications and occurs on a variety of RNA species including mRNA, thereby regulating gene expression. Here we investigated the prognostic role of m5C-regulator-associated transcriptional signature in PDAC. We evaluated m5C-regulator status and expression in 239 PDAC samples from publicly available datasets. We used unsupervised consensus clustering analyses to classify PDACs based on m5C-regulator expression. From the resulting signature of differentially expressed genes (DEGs), we selected prognosis-relevant DEGs to stratify patients and build a scoring signature (m5C-score) through LASSO and multivariate Cox regression analyses. The m5C-score represented a highly significant independent prognostic marker. A high m5C-score correlated with poor prognosis in different PDAC cohorts, and was associated with the squamous/basal subtype as well as activated cancer-related pathways including Ras, MAPK and PI3K pathways. Furthermore, the m5C-score correlated with sensitivity to pathway-specific inhibitors of PARP, EGFR, AKT, HER2 and mTOR. Tumors with high m5C-score were characterized by overall immune exclusion, low CD8(+) T-cell infiltration, and higher PD-L1 expression. Overall, the m5C-score represented a robust predictor of prognosis and therapy response in PDAC, which was associated with unfavorable molecular subtypes and immune microenvironment.
CRIS-Team WoS Importer:2022-09-16

A Novel Anti-Cancer Therapy: CRISPR/Cas9 Gene Editing - Chen, Xin-Zhu; Guo, Rong; Zhao, Cong; Xu, Jing; Song, Hang; Yu, Hua; Pilarsky, Christian; Nainu, Firzan; Li, Jing-Quan; Zhou, Xin-Ke; Zhang, Jian-Ye (Frontiers in Pharmacology, 2022)
Cancer becomes one of the main causes of human deaths in the world due to the high incidence and mortality rate and produces serious economic burdens. With more and more attention is paid on cancer, its therapies are getting more of a concern. Previous research has shown that the occurrence, progression, and treatment prognosis of malignant tumors are closely related to genetic and gene mutation. CRISPR/Cas9 has emerged as a powerful method for making changes to the genome, which has extensively been applied in various cell lines. Establishing the cell and animal models by CRISPR/Cas9 laid the foundation for the clinical trials which possibly treated the tumor. CRISPR-Cas9-mediated genome editing technology brings a great promise for inhibiting migration, invasion, and even treatment of tumor. However, the potential off-target effect limits its clinical application, and the effective ethical review is necessary. The article reviews the molecular mechanisms of CRISPR/Cas9 and discusses the research and the limitation related to cancer clinical trials.
CRIS-Team WoS Importer:2022-08-12

A novel approach to 3-D Endoscopy in Minimally Invasive Surgery - Krüger, Sophie; Penne, Jochen; Hornegger, Joachim; Hohenberger, Werner; Horbach, Thomas (Abstractband curac 2006, 2006)

A novel chip-based parallel transfection assay to evaluate paracrine cell interactions - Kühn, Elisabeth; Naschberger, Elisabeth; Konrad, Andreas; Croner, Roland S.; Britzen-Laurent, Nathalie; Jochmann, Ramona; Münstedt, Helmut; Stürzl, Michael (Lab on A Chip, 2012)
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A Novel Magnetic Field Device for Inducing Hyperthermia Using Magnetic Nanoparticles - Dürr, Stephan; Schmidt, Oliver; Janko, Christina; Kraemer, H P; Tripal, Philipp; Eiermann, F; Tietze, R; Lyer, Stefan; Alexiou, Christoph (Biomedizinische Technik, 2013)
A new alternating current (AC) magnetic field applicator was designed to induce hyperthermia in an animal tumour model using superparamagnetic iron oxidenanoparticles (SPION). First experiments on phantoms including different concentrations of SPION were conducted.The results confirmed that the new AC magnetic field applicator could heat-p SPION. This proofs the capability to induce hyperthermia by SPION, dependent on the concentration
EVALuna2:19922
Keywords: Magnetic drug targeting; nanoparticles; alternating current magnetic field; hyperthermia

An overview of proteomic methods for the study of ‘cytokine storms’ - David, Paul; Hansen, Frederik; Bhat, Adil; Weber, Georg (Expert Review of Proteomics, 2021)
Introduction: The cytokine storm is a form of excessive systemic inflammatory reaction triggered by a myriad of factors that may lead to multi-organ failure, and finally to death. The cytokine storm can occur in a number of infectious and noninfectious diseases including COVID-19, sepsis, ebola, avian influenza, and graft versus host disease, or during the severe inflammatory response syndrome. Area covered: This review mainly focuses on the most common and well-known methods of protein studies (PAGE, SDS-PAGE, and high- performance liquid chromatography). It also discusses other modern technologies in proteomics like mass spectrometry, soft ionization techniques, cytometric bead assays, and the next generation of microarrays that have been used to get an in-depth understanding of the pathomechanisms involved during the cytokine storm. Expert opinion: Overactivation of leukocytes drives the production and secretion of inflammatory cytokines fueling the cytokine storm. These events lead to a systemic hyper-inflammation, circulatory collapse and shock, and finally to multiorgan failure. Therefore, monitoring the patient’s systemic cytokine levels with proteomic technologies that are redundant, economical, and require minimal sample volume for real-time assessment might help in a better clinical evaluation and management of critically ill patients.
CRIS-Team Scopus Importer:2021-04-30
Keywords: COVID-19; Cytokine storm; immunoassays; immunotherapies; mass spectrometry; proteomic methods

ANTAGONISM OF PLATELET-DERIVED SEROTONIN (5-HT) MODULATES MACROPHAGE-MEDIATED TRANSPLANT VASCULOPATHY AFTER AORTIC TRANSPLANTATION BUT NOT LARGE AIRWAY REMODELING IN MURINE TRACHEAL ALLOGRAFTS - Bujnoch, Daniel; Gocht, A.; Distler, Jörg; Spriewald, B.; Ramsperger-Gleixner, Martina; Weyand, Michael; Ensminger, S.; Heim, Christian (2018)
EVALuna2:34953

Anti-DNA-IgM Favors the Detection of NET-Associated Extracellular DNA - Wang, Han; Stehr, Antonia; Singh, Jeeshan; Zlatar, Leticija; Hartmann, Arndt; Evert, Katja; Naschberger, Elisabeth; Von Stillfried, Saskia; Boor, Peter; Munoz, Luis Enrique; Knopf, Jasmin; Stürzl, Michael; et al. (International Journal of Molecular Sciences, 2023)
During inflammatory responses, neutrophils enter the sites of attack where they execute various defense mechanisms. They (I) phagocytose microorganisms, (II) degranulate to release cytokines, (III) recruit various immune cells by cell-type specific chemokines, (IV) secrete anti-microbials including lactoferrin, lysozyme, defensins and reactive oxygen species, and (V) release DNA as neutrophil extracellular traps (NETs). The latter originates from mitochondria as well as from decondensed nuclei. This is easily detected in cultured cells by staining of DNA with specific dyes. However, in tissues sections the very high fluorescence signals emitted from the condensed nuclear DNA hamper the detection of the widespread, extranuclear DNA of the NETs. In contrast, when we employ anti-DNA-IgM antibodies, they are unable to penetrate deep into the tightly packed DNA of the nucleus, and we observe a robust signal for the extended DNA patches of the NETs. To validate anti-DNA-IgM, we additionally stained the sections for the NET-markers histone H2B, myeloperoxidase, citrullinated histone H3, and neutrophil elastase. Altogether, we have described a fast one-step procedure for the detection of NETs in tissue sections, which provides new perspectives to characterize neutrophil-associated immune reactions in disease.
CRIS-Team Scopus Importer:2023-03-10
Keywords: anti-DNA-IgM; extracellular DNA; NETs

Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis - Lankes, Katharina; Hundorfean, Gheorghe; Harrer, Thomas; Pommer, Ansgar J.; Agaimy, Abbas; Angelovska, Irena; Tajmir-Riahi, Azadeh; Göhl, Jonas; Schuler, Gerold; Neurath, Markus; Hohenberger, Werner; Heinzerling, Lucie (OncoImmunology, 2016)
Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics.
EVALuna2:2063

Aortic valve stenosis: computed tomography prior to transcatheter aortic valve implantation (TAVI). How can the outcome be improved? - Hell, M.; Achenbach, Susanne; Arnold, Martin (Herz, 2015)
Computed tomography (CT) plays an important role in the preinterventional work-up of patients referred for transcatheter aortic valve implantation (TAVI). Contrast-enhanced CT allows a comprehensive examination with evaluation of both the vascular access route as well as aortic valve and aortic root geometry. Analysis of the minimum luminal vessel diameter, tortuosity and vascular calcification are important to determine the ability to perform the procedure via a transfemoral access. The size of the aortic annulus can be accurately measured by CT to aid selection of the appropriate prosthesis and the use of CT for prosthesis sizing has been associated with a decreased incidence of paravalvular leakage as compared to 2-dimensional echocardiography. In addition CT permits accurate assessment of aortic root anatomy, distance between coronary ostia and the annulus plane as well as the dimensions of the ascending aorta. Furthermore, suitable fluoroscopic projections that permit an exact orthogonal visualization of the aortic annulus plane by fluoroscopy during the procedure can be extracted from the CT data set. In summary, CT permits comprehensive imaging in TAVI candidates and optimizes procedural outcome.
EVALuna2:12072

A Pilot Study of Non-invasive Sacral Nerve Stimulation in Treatment of Constipation in Childhood and Adolescence - Besendörfer, Manuel; Kohl, Martin; Schellerer, Vera; Carbon, Roman; Diez, Sonja (Frontiers in Pediatrics, 2020)
Background/Aims: Constipation shows both, a high prevalence and a significant impact. However, it is often perceived as minor and treatment choices are limited. The neuromodulation approach is a valuable option to be considered. This study assesses the use of non-invasive sacral nerve stimulation to reduce constipation in children. Methods: Between February 2013 and May 2015, pediatric patients with chronic constipation were treated with this non-invasive neuromodulation procedure, adapted from classical sacral nerve stimulation. A stimulation device attached to adhesive electrodes on the lower abdomen and back generated an electrical field with a stable frequency of 15 Hz via variable stimulation intensity (1–10 V). The effect of therapy was evaluated in routine check-ups and by specialized questionnaires. Results: The study assessed non-invasive sacral nerve stimulation in 17 patients (9 boys, 8 girls, mean age 6.5 years). They underwent stimulation with 6–9 V for a mean of 11 h per day (range 0.5–24 h) over a mean of 12.7 weeks. Improvement of constipation was achieved in more than half of the patients (12/17) and sustained in almost half of these patients (5/12). Complications were minor (skin irritation, electrode dislocation). Conclusions: Non-invasive sacral nerve stimulation appears to be effective in achieving improvement in pediatric patients with chronic constipation. As an additional external neuromodulation concept, this stimulation may represent a relevant addition to currently available therapeutic options. Further studies are needed to confirm these results.
CRIS-Team Scopus Importer:2020-05-08
Keywords: electrostimulation; Hirschsprung's disease; non-invasive sacral nerve stimulation; pediatric surgery; slow-transit constipation

A Pleomorphic Puzzle: Heterogeneous Pulmonary Vascular Occlusions in Patients with COVID-19 - Singh, Jeeshan; Herrmann, Irmgard; Mahajan, Aparna; Schauer, Christine; Shan, Xiaomei; Hartmann, Arndt; Rieker, Ralf; Evert, Katja; Falkeis, Christina; Naschberger, Elisabeth; von Stillfried, Saskia; Boor, Peter; et al. (International Journal of Molecular Sciences, 2022)
Vascular occlusions in patients with coronavirus diseases 2019 (COVID-19) have been frequently reported in severe outcomes mainly due to a dysregulation of neutrophils mediating neutrophil extracellular trap (NET) formation. Lung specimens from patients with COVID-19 have previously shown a dynamic morphology, categorized into three types of pleomorphic occurrence based on histological findings in this study. These vascular occlusions in lung specimens were also detected using native endogenous fluorescence or NEF in a label-free method. The three types of vascular occlusions exhibit morphology of DNA rich neutrophil elastase (NE) poor (type I), NE rich DNA poor (type II), and DNA and NE rich (type III) cohort of eleven patients with six males and five females. Age and gender have been presented in this study as influencing variables linking the occurrence of several occlusions with pleomorphic contents within a patient specimen and amongst them. This study reports the categorization of pleomorphic occlusions in patients with COVID-19 and the detection of these occlusions in a label-free method utilizing NEF.
CRIS-Team Scopus Importer:2022-12-23
Keywords: age; COVID-19; gender; immunothrombosis; native endogenous fluorescence; occlusions; pleomorphism; SARS-CoV-2

A Possible Distinct Molecular Subtype (Quintuple-Wildtype) of Metastatic Colorectal Cancer in First-Line Anti-EGFR Therapy with Cetuximab Plus FOLFIRI - Palliative Precision Therapy and a Multidisciplinary Treatment Approach: Interim Analysis of the IVOPAK II Trial with Early Results - Wein, Axel; Stöhr, Robert; Kersting, Stephan; Siebler, Jürgen; Merkel, Susanne; Busse, Daniel; Wolff, Kerstin; Ostermeier, Nicola; Neufert, Clemens; Vitali, Francesco; Eckstein, Markus; Roth, Jan-Peter; et al. (Oncology, 2021)
Objective: The study aimed to prospectively evaluate a new molecular biomarker panel (KRAS, NRAS, BRAF, PIK3CA, and ERBB2) for palliative first-line treatment of colorectal cancer (CRC), including a multidisciplinary treatment approach. The rate of secondary metastasis resections was assessed. Patients and Methods: A total of 40 patients with definitively nonresectable metastatic CRC were enrolled from 10 centers before the interim analysis (June 2019) of the IVOPAK II trial (Interdisciplinary Care with Quality Control in Palliative Treatment of Colorectal Cancer). After determination of 5 molecular biomarkers in the tumor (KRAS, exons 2-4; NRAS, exons 2-4; BRAF V600E; PIK3CA; and ERBB2), patients in the IVOPAK II study received FOLFIRI plus cetuximab for all-RAS/quintuple-wildtype disease and FOLFIRI plus bevacizumab in the case of RAS mutations. The current article presents the early description of the clinical outcome of the interim analysis of IVOPAK II comparing the all-RAS/quintuple-wildtype and RAS-mutations populations, including a multidisciplinary-treated case report of a quintuple-wildtype patient. Results: The quintuple-wildtype population treated with FOLFIRI plus cetuximab in first-line exhibited a significantly higher response rate and enhanced early tumor shrinkage in the interim analysis than the RAS-mutations population, as well as a high rate of secondary metastatic resections. Conclusion: Initial results of this new biomarker panel (quintuple-wildtype) are promising for anti-EGFR therapy with cetuximab plus doublet chemotherapy (FOLFIRI) in first-line treatment of metastatic CRC. These results warrant confirmation with higher case numbers in the IVOPAK II trial.
CRIS-Team WoS Importer:2021-11-05

A possible role for interferon-alpha and activated natural killer cells in remission of AIDS-related Kaposi's sarcoma: in vitro studies. - Reiter, Z; Ozés, O N; Blatt, L M; Stürzl, Michael; Taylor, M W (Journal of Acquired Immune Deficiency Syndromes, 1992)
The effect of consensus interferon-alpha on the growth of AIDS-related Kaposi's sarcoma-derived cells was studied. Interferon caused a low but significant in vitro inhibition of cell growth. Whereas Kaposi's sarcoma cells were resistant to the cytotoxic effect of natural killer (NK) cells, treatment of NK cells with either interferon or interleukin-2 activated the cell-mediated cytotoxic response. Pretreatment of the Kaposi's sarcoma cells with interferon reduced their sensitivity to interferon-primed natural killer cell or lymphokine (interleukin-2)-activated killer (LAK) cell cytotoxicity. The resistance of Kaposi's sarcoma cells to NK cell-mediated cytotoxicity did not reside in conjugate formation but was due to an inability of Kaposi's sarcoma cells to induce NK cytotoxic factor. Although interferon reduces the sensitivity of Kaposi's sarcoma cells to interferon-primed NK cell and LAK cell activities, the level of natural killing susceptibility remained significantly higher than the poor sensitivity of Kaposi's sarcoma cells to unprimed NK cell activity. Thus, the potential antitumor effect of interferon against Kaposi's sarcoma cells could be mediated both directly (antiproliferative) and/or indirectly by activation of NK cells.

Application of machine learning algorithms for multiparametric MRI-based evaluation of murine colitis - Ellmann, Stephan; Langer, Victoria; Britzen-Laurent, Nathalie; Hildner, Kai; Huber, Carina; Tripal, Philipp; Seyler, Lisa; Waldner, Maximilian; Uder, Michael; Stürzl, Michael; Bäuerle, Tobias (PLoS ONE, 2018)
Magnetic resonance imaging (MRI) allows non-invasive evaluation of inflammatory bowel disease (IBD) by assessing pathologically altered gut. Besides morphological changes, relaxation times and diffusion capacity of involved bowel segments can be obtained by MRI. The aim of this study was to assess the use of multiparametric MRI in the diagnosis of experimentally induced colitis in mice, and evaluate the diagnostic benefit of parameter combinations using machine learning. This study relied on colitis induction by Dextran Sodium Sulfate (DSS) and investigated the colon of mice in vivo as well as ex vivo. Receiver Operating Characteristics were used to calculate sensitivity, specificity, positive- and negative-predictive values (PPV and NPV) of these single values in detecting DSS-treatment as a reference condition. A Model Averaged Neural Network (avNNet) was trained on the multiparametric combination of the measured values, and its predictive capacity was compared to those of the single parameters using exact binomial tests. Within the in vivo subgroup (n = 19), the avNNet featured a sensitivity of 91.3% (95% CI: 86.6-96.0%), specificity of 92.3% (95% CI: 85.1-99.6%), PPV of 96.9% (94.0-99.9%) and NPV of 80.0% (95% CI: 69.9-90.1%), significantly outperforming all single parameters in at least 2 accuracy measures (p < 0.003) and performing significantly worse compared to none of the single values. Within the ex vivo subgroup (n = 30), the avNNet featured a sensitivity of 87.4% (95% CI: 82.6-92.2%), specificity of 82.9% (95% CI: 76.1-89.7%), PPV of 88.9% (84.3-93.5%) and NPV of 80.8% (95% CI: 73.8-87.9%), significantly outperforming all single parameters in at least 2 accuracy measures (p < 0.015), exceeded by none of the single parameters. In experimental mouse colitis, multiparametric MRI and the combination of several single measured values to an avNNet can significantly increase diagnostic accuracy compared to the single parameters alone. This pilot study will provide new avenues for the development of an MR-derived colitis score for optimized diagnosis and surveillance of inflammatory bowel disease.
EVALuna2:35135

Application of microfluidic chips in anticancer drug screening - Fan, Xin Yue; Deng, Zhuo Fen; Yan, Yan Yan; E Orel, Valerii; Shypko, Andrii; B Orel, Valerii; Ivanova, Donika; Pilarsky, Christian; Tang, Jing; Chen, Zhe Sheng; Zhang, Jian Ye (Bosnian Journal of Basic Medical Sciences, 2022)
With the continuous development of drug screening technology, new screening methodologies and technologies are constantly emerging, driving drug screening into rapid, efficient and high-throughput development. Microfluidics is a rising star in the development of innovative approaches in drug discovery. In this article, we summarize the recent years' progress of microfluidic chip technology in drug screening, including the developmental history, structural design, and applications in different aspects of microfluidic chips on drug screening. Herein, the existing microfluidic chip screening platforms are summarized from four aspects: chip structure design, sample injection and drive system, cell culture technology on a chip, and efficient remote detection technology. Furthermore, this review discusses the application and developmental prospects of using microfluidic chips in drug screening, particularly in screening natural product anticancer drugs based on chemical properties, pharmacological effects, and drug cytotoxicity.
CRIS-Team Scopus Importer:2022-06-17

A proposed system for standardized terminology in minimally invasive surgery – a video vignette - Zawadzki, M.; Gómez Ruiz, M.; Tou, S.; Jeffels, A.; Matzel, Klaus (Colorectal Disease, 2020)
CRIS-Team Scopus Importer:2020-09-25

A prospective survey study on the education and awareness about walking exercise amongst inpatients with symptomatic peripheral arterial disease in Germany - Li, Yi; Rother, Ulrich; Rosenberg, Yvonne; Hinterseher, Irene; Uhl, Christian; Mylonas, Spyridon; Grambow, Eberhard; Gombert, Alexander; Busch, Albert; Bresler, Ayko; Öz, Tugce; Görtz, Hartmut; et al. (Vasa-Journal of Vascular Diseases, 2023)
Summary: Background: To determine the adherence to supervised exercise training and underlying reasons for non-adherence amongst patients with inpatient treatment of symptomatic lower extremity peripheral arterial disease (PAD). Patients: This was a prospective questionnaire-based survey study of all consecutively treated inpatients with treatment for either intermittent claudication or chronic limb-threatening ischaemia (CLTI) surveyed at sixteen participating centres in Germany. Results: A total of 235 patients (median age 70 years) were included, thereof 29.4% females and 34.6% with CLTI. The median time from first PAD diagnosis was 4 years (IQR: 1-8). Only 11.4% have previously participated in any walking exercise programme before the index treatment, thereby 10.0% in the IC subgroup and 12.0% with CLTI. Amongst all patients, 35.6% responded they were appropriately informed about the necessity and benefits of walking exercise programmes by their hospital physicians (25.8% by general practitioners), and 65.3% agreed that adherence to supervised exercise may improve their pain-free walking distance. A total of 24.5% responded they had access to necessary information concerning local walking exercise programmes. Amongst 127 free text comments on the reasons for non-adherence to supervised exercise training, 64% of the comments contained lack of information or consent on such measures. Conclusions: Less than 12% of the patients enrolled in the current study have ever participated in a walking exercise programme during their life course. Although all practice guidelines contain corresponding class I recommendations, especially for patients suffering from IC, most patients responded that they were not appropriately informed about the necessity of exercise training along with the fact that 65% agreed that exercise may increase the pain-free walking distance. Taken all together, these results emphasise that we miss an important opportunity in the patient-physician communication. Efforts should be made to improve acceptance and application of structured walking-exercise for patients with PAD.
CRIS-Team Scopus Importer:2023-02-17
Keywords: best medical treatment; health behaviour; health services research; intermittent claudication; peripheral arterial disease; Walking exercise

APSified OCT-angiography analysis: Macula vessel density in healthy eyes during office hours - Müller, Meike; Schottenhamml, Julia; Hosari, Sami; Hohberger, Bettina; Mardin, Christian Y. (PLoS ONE, 2023)
Purpose Optical coherence tomography angiography (OCT-A) can visualize retinal capillary microcirculation non-invasively. In order to investigate potential factors influencing OCT-A diagnostics, the aim of the present study was to determine circadian changes in macular vessel density (VD) in healthy adults during office hours, considering axial length (AL) and subfoveal choroidal thickness (CT). Methods In the prospective study 30 eyes of 30 healthy subjects (mean age 28.7 ± 11.8, range 19–60 years) were recruited who underwent repeated measurements of AL, subfoveal CT and three-layer macula VD (superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP)) on a single day at three predetermined timepoints (9 AM, 3 PM, and 9 PM). For better intra- and interindividual scan comparability, the new Anatomic Positioning System function (APS, part of Glaucoma Module Premium Edition [GMPE], Heidelberg Engineering, Germany) allowing analysis of identical retinal areas, was used for quantitative OCT-A analysis. Results Overall mean macula VD was unchanged during office hours in SVP, ICP and DCP, respectively (p>0.05). In addition, AL and CT showed no statistically significant changes over time (p>0.05). Rather, a large interindividual variance of VD with different peak time was observed. Contrary to the overall data, sectorial VD changed in dependency of office hours in all layers with an increase of VD in SVP between 9 AM and 9 PM (p = 0.003), in ICP between 3 PM and 9 PM (p = 0.000), in DCP between 9 AM and 9 PM (p = 0.048), and 3 PM and 9 PM (p = 0.000), respectively. Conclusion Overall mean macula VD, subfoveal CT and AL tended not to show statistically significant changes over time in this cohort, whereas a regional analysis of VD did. Therefore, a circadian influence on capillary microcirculation should be kept in mind. Moreover, the results highlight the importance of a more detailed analysis of VD in different sectors and different vascular layers. In addition, the pattern of diurnal variation could vary inter-individually, thus a patient-specific fluctuation pattern would need to be considered when evaluating these parameters in clinical practice.
CRIS-Team Scopus Importer:2023-03-24

Arbeitsanweisung in Herzkatheterlabor und Hybridoperationssaal - Schächinger, V.; Nef, H.; Achenbach, Susanne; Butter, C.; Deisenhofer, I.; Eckardt, L.; Eggebrecht, H.; Kuon, E.; Levenson, B.; Linke, A.; Madlener, K.; Mudra, H.; et al. (Der Kardiologe, 2015)
According to the German Radiation Act §18 (2) (Röntgenverordnung) every radiation facility administering radiation to humans has to provide written working instructions for those examinations and treatment procedures which are frequently performed. This is also valid for catheterization laboratories and hybrid operating rooms. It is the duty of the radiation protection officer (Strahlenschutzbeauftragte), a person who has to be appointed by German law (§15 Abs. 2 Nr. 1 Röntgenverordnung) to formulate and implement the working instructions. The current manuscript is a template to create such working instructions, which fulfill the legal requirements.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Cardiac catheterization; Hybrid operating room; Radiation act; Radiation protection; Work instruction

A role for MALT1 activity in Kaposi's sarcoma-associated herpes virus latency and growth of primary effusion lymphoma - Bonsignore, L.; Passelli, K.; Pelzer, C.; Perroud, M.; Konrad, A.; Thurau, Mathias; Stürzl, Michael; Dai, L.; Trillo-Tinoco, Jimena; Del Valle, L.; Qin, Z.; Thome, Margot (Leukemia, 2017)
Primary effusion lymphoma (PEL) is an incurable malignancy that develops in immunodeficient patients as a consequence of latent infection of B-cells with Kaposi's sarcoma-associated herpes virus (KSHV). Malignant growth of KSHV-infected B cells requires the activity of the transcription factor nuclear factor (NF)-?B, which controls maintenance of viral latency and suppression of the viral lytic program. Here we show that the KSHV proteins K13 and K15 promote NF-?B activation via the protease mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1), a key driver of NF-?B activation in lymphocytes. Inhibition of the MALT1 protease activity induced a switch from the latent to the lytic stage of viral infection, and led to reduced growth and survival of PEL cell lines in vitro and in a xenograft model. These results demonstrate a key role for the proteolytic activity of MALT1 in PEL, and provide a rationale for the pharmacological targeting of MALT1 in PEL therapy.
EVALuna2:15308

Arterial injury and pseudoaneurysm formation after lesser trochanter fracture - Regus, Susanne; Lang, Werner (International Journal of Surgery Case Reports, 2015)
Vascular complications after hip fracture are rare but can be life-threatening, especially in the elderly and if diagnosed late.We report a false aneurysm of the calcified deep femoral artery after hip fracture and uneventful stabilization with a gamma nail, in an 85 year old woman. Three weeks after surgery there was swelling of the proximal thigh. Ultrasound scan revealed a false aneurysm of the deep femoral artery and plain X-ray showed a lesser trochanter fragment spiking the calcified deep femoral artery. Open repair of the pseudo-aneurysm with a vein patch was performed.Nowadays the preferred imaging of false aneurysms is by computed tomographic (CT) angiography but this involves high radiation and nephrotoxic contrast agents and may delay diagnosis. What made this a special case was the post-operative plain X-ray which showed a displaced fragment of the lesser trochanter spiking the calcified deep femoral artery, as confirmed on CT scanning.Surgeons should pay attention to any displaced bone fragments close to calcified vessels, especially in the evaluation of routine x-rays following surgical treatment of fractures. This could minimize the potential life-threatening risk of delayed diagnosis, especially because it represents a routine image following surgical fracture treatments.
EVALuna2:15217

ARTFM: Augmented Reality Visualization of Tool Functionality Manuals in Operating Rooms - Kleinbeck, Constantin; Schieber, Hannah; Andress, Sebastian; Krautz, Christian; Roth, Daniel (Proceedings - 2022 IEEE Conference on Virtual Reality and 3D User Interfaces Abstracts and Workshops, VRW 2022, 2022)
Error-free surgical procedures are crucial for a patient's health. However, with the increasing complexity and variety of surgical instruments, it is difficult for clinical staff to acquire detailed assembly and usage knowledge leading to errors in process and preparation steps. Yet, the gold standard in retrieving necessary information when problems occur is to get the paperbased manual. Reading through the necessary instructions is time-consuming and decreases care quality. We propose ARTFM, a process integrated manual, highlighting the correct parts needed, their location, and step-by-step instructions to combine the instrument using an augmented reality head-mounted display.
CRIS-Team Scopus Importer:2022-05-20
Keywords: Human computer interaction (HCI); Human-centered computing; Interaction paradigms; Mixed/augmented reality

A simplified extracorporeal photopheresis procedure based on single high-dose ultraviolet A light irradiation shows similar in vitro efficacy - Buchele, Vera; Hackstein, Holger (Transfusion, 2020)
Background: Extracorporeal photopheresis (ECP) is one of the most widely used and effective cell-based therapies for the treatment of T-cell–mediated diseases. The patients' white blood cells (WBCs) are collected by apheresis and exposed to the photosensitizer 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) light before retransfusion. The UVA/8-MOP combination has been in use in ECP for more than 4 decades; however, whether ECP can be simplified by UVA light irradiation only has never been analyzed. Study Design and Methods: Peripheral blood mononuclear cells were treated with classical ECP or different UVA light doses only (UVAonly). Treatment efficacy was investigated by apoptosis induction in WBC subsets, inhibition of T-cell proliferation, and the ability of monocytes to induce allogeneic T-cell expansion and to respond to lipopolysaccharide and interferon-γ stimulation in vitro. Results: High-dose UVAonly treatment (5 J/cm2) was as efficient as ECP to induce apoptosis within 48 hours. UVAonly treatment modulated the composition of the surviving cells by improving monocyte survival and promoting CD8+ T-cell apoptosis. Both ECP and UVAonly treatment inhibited anti-CD3/anti-CD28 triggered T-cell proliferation. Interestingly, whereas ECP-treated monocytes exhibited a markedly reduced capacity to respond to stimulation and to induce allogeneic T-cell proliferation, UVAonly treatment preserved monocyte functionality to some degree. Conclusions: High-dose UVAonly and standard ECP showed comparable efficacy in inducing apoptosis and inhibiting direct T-cell proliferation. Hence, UVAonly treatment can be a simplified alternative to ECP therapy. Furthermore, increased monocyte survival with partially preserved functionality after UVAonly treatment may provide a novel method for immunoregulation.
CRIS-Team Scopus Importer:2020-12-25
Keywords: apoptosis; extracorporeal photopheresis; UVA light

A single-center, retrospective Analysis for the Detection of Distant Metastases in Patients with regionally metastatic Melanoma in the Era of effective adjuvant Therapies - Toussaint, Frédéric; Kramer, Robert Anton; Bender-Säbelkampf, Sophia; Hornung-Eichler, Annkathrin; Karimi, Bita; Heppt, Markus; Bosch-Voskens, Caroline; Berking, Carola; Erdmann, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

ASO Visual Abstract: Radical Resection in Enteropancreatic Neuroendocrine Tumors-Recurrence-Free Survival Rate and Definition of a Risk Score for Recurrence - Merola, Elettra; Pascher, A.; Rinke, A.; Bartsch, D. K.; Zerbi, A.; Nappo, G.; Carnaghi, C.; Ciola, M.; Mcnamara, M. G.; Zandee, W.; Bertani, E.; Marcucci, S.; et al. (Annals of Surgical Oncology, 2022)
CRIS-Team WoS Importer:2022-07-15

Assessing psychosocial vulnerability and care needs of pretransplant patients by means of the INTERMED - Ludwig, Gundula; Dobe-Tauchert, Perdita; Nonnast-Daniel, Barbara; Stiefel, Friedrich; De Jonge, Peter; Lobo, Elena; Richter, Rainer; Eckardt, Kai-Uwe; Hohenberger, Werner; Weyand, Michael; Soellner, Wolfgang (Zeitschrift für Psychosomatische Medizin und Psychotherapie, 2014)
We investigated whether the INTERMED, a generic instrument for assessing biopsychosocial case complexity and direct care, identifies organ transplant patients at risk of unfavourable post-transplant development by comparing it to the Transplant Evaluation Rating Scale (TERS), the established measure for pretransplant psychosocial evaluation.One hundred nineteen kidney, liver, and heart transplant candidates were evaluated using the INTERMED, TERS, SF-36, EuroQol, Montgomery-Åsberg Depression Rating Scale (MADRS), and Hospital Anxiety & Depression Scale (HADS).We found significant relationships between the INTERMED and the TERS scores. The INTERMED highly correlated with the HADS,MADRS, and mental and physical health scores of the SF-36 Health Survey.The results demonstrate the validity and usefulness of the INTERMED instrument for pretransplant evaluation. Furthermore, our findings demonstrate the different qualities of INTERMED and TERS in clinical practice. The advantages of the psychiatric focus of the TERS and the biopsychosocial perspective of the INTERMED are discussed in the context of current literature on integrated care.
EVALuna2:3696

Association of clinical factors with postoperative complications of esophageal atresia - Besendörfer, Manuel; Müller, Hanna; Weiss, Christel; Wagner, Alexandra; Schellerer, Vera; Hörning, André; Diez, Sonja (Pediatrics and Neonatology, 2020)
Background: Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) remains one of the most common gastrointestinal neonatal malformations. Even though postoperative management is standardized, it differs between hospitals and disease-associated clinical factors that may play a role in outcome have not yet been assessed in detail. Methods: In this monocentric retrospective study, data of 43 patients with EA between 2010 and 2018 were analyzed. Analysis includes assessment of the clinical background, surgical technique, postoperative management including application of continuous muscle relaxation (CMR), influence of coagulation parameters such as factor XIII and incidence of complications. Results: 21 patients (49%) were preterm infants with birth weights between 490 and 2840 g (median 1893 g). Only 35% (n = 15) presented without any concomitant malformations. Within the entire study population, representing Vogt II, IIIb and IIIc, we observed an association between the development of a postoperative pneumothorax and anastomotic failure (AF) (p = 0.0013). Furthermore, pneumothorax was associated with anastomotic stenosis (AS) in Vogt IIIb patients (p = 0.0129). CMR (applied since March 2017 in 7 patients in an attempt to prevent anastomotic problems due to high complication rates) and coagulation factor XIII did not significantly correlate with postoperative outcome. Conclusion: Appearance of pneumothorax was correlated with postoperative complications. These children should be monitored carefully in closer scheduled gastroenterological follow-up esophago-gastro-duodenoscopies. CMR and factor XIII substitution did not reduce anastomotic leakage but should be tested within an enlarged study population.
CRIS-Team Scopus Importer:2020-10-23
Keywords: continuous muscle relaxation; esophageal surgery; neonatal surgery; pneumothorax; postoperative relaxation

Association of genetic and psychological factors with persistent pain after cosmetic thoracic surgery - Dimova, Violeta; Loetsch, Joern; Hühne, Kathrin; Winterpacht, Andreas; Heesen, Michael; Parthum, Andreas; Weber, Peter G.; Carbon, Roman; Grießinger, Norbert; Sittl, Reinhard; Lautenbacher, Stefan (Journal of Pain Research, 2015)
The genetic control of pain has been repeatedly demonstrated in human association studies. In the present study, we assessed the relative contribution of 16 single nucleotide polymorphisms in pain-related genes, such as cathechol-O-methyl transferase gene (COMT), fatty acid amino hydrolase gene (FAAH), transient receptor potential cation channel, subfamily V, member 1 gene (TRPV1), and ?-opioid receptor gene (OPRD1), for postsurgical pain chronification. Ninety preoperatively pain-free male patients were assigned to good or poor outcome groups according to their intensity or disability score assessed at 1 week, 3 months, 6 months, and 1 year after funnel chest correction. The genetic effects were compared with those of two psychological predictors, the attentional bias toward positive words (dot-probe task) and the self-reported pain vigilance (Pain Vigilance and Awareness Questionnaire [PVAQ]), which were already shown to be the best predictors for pain intensity and disability at 6 months after surgery in the same sample, respectively. Cox regression analyses revealed no significant effects of any of the genetic predictors up to the end point of survival time at 1 year after surgery. Adding the genetics to the prediction by the attentional bias to positive words for pain intensity and the PVAQ for pain disability, again no significant additional explanation could be gained by the genetic predictors. In contrast, the preoperative PVAQ score was also, in the present enlarged sample, a meaningful predictor for lasting pain disability after surgery. Effect size measures suggested some genetic variables, for example, the polymorphism rs1800587G>A in the interleukin 1 alpha gene (IL1A) and the COMT haplotype rs4646312T>C/rs165722T>C/rs6269A>G/rs4633T>C/rs4818C>G/rs4680A>G, as possible relevant modulators of long-term postsurgical pain outcome. A comparison between pathophysiologically different predictor groups appears to be helpful in identifying clinically relevant predictors of chronic pain.
EVALuna2:9288

Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer: Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial - Kitz, Julia; Fokas, Emmanouil; Beissbarth, Tim; Stroebel, Philipp; Wittekind, Christian; Hartmann, Arndt; Rueschoff, Josef; Papadopoulos, Thomas; Roesler, Elisabeth; Ortloff-Kittredge, Peter; Kania, Ulrich; Schlitt, Hans; et al. (JAMA Surgery, 2018)
Importance: Previous retrospective studies have shown that surgical quality affects local control in rectal cancer.. Objective: In this secondary end point analysis, we evaluated the prognostic effect of the total mesorectal excision (TME) plane in the CAO/ARO/AIO-04 phase 3 randomized clinical trial. Design, Setting, and Participants: The CAO/ARO/AIO-04 trial enrolled 1236 patients with cT3-4 and/or node-positive rectal adenocarcinoma from 88 centers in Germany between July 25, 2006, and February 26, 2010. Interventions: Patients were randomized to receive treatment with standard fluorouracil-based preoperative chemoradiotherapy (CRT) alone (control arm) or oxaliplatin (experimental arm) followed by TME and adjuvant chemotherapy. Main Outcomes and Measures: The TME quality (mesorectal, intramesorectal, and muscularis propria plane) was prospectively assessed in 1152 operation specimens. An assessment was performed independently by pathologists and surgeons. The results were correlated with clinicopathologic data and the clinical outcome was tested, including multivariable analysis with the Cox regression model. Results: Of 1152 German Caucasian participants, 332 (28.8) were women and the mean age was 63 years. The plane of TME was mesorectal in 930 patients (80.7%), intramesorectal in 169 (14.7%), and muscularis propria in 53 (4.6%). In a univariable analysis, the TME plane was significantly associated with 3-year disease-free survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 73.1-78.8 vs 61.6-76.0 vs 55.6-81.3, respectively; P = .01), cumulative incidence of local and distant recurrences (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 2.0-4.5 vs 1.2-8.1 vs 2.5-20.5, respectively; P < .001; and mesorectal vs intramesorectal vs muscularis propria, 95% CI, 17.0-22.4 vs 18.3-32.0 vs 14.2-39.0, respectively; P = .03, respectively), and overall survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 88.3-92.3 vs 79.7-91.0 vs 81.6-98.7, respectively; P = .02). In contrast to the pathologist-based evaluation, the assessment of TME plane by the operating surgeon failed to demonstrate prognostic significance for any of these clinical end points. In a multivariable analysis, the plane of surgery (mesorectal vs muscularis propria TME) constituted an independent factor for local recurrence (P = .002). Conclusions and Relevance: This phase 3 randomized clinical trial confirms the long-term clinical effect of TME plane quality on local recurrence, as initially reported in the MRC CR07 study. The data highlight the key role of pathologists and surgeons in the multidisciplinary management of rectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT00349076.
EVALuna2:34814

A survey among physicians in surgery and anesthesiology departments after the first surge of SARS-CoV-2 infections in Germany Preparing for further challenges ahead - Grishina, Anna; Link, Fabian; Arend, Arne; Kleemann, Florentine; Tober-Lau, Pinkus; Andree, Dominik; Muenn, Friederike; Gruendl, Magdalena; Quante, Markus; Lederhuber, Hans; Albertsmeier, Markus; Struller, Florian; et al. (Wiener Klinische Wochenschrift, 2022)
Background The SARS-CoV-2 pandemic has extensively challenged healthcare systems all over the world. Many elective operations were postponed or cancelled, changing priorities and workflows in surgery departments. Aims The primary aim of this cross-sectional study was to assess the workload and psychosocial burden of surgeons and anesthesiologists, working in German hospitals during the first wave of SARS-CoV-2 infections in 2020. Methods Quantitative online survey on the workplace situation including psychosocial and work-related stress factors among resident and board-certified surgeons and anesthesiologists. Physicians in German hospitals across all levels of healthcare were contacted via departments, professional associations and social media posts. Results Among 154 total study participants, 54% of respondents stated a lack of personal protective equipment in their own wards and 56% reported increased staff shortages since the onset of the pandemic. While routine practice was reported as fully resumed in 71% of surgery departments at the time of the survey, work-related dissatisfaction among responding surgeons and anesthesiologists increased from 24% before the pandemic to 36% after the first wave of infections. As a countermeasure, 94% of participants deemed the establishment of action plans to increase pandemic preparedness and strengthening German public health systems a useful measure to respond to current challenges. Conclusion The aftermath of the first wave of SARS-CoV-2 infections in Germany has left the surgical staff strained, despite temporarily decreased workloads. Overall, a critical review of the altered conditions is indispensable to identify and promote effective solutions and prudent action plans required to address imminent challenges.
CRIS-Team WoS Importer:2022-01-28

Asymmetric Omphalopagus in a Triplet after In Vitro Fertilization: A Rare Case of Conjoined Twinning - Jabari, Samir; Carbon, Roman; Besendörfer, Manuel; Hartmann, Arndt; Rompel, Oliver; Hoerning, Andre; Söder, Stephan (Case Reports in Pediatrics, 2018)
Introduction: Asymmetric omphalopagus is a rare situation of conjoined twinning, in which a grossly defective twin is attached to the thorax and upper abdomen of the main twin. We describe a case of an asymmetric omphalopagus accompanied by a normal triplet after assisted reproductive technology (ART) and tried to further characterize the all aspects of the conjoined twins. Case Presentation: Perioperative diagnostic imaging was carried out followed by an autopsy to evaluate all aspects of the parasite accompanied by histological, immunohistochemical, and molecular biological evaluation. The parasite had well-developed lower extremities as well as upper extremities with a cleft hand syndrome. The sex was nondeterminable, but DNA fingerprinting revealed that both parasite and autosite are monozygotic, so are females. There was no sign of any axial skeleton or central nervous system. We found a rudimentary rectum with a nonpervious anus, a kidney, ureter, urinary bladder, and a blind-ending urethra. The blood supply of the parasite was connected to the vessel system of the autosite. Conclusions: To our knowledge, only two cases of parasitic omphalopagus after ART have been described to date. Altogether, 52 cases have been reported, and in most of them, the parasites were successfully separated.
EVALuna2:34614

A systems biology approach to identify the combination effects of human herpesvirus 8 genes on NF-κB activation - Konrad, Andreas; Wies, Effi; Thurau, Mathias; Marquardt, Gaby; Naschberger, Elisabeth; Hentschel, Sonja; Jochmann, Ramona; Schulz, Thomas F.; Erfle, Holger; Brors, Benedikt; Lausen, Berthold; Neipel, Frank; et al. (Journal of Virology, 2009)
Human herpesvirus 8 (HHV-8) is the etiologic agent of Kaposi's sarcoma and primary effusion lymphoma. Activation of the cellular transcription factor nuclear factor-kappa B (NF-κB) is essential for latent persistence of HHV-8, survival of HHV-8-infected cells, and disease progression. We used reverse-transfected cell microarrays (RTCM) as an unbiased systems biology approach to systematically analyze the effects of HHV-8 genes on the NF-κB signaling pathway. All HHV-8 genes individually (n = 86) and, additionally, all K and latent genes in pairwise combinations (n = 231) were investigated. Statistical analyses of more than 14,000 transfections identified ORF75 as a novel and confirmed K13 as a known HHV-8 activator of NF-κB. K13 and ORF75 showed cooperative NF-κB activation. Small interfering RNA-mediated knockdown of ORF75 expression demonstrated that this gene contributes significantly to NF-κB activation in HHV-8-infected cells. Furthermore, our approach confirmed K10.5 as an NF-κB inhibitor and newly identified K1 as an inhibitor of both K13- and ORF75-mediated NF-κB activation. All results obtained with RTCM were confirmed with classical transfection experiments. Our work describes the first successful application of RTCM for the systematic analysis of pathofunctions of genes of an infectious agent. With this approach, ORF75 and K1 were identified as novel HHV-8 regulatory molecules on the NF-κB signal transduction pathway. The genes identified may be involved in fine-tuning of the balance between latency and lytic replication, since this depends critically on the state of NF-κB activity. Copyright © 2009, American Society for Microbiology.
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A Temperature-Based Bioimpedance Correction for Water Loss Estimation During Sports - Ring, Matthias; Lohmüller, Clemens; Rauh, Manfred; Mester, Joachim; Eskofier, Björn (IEEE Journal of Biomedical and Health Informatics, 2016)
The amount of total body water (TBW) can be estimated based on bioimpedance measurements of the human body. In sports, TBW estimations are of importance because mild water losses can impair muscular strength and aerobic endurance. Severe water losses can even be life threatening. TBW estimations based on bioimpedance, however, fail during sports because the increased body temperature corrupts bioimpedance measurements. Therefore, this paper proposes a machine learning method that eliminates the effects of increased temperature on bioimpedance and, consequently, reveals the changes in bioimpedance that are due to TBW loss. This is facilitated by utilizing changes in skin and core temperature. The method was evaluated in a study in which bioimpedance, temperature, and TBW loss were recorded every 15 minutes during a two-hour running workout. The evaluation demonstrated that the proposed method is able to reduce the error of TBW loss estimation by up to 71%, compared to the state of art. In the future, the proposed method in combination with portable bioimpedance devices might facilitate the development of wearable devices for continuous and noninvasive TBW loss monitoring during sports.
EVALuna2:15227

ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2 - Hübner, Kerstin; Erlenbach-Wünsch, Katharina; Prochazka, Jan; Sheraj, Ilir; Hampel, Chuanpit; Mrazkova, Blanka; Michalcikova, Tereza; Tureckova, Jolana; Iatsiuk, Veronika; Weissmann, Anne; Ferrazzi, Fulvia; Kunze, Philipp; et al. (Cellular and Molecular Life Sciences, 2022)
In cancer, the activating transcription factor 2 (ATF2) has pleiotropic functions in cellular responses to growth stimuli, damage, or inflammation. Due to only limited studies, the significance of ATF2 in colorectal cancer (CRC) is not well understood. We report that low ATF2 levels correlated with worse prognosis and tumor aggressiveness in CRC patients. NanoString gene expression and ChIP analysis confirmed trophoblast cell surface antigen 2 (TROP2) as a novel inhibitory ATF2 target gene. This inverse correlation was further observed in primary human tumor tissues. Immunostainings revealed that high intratumoral heterogeneity for ATF2 and TROP2 expression was sustained also in liver metastasis. Mechanistically, our in vitro data of CRISPR/Cas9-generated ATF2 knockout (KO) clones revealed that high TROP2 levels were critical for cell de-adhesion and increased cell migration without triggering EMT. TROP2 was enriched in filopodia and displaced Paxillin from adherens junctions. In vivo imaging, micro-computer tomography, and immunostainings verified that an ATF2(KO)/TROP2(high) status triggered tumor invasiveness in in vivo mouse and chicken xenograft models. In silico analysis provided direct support that ATF2(low)/TROP2(high) expression status defined high-risk CRC patients. Finally, our data demonstrate that ATF2 acts as a tumor suppressor by inhibiting the cancer driver TROP2. Therapeutic TROP2 targeting might prevent particularly the first steps in metastasis, i.e., the de-adhesion and invasion of colon cancer cells.
CRIS-Team WoS Importer:2022-07-29

A Treatment Approach for Carotid Blowout Syndrome and Soft Tissue Reconstruction after Radiotherapy in Patients with Oral Cancer: A Report of 2 Cases - Möst, Tobias; Kesting, Marco Rainer; Rohde, Maximilian; Lang, Werner; Meyer, Alexander; Weber, Manuel; Lutz, Rainer (Journal of Clinical Medicine, 2023)
Background: This retrospective case series study aims to demonstrate a salvage technique for the treatment of carotid blow-out syndrome (CBS) in irradiated head and neck cancer patients with a vessel-depleted neck. Methods: Between October 2017 and October 2021, two patients (N = 2) with CBS were treated at our institution in a multidisciplinary approach together with the Department of Vascular Surgery. Patients were characterized based on diagnoses, treatment procedures, and the subsequent postoperative course. Results: Surgical emergency intervention was performed in both cases. The transition zone from the common carotid artery (CCA) to the internal carotid artery (ICA) was resected and reconstructed with a xenogic (case 1) or autogenic (case 2) interposition (end-to-end anastomosis). To allow reconstruction of the vascular defect, an additional autologous vein graft was anastomosed to the interposition graft in an end-to-side technique, allowing arterial anastomosis for a free microvascular flap without re-clamping of the ICA. Because of the intraoperative ICA reconstruction, none of the patients suffered a neurological deficit. Conclusions: The techniques presented in the form of two case reports allow for acute bleeding control, cerebral perfusion, and the creation of a vascular anastomosis option in the vessel-depleted neck.
CRIS-Team Scopus Importer:2023-05-26
Keywords: carotid blow out syndrome; irradiation; vessel graft; vessel-depleted neck

A Two-Stage Regression Using Bioimpedance and Temperature for Hydration Assessment During Sports - Ring, Matthias; Lohmüller, Clemens; Rauh, Manfred; Eskofier, Björn (Proceedings of the 2014 22nd International Conference on Pattern Recognition (ICPR), 2014)
Bioimpedance analysis (BIA) estimates the amount of total body water (TBW) in the human body. During sports, however, the increased skin temperature distorts bioimpedance measurements and, thus, prevents the application of BIA. In this paper, we propose a two-stage regression that includes temperature information in order to correct the temperature-distorted bioimpedance. In detail, the first regression stage corrects temperature-distored bioimpedance using information of skin and core temperature. The second regression stage estimates TBW loss on basis of the corrected bioimpedance. The two-stage regression was evaluated using data of an ongoing study. The results showed that estimations of TBW loss during sports can be considerably improved if temperature information is included. However, a remaining error was still observed. Therefore, additional measurements, e.g., skin blood flow, are discussed because they also influence bioimpedance and could further reduce the error.

Author response to: Comment on: Prognosis of patients with colonic carcinoma before, during and after implementation of complete mesocolic excision - Merkel, Susanne; Hohenberger, Werner (British Journal of Surgery, 2020)
CRIS-Team Scopus Importer:2020-03-17

Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis - Voskens, Caroline; Stoica, Diane; Rosenberg, Marita; Vitali, Francesco; Zundler, Sebastian; Ganslmayer, Marion; Knott, Heike; Wiesinger, Manuel; Wunder, Jutta; Kummer, Mirko; Siegmund, Britta; Schnoy, Elisabeth; et al. (Gut, 2022)
Objective Ulcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available.
CRIS-Team WoS Importer:2022-04-29

Automated Lesion Detection in Endoscopic Imagery for Small Animal Models - Eixelberger, Thomas; Fang, Qi; Zohud, Bisan; Hackner, Ralf; Jackstadt, Rene; Stürzl, Michael; Naschberger, Elisabeth; Wittenberg, Thomas (Bildverarbeitung für die Medizin 2024. BVM 2024, 2024)
Murine animal models are routinely used in research of gastrointestinal diseases, for example to analyze colorectal cancer or chronic inflammatory bowel diseases. By using suitable (miniaturized) endoscopy systems, it is possible to examine the large intestine of mice with respect to inflammatory, vascular or neoplastic changes without the need to sacrifice the animals. This enables the acquisition of high-resolution colonoscopy image sequences that can be used for the visual examination of tumors, the assessment of inflammation or the vasculature. Since the human resources for analyzing a multitude of videos, are limited, an automated evaluation of such image data is desirable. Video recordings (n = 49) of mice with and without colorectal cancer (CRC) were employed for this purpose and scored by clinical experts. The videos contained mice with tumors in 33 cases and 16 are pathologically normal. For the automatic detection of neoplastic changes (e.g. polyps), a deep neural network based on the YOLOv7- tiny architecture was applied. This network was previously trained on >36,000 human colon images with neoplasias visible in all frames. On test data with human images, the precision of the network is Prec = 0.92, and Rec = 0.90. The network was applied to the mouse data without any changes. To avoid falsepositive detections a color-based method was added to differentiate between stool residues and polyps. With the framework for the detection of neoplastic changes and classification of stool residues, we achieve results of Prec = 0.90, Rec = 0.98, F1 score = 0.94.Without the detection of stool residues, the values were dropping to Prec = 0.65 and Rec = 0.98, as 19 occurrences of stool are incorrectly classified as tumors. Our network trained on human data for neoplasia detection is able to accurately detect tumors in the murine colon. An additional module for the separation of stool residues is essential to avoid integration of wrongly positive cases.
CRIS-Team Scopus Importer:2024-03-29

Automatic Detection of Tumor Buds in Pan-Cytokeratin Stained Colorectal Cancer Sections by a Hybrid Image Analysis Approach - Bergler, Matthias; Benz, Michaela; Rauber, David; Hartmann, David; Kötter, Malte; Eckstein, Markus; Schneider-Stock, Regine; Hartmann, Arndt; Merkel, Susanne; Bruns, Volker; Wittenberg, Thomas; Geppert, Carol-Immanuel (Digital Pathology, 2019)
This contribution introduces a novel approach to the automatic detection of tumor buds in a digitalized pan-cytokeratin stained colorectal cancer slide. Tumor buds are representing an invasive pattern and are frequently investigated as a new diagnostic factor for measuring the aggressiveness of colorectal cancer. However, counting the number of buds under the microscope in a high power field by eyeballing is a strenuous, lengthy and error-prone task, whereas an automated solution could save time for the pathologists and enhance reproducibility. We propose a new hybrid method that consists of two steps. First possible tumor bud candidates are detected using a chain of classical image processing methods. Afterwards a convolutional deep neural network is applied to filter and reduce the number of false positive candidates detected in the first step. By comparing the automatically detected buds with a gold standard created by manual annotations, we gain a score of 0.977 for precision and 0.934 for sensitivity in our test sets on over 8.000 tumor buds.

Autonomously vascularized cellular constructs in tissue engeneering: opening a new perspective for biomedical science - Polykandriotis, Elias; Arkudas, Andreas; Horch, Raymund E.; Stürzl, Michael; Kneser, Ulrich (Journal of cellular and molecular medicine, 2007)
In tissue engineering cell cultures play a crucial role besides the matrix materials for the end of substituting lost tissue functions. The cell itself is situated at the cross-roads leading to different orders of scale, from molecule to organism and different levels of function, from biochemistry to macrophysiology. Extensive in vitro investigations have dissected a vast amount of cellular phenomena and the role of a number of bioactive substances has been elucidated in the past. Further, recombinant DNA technologies allow modulation of the expression profiles of virtually all kinds of cells. However, issues of vascularization in vivo limit transferability of these observations and restrict upscaling into clinical applications. Novel in vivo models of vascularization have evolved inspired from reconstructive microsurgical concepts and they encompass axial neovascularization by means of vascular induction. This work represents a brief description of latest developments and potential applications of neovascularization and angiogenesis in tissue engineering.
UnivIS-Import:2015-04-14:Pub.2007.med.packli.pchw2.autono

Autonomously vascularized cellular constructs in tissue engineering: opening a new perspective for biomedical science. - Polykandriotis, Elias; Arkudas, Andreas; Horch, Raymund E.; Stürzl, Michael; Kneser, Ulrich (Journal of Cellular and Molecular Medicine, 2007)
In tissue engineering cell cultures play a crucial role besides the matrix materials for the end of substituting lost tissue functions. The cell itself is situated at the cross-roads leading to different orders of scale, from molecule to organism and different levels of function, from biochemistry to macrophysiology. Extensive in vitro investigations have dissected a vast amount of cellular phenomena and the role of a number of bioactive substances has been elucidated in the past. Further, recombinant DNA technologies allow modulation of the expression profiles of virtually all kinds of cells. However, issues of vascularization in vivo limit transferability of these observations and restrict upscaling into clinical applications. Novel in vivo models of vascularization have evolved inspired from reconstructive microsurgical concepts and they encompass axial neovascularization by means of vascular induction. This work represents a brief description of latest developments and potential applications of neovascularization and angiogenesis in tissue engineering.

Avoidance of complications in oncological surgery of the pelvic region : Combined oncosurgical and plastic reconstruction measures - Beier, Justus; Croner, R. S.; Lang, Werner; Arkudas, Andreas; Schmitz, Marweh; Göhl, Jonas; Hohenberger, Werner; Horch, Raymund E. (Chirurg, 2015)
Prevention of perioperative and postoperative complications resulting from surgical oncology in the pelvic region remains a major interdisciplinary challenge. With modern interdisciplinary concepts joining forces of various surgical specialties, tumor resection can be sufficiently carried out with wide margins and the patients benefit from reduced morbidity even in complex situations. As an example chronic fistulation and secretion from the presacral cavity and sinus may result as potential sequelae from intra-abdominal and intrapelvic tumor resection, especially when neoadjuvant multimodal therapies have been applied. This can be prevented by simultaneous transplantation of for example transpelvic vertical rectus abdominis myocutaneous (VRAM) flap transfer, while extensive perineal skin and soft tissue defects may also be simultaneously reconstructed. In cases of malignant soft tissue tumors in the pelvic region a staged surgical procedure can be performed with a period of time between tumor resection and reconstruction. Thus, a histological R0 status can be secured prior to plastic reconstruction surgery in order to increase oncological safety. In cases of postresectional exposition of e. g. pelvic or femoral vessels or intrapelvic and intra-abdominal organs simultaneous flap procedure is mandatory.The reconstructive armamentarium of the plastic surgeon should contain not only pedicled but also free microsurgical flaps so that no compromise in terms of the extent of the oncological resection has to be accepted. At the same time perioperative and postoperative complications may be avoided and the patient quality of life can be preserved even in more complex cases.
EVALuna2:15195

Avoidance of Overtreatment of Rectal Cancer by Selective Chemoradiotherapy: Results of the Optimized Surgery and MRI-Based Multimodal Therapy Trial - Ruppert, Reinhard; Kube, Rainer; Strassburg, Joachim; Lewin, Andreas; Baral, Joerg; Maurer, Christoph A.; Sauer, Joerg; Junginger, Theodor; Hermanek, Paul; Merkel, Susanne; Kreis, Martin E.; Winde, Guenther; et al. (Journal of the American College of Surgeons, 2020)
Background: Neoadjuvant chemoradiotherapy (nCRT) in patients with rectal cancer carries a high risk of adverse effects. The aim of this study was to examine the selective application of nCRT based on patient risk profile, as determined by MRI, to find the optimal range between undertreatment and overtreatment. Study Design: In this prospective multicenter observational study, nCRT before total mesorectal excision (TME) was indicated in high-risk patients with involved or threatened mesorectal fascia (≤1 mm), or cT4 or cT3 carcinomas of the lower rectal third. All other patients received primary surgery. Results: Of the 1,093 patients, 878 (80.3%) were treated according to the protocol, 526 patients (59.9%) underwent primary surgery, and 352 patients (40.1%) underwent nCRT followed by surgery. The 3-year locoregional recurrence (LR) rate was 3.1%. Of 604 patients with clinical stages II and III, 267 (44.2%) had primary surgery; 337 (55.8%) received nCRT followed by TME. The 3-year LR rate was 3.9%, without significant differences between groups. In patients with clinical stages II and III who underwent primary surgery, 27.3% were diagnosed with pathological stage I. Conclusions: The results justify the restriction of nCRT to high-risk patients with rectal cancer classified by pretreatment MRI. Provided that a high-quality MRI diagnosis, TME surgery, and standardized examination of the resected specimen are performed, nCRT, with its adverse effects, costs, and treatment time can be avoided in more than 40% of patients with stage II or III rectal cancer with minimal risk of undertreatment. (clinicaltrials.gov NCT325649)
CRIS-Team Scopus Importer:2020-09-04

Awareness of smoking cessation amongst German vascular surgeons: First national survey - Bischoff, Moritz; Meisenbacher, Katrin; Rother, Ulrich; Cotta, Livia; Böhner, Hinrich; Storck, Martin; Behrendt, Christian Alexander (Vasa-Journal of Vascular Diseases, 2024)
Background: Smoking represents the well-known enemy of vascular well-being. Numerous previous studies emphasised the important role of smoking on the development and progression of atherosclerotic cardiovascular disease. The current study aimed to identify hurdles and barriers for an insufficient implementation of secondary prevention in the treatment of lower extremity peripheral arterial disease (PAD). Methods: All members of the German Society for Vascular Surgery and Vascular Medicine (DGG) with valid email addresses were invited to participate in an electronic survey on smoking. Results are descriptively presented. Results: Amongst 2716 invited participants, 327 (12%) submitted complete responses, thereof 33% women and 80% between 30 and 59 years old (87% board certified specialists). 83% were employed by hospitals (56% teaching hospital, 14% university, 13% non-academic) and 16% by outpatient facilities. 6% are active smokers (63% never) while a mean of five medical education activities on smoking cessation were completed during the past five years of practice. Only 27% of the institutions offered smoking cessation programs and 28% of the respondents were aware of local programs while a mean of 46% of their patients were deemed eligible for participation. 63% of the respondents deemed outpatient physicians primarily responsible for smoking cessation, followed by medical insurance (26%). Conclusions: The current nationwide survey of one scientific medical society involved in the care of patients with vascular disease revealed that smoking cessation, although being commonly accepted as important pillar of comprehensive holistic care, is not sufficiently implemented in everyday clinical practice.
CRIS-Team Scopus Importer:2024-02-23
Keywords: Best Medical Treatment; Health Behaviour; Health Services Research; Intermittent Claudication; Peripheral Arterial Disease; Smoking

Axial prevascularization of porous matrices using an arteriovenous loop promotes survival and differentiation of transplanted autologous osteoblasts. - Arkudas, Andreas; Beier, Justus P.; Heidner, Kristina; Tjiawi, Jimmy; Polykandriotis, Elias; Srour, Safwan; Stürzl, Michael; Horch, Raymund E.; Kneser, Ulrich (Tissue Engineering -Larchmont, 2007)
Generation of axially vascularized bioartificial bone might be performed using matrix neovascularization in connection with osteoblast injection. We sought to evaluate whether prevascularization of porous hard matrices using an arteriovenous (AV) loop promotes survival of transplanted osteoblasts. A processed bovine cancellous bone matrix was inserted into the AV loop. Six weeks later, 5 x 10(6) carboxyfluorescein diacetate-stained osteoblasts were injected into the matrix (group A, n = 34). Osteoblast-seeded matrices without prevascularization were implanted subcutaneously as controls (group B, n = 32). Specimens were subjected to histologic, morphometric, and molecular-biological analysis after 1, 4, 8, and 16 weeks. Upon cell injection, matrices were completely vascularized. An intense foreign body reaction was observed in matrices from both groups. Group A was significantly superior to group B in terms of osteoblast survival at any time point. Expression of bone-specific genes was detected in the AV loop group but not in the subcutaneous control. Bone formation was only detectable in 1 long-term animal of group A. This study demonstrates for the first time that axial prevascularization increases the survival of implanted osteoblasts in porous matrices. Matrices with optimized biocompatibility might eventually facilitate generation of axially vascularized bone tissue after injection of osteogenic cells in the AV loop model.

Azidothymidine Sensitizes Primary Effusion Lymphoma Cells to Kaposi Sarcoma-Associated Herpesvirus-Specific CD4+ T Cell Control and Inhibits vIRF3 Function - Williamson, Samantha J.; Nicol, Samantha M.; Stürzl, Michael; Sabbah, Shereen; Hislop, Andrew D. (PLoS Pathogens, 2016)
Kaposi sarcoma-associated herpesvirus (KSHV) is linked with the development of Kaposi sarcoma and the B lymphocyte disorders primary effusion lymphoma (PEL) and multi-centric Castleman disease. T cell immunity limits KSHV infection and disease, however the virus employs multiple mechanisms to inhibit efficient control by these effectors. Thus KSHV-specific CD4+ T cells poorly recognize most PEL cells and even where they can, they are unable to kill them. To make KSHV-infected cells more sensitive to T cell control we treated PEL cells with the thymidine analogue azidothymidine (AZT), which sensitizes PEL lines to Fas-ligand and TRAIL challenge; effector mechanisms which T cells use. PELs co-cultured with KSHV-specific CD4+ T cells in the absence of AZT showed no control of PEL outgrowth. However in the presence of AZT PEL outgrowth was controlled in an MHC-restricted manner. To investigate how AZT sensitizes PELs to immune control we first examined BJAB cells transduced with individual KSHV-latent genes for their ability to resist apoptosis mediated by stimuli delivered through Fas and TRAIL receptors. This showed that in addition to the previously described vFLIP protein, expression of vIRF3 also inhibited apoptosis delivered by these stimuli. Importantly vIRF3 mediated protection from these apoptotic stimuli was inhibited in the presence of AZT as was a second vIRF3 associated phenotype, the downregulation of surface MHC class II. Although both vFLIP and vIRF3 are expressed in PELs, we propose that inhibiting vIRF3 function with AZT may be sufficient to restore T cell control of these tumor cells.
EVALuna2:15266

Baseline Results of the German Health Services Research Study PROSa - quality of care and patient reported outcomes - Eichler, M.; Richter, S.; Hohenberger, P.; Kasper, B.; Andreou, D.; Pink, D.; Golcher, H.; Fung, S.; Wardelmann, E.; Arndt, K.; Hentschel, L.; Eberlein-Gonska, M.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2019)
CRIS-Team WoS Importer:2020-10-02

BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease - Ullrich, Evelyn; Abendroth, Benjamin; Rothamer, Johanna; Huber, Carina; Büttner-Herold, Maike; Buchele, Vera; Vogler, Tina; Longerich, Thomas; Zundler, Sebastian; Völkl, Simon; Beilhack, Andreas; Rose-John, Stefan; et al. (Journal of Clinical Investigation, 2018)
Acute graft-versus-host disease (GVHD) represents a severe, T cell-driven inflammatory complication following allogeneic hematopoietic cell transplantation (allo-HCT). GVHD often affects the intestine and is associated with a poor prognosis. Although frequently detectable, proinflammatory mechanisms exerted by intestinal tissue-infiltrating Th cell subsets remain to be fully elucidated. Here, we show that the Th17-defining transcription factor basic leucine zipper transcription factor ATF-like (BATF) was strongly regulated across human and mouse intestinal GVHD tissues. Studies in complete MHC-mismatched and minor histocompatibility-mismatched (miHA-mismatched) GVHD models revealed that BATF-expressing T cells were functionally indispensable for intestinal GVHD manifestation. Mechanistically, BATF controlled the formation of colon-infiltrating, IL-7 receptor-positive (IL-7R+), granulocyte-macrophage colony-stimulating factor-positive (GM-CSF+), donor T effector memory (Tem) cells. This T cell subset was sufficient to promote intestinal GVHD, while its occurrence was largely dependent on T cell-intrinsic BATF expression, required IL-7-IL-7R interaction, and was enhanced by GM-CSF. Thus, this study identifies BATF-dependent pathogenic GM-CSF+ effector T cells as critical promoters of intestinal inflammation in GVHD and hence putatively provides mechanistic insight into inflammatory processes previously assumed to be selectively Th17 drive
EVALuna2:25783

Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer - Punkenburg, Elise; Vogler, Tina; Büttner, Maike; Amann, Kerstin Ute; Waldner, Maximilian; Atreya, Raja; Abendroth, Benjamin; Mudter, Jonas; Merkel, Susanne; Gallmeier, Eike; Rose-John, Stefan; Neurath, Markus; et al. (Gut, 2016)
IBDs have an increased risk for development of colorectal cancer (CRC). Here, we aimed at the characterisation of the functional role of Th17-associated transcription factors in sporadic and colitis-associated colon cancer in vivo.We used mice deficient or transgenic for the activating protein 1 family member basic leucine zipper transcription factor ATF-like (Batf) to evaluate the role of Th17 cells during sporadic and inflammation-induced colon carcinogenesis. We also studied the expression of Batf and ROR?t in patients with IBD and CRC.Batf but not retinoic acid-related orphan receptor ?t(ROR?t) expression was significantly increased together with interleukin (IL) 23 expression in UC but not in Crohn's disease (CD) tissue samples. In CRC also Batf but not ROR?t expression was increased and its expression correlated with the IL-23 and IL-23 receptor (IL-23R) expression. Finally, Batf but not ROR?t was coexpressed with IL-17a, IL-23R and IL-6 within CRC-infiltrating CD4(+) T cells. Functional studies in mice revealed that Batf-dependent T cells are crucial regulators of sporadic and inflammation-induced CRC. Colitis-associated Batf(-/-) tumours lacked IL-17a(+)IL-23R(+)IL-6(+)CD4(+) T cells, hence displaying characteristics reminiscent of human CRC-infiltrating CD4(+) T cells. Strikingly, Batf(-/-) tumours contained low IL-23 but high IL-17a expression levels. Tumour formation and intratumoral IL-23 expression could be restored by administration of Hyper-IL-6 consisting of IL-6 and soluble IL-6 receptor.Batf-dependent IL-23R(+)IL-6(+)CD4(+) Th17 cells critically control IL-23 driven colitis-associated tumour formation and the progression of sporadic colon tumours. Batf-dependent IL-23R(+) T cells represent a potential future therapeutic target limiting CRC progression.
EVALuna2:2026

Behandlung der chronischen peripheren arteriellen Verschlusskrankheit (pAVK): Indikationsstellung, etagenspezifische Therapie und Follow-up-Regime - Behrendt, Christian Alexander; Heidemann, Franziska; Meyer, Alexander; Werra, Ursula Elisabeth Maria; Rother, Ulrich (Gefässchirurgie, 2024)
The heterogeneous clinical manifestations of peripheral arterial occlusive disease (PAOD) necessitate a systematic stepwise diagnostic procedure as well as a stage-related and realistic target-oriented treatment. Although preventive medical aspects in all stages of the disease are currently considered the foundations of complementary treatment before, during and after every invasive revascularization, open surgical, interventional and hybrid procedures can be carried out to improve symptoms and to save the limbs. The choice of appropriate approaches and their combination is oriented to patient-specific factors and also the local expertise and infrastructure. All technical decisions should consider the alternative complementary treatment approaches in a balanced way. In addition to the PAOD-associated case volume of the hospital and the patient-specific risk factors, the adherence to guideline-compliant recommendations in particular is an important predictor of the long-term treatment results.
CRIS-Team Scopus Importer:2024-03-08
Keywords: Atherosclerosis; Endovascular techniques; Intermittent claudication; Preventive medicine; Revascularization

Benefits of Long Versus Short Thrombolysis Times for Acutely Thrombosed Hemodialysis Native Fistulas - Regus, Susanne; Lang, Werner; Heinz, Marco; Uder, Michael; Schmid, Axel (Vascular and Endovascular Surgery, 2017)
Local thrombolysis with a time of exposure to recombinant tissue plasminogen activator of 15 to 150 minutes is commonly used to declot acutely thrombosed hemodialysis fistulas. The duration of thrombolysis for the restoration of arteriovenous blood flow remains controversial. The aim of this study was to investigate the outcomes of long thrombolysis treatment (LTT, 3 hours or more) and short thrombolysis treatment (STT, less than 3 hours) in our institution.We retrospectively analyzed 86 interventional declotting procedures (28 STT and 58 LTT) applied to 86 acutely thrombosed hemodialysis fistulas. The intervention time (IT) following thrombolysis (from the initial fistulography to the end of the angioplasty maneuvers), the time of day of the intervention (ie, during working hours vs off-hours), and the need for temporary catheter placement (TCP) were assessed. Success was defined as complete access recanalization, and major adverse events were defined as ischemia, bleeding, and access rupture.The ITs were reduced after LTT (63.3 [9.3] minutes) compared to STT (106.7 [24.7], P = .01), but there was no difference in success rate (85.7% STT, 89.7% LTT, P = .722). While all (100%, 58/58) of the angioplasty maneuvers after LTT were performed during regular working hours, 75% (21/28) of those following STT were managed during off-hours ( P < .001). Despite the longer treatment, the need for TCP was not increased after LTT (10.7%) compared to STT (12.1%, P = .515), and the major complication rate was reduced (3.4% after LTT and 28.6% after STT, P = .004).Long thrombolysis treatment results in shorter and less complicated percutaneous stenosis treatments during regular working hours. Despite the LTT of up to 25 hours until access for dialysis was achieved, no increase in the risks of TCP or major adverse events were observed following LTT.
EVALuna2:14643

Beta-6-Integrin serves as a novel tumor marker and therapeutic target for colorectal carcinoma - Bengs, Susan; Becker, Eugenia; Spalinger, Marianne R.; Raselli, Tina; Kasper, Stephanie; Lang, Silvia; Atrott, Kirstin; Mamie, Celine; Britzen-Laurent, Nathalie; Von Boehmer, Lotta; Knuth, Alexander; Tuomisto, Anne; et al. (2017)
EVALuna2:35840

Better Function With a Colonic J-Pouch or a Side-to-end Anastomosis?: A Randomized Controlled Trial to Compare the Complications, Functional Outcome, and Quality of Life in Patients With Low Rectal Cancer After a J-Pouch or a Side-to-end Anastomosis - Parc, Yann; Ruppert, Reinhard; Fuerst, Alois; Goldcher, Henriette; Zutshi, Massarat; Hull, Tracy; Tiret, Emmanuel; Hemminger, Felix; Galandiuk, Susan; Fender, Svenja; Weber, Klaus; Zimmerman, Anton; et al. (Annals of Surgery, 2019)
BACKGROUND INFORMATION: We aimed to compare prospectively the complications and functional outcome of patients undergoing a J-Pouch (JP) or a side-to-end anastomosis (SE) for treatment of low rectal cancer at a 2-year time point after resection for rectal cancer. METHODS: A multicenter study was conducted on patients with low rectal cancer who were randomized to receive either a JP or SE and were followed for 24 months utilizing SF-12 and FACT-C surveys to evaluate the quality of life (QOL). Fecal incontinence was evaluated using the Fecal Incontinence Severity Index (FISI). Bowel function, complications, and their treatments were recorded. RESULTS: Two hundred thirty-eight patients (165 males) were randomized with 167 final eligible patients, 80 in the JP group and 87 in the SE group for evaluation. The mean age at surgery was 61 (range 29 to 82) years. The overall mean recurrence rate was 12 of 238, 5% and similar in both groups. COMPLICATIONS: Overall, 37 of 190 (19%) patients reported complications, 14 of these were Clavien Dindo Grade 3b and 2 were 3a: leak 3 (2 JP,1 SE), fistula 4 (1 JP, 3 SE), small bowel obstruction 4 (3JP, 1 SE), stricture 4 (3 SE, 1 SA), pouch necrosis 2 (JP), and wound infection 5 (2 JP, 3 SE). QOL scores using either instrument between the 2 groups at 12 and 24 months were similar (P > 0.05). Bowel movements, clustering, and FISI scores were similar. CONCLUSION: At time points of 1 and 2 years after a JP or a SE for low rectal cancer, QOL, functional outcome, and complications are comparable between the groups. Although choosing a particular procedure may depend on surgeon/patient choice or anatomical considerations at the time of surgery, SE functions similar to JP and may be chosen due to the ease of construction.
CRIS-Team Scopus Importer:2019-05-07

Better Therapy for Pancreatic Cancer through More Radical Surgery? Bessere Therapie des Pankreaskarzinoms durch radikalere Chirurgie? - Brunner, Maximilian; Krautz, Christian; Grützmann, Robert; Weber, Georg (Zentralblatt für Chirurgie, 2022)
Despite advances in the treatment of pancreatic cancer, the survival of affected patients remains limited. A more radical surgical therapy could help to improve the prognosis, in particular by reducing the local recurrence rate, which is around 45% in patients with resected pancreatic cancer. In addition, patients with oligometastatic pancreatic cancer could also benefit from a more radical indication for surgery.Based on an analysis of the literature, important principles of pancreatic cancer surgery were examined.Even if even more radical surgical approaches such as an "extended" lymphadenectomy or a standard complete pancreatectomy do not bring any survival advantage, complete resection of the tumour (R0), a thorough locoregional lymphadenectomy and an adequate radical dissection in the area of the peripancreatic vessels including periarterial nerve plexuses should be the standard of pancreatic carcinoma resections. Whenever necessary to achieve an R0 resection, resections of the pancreas have to be extended, as well as additional venous vascular resections and multivisceral resections had to be performed. Simultaneous arterial vascular resections as part of pancreatic resections as well as surgical resections in oligometastatic patients should, however, be reserved for selected patients. These aspects of the surgical technique in pancreatic carcinoma mentioned above must not be neglected from the point of view of an "existing limited prognosis". On the contrary, they form the absolutely necessary basis in order to achieve good survival results in combination with system therapy. However, it may always be necessary to adapt these standards according to the age, comorbidities and wishes of the patient.
CRIS-Team Scopus Importer:2022-04-15

Big but weak: how many pathogenic genes does human herpesvirus-8 need to cause Kaposi's sarcoma? (Review). - Stürzl, Michael; Ensoli, Barbara (International Journal of Oncology, 1999)
Human herpesvirus-8 (HHV-8) is implicated in the pathogenesis of Kaposi's sarcoma (KS). In the last two years several HHV-8 gene products were heralded to 'cause KS' without any evidence that the respective gene is expressed in the tumor cells of KS lesions. In this framework it is of interest that almost 10% of the genes encoded by HHV-8 have been suggested to promote KS development due to either mitogenic, anti-apoptotic, chemoattractive, angiogenic or transforming activities. The rapidly growing number of HHV-8-encoded genes with 'KS causing' activities raises the question of why HHV-8 may need so many genes to trigger growth of KS that appears to be more closely related to a hyperplasia than to a real sarcoma. In this review an overview of the current knowledge of HHV-8 gene expressions in KS lesions in vivo is presented.

Biological roles of RNA m5C modification and its implications in Cancer immunotherapy - Song, Hang; Zhang, Jianye; Liu, Bin; Xu, Jing; Cai, Biao; Yang, Hai; Straube, Julia; Yu, Xiyong; Ma, Teng (Biomarker Research, 2022)
Epigenetics including DNA and RNA modifications have always been the hotspot field of life sciences in the post-genome era. Since the first mapping of N6-methyladenosine (m6A) and the discovery of its widespread presence in mRNA, there are at least 160-170 RNA modifications have been discovered. These methylations occur in different RNA types, and their distribution is species-specific. 5-methylcytosine (m5C) has been found in mRNA, rRNA and tRNA of representative organisms from all kinds of species. As reversible epigenetic modifications, m5C modifications of RNA affect the fate of the modified RNA molecules and play important roles in various biological processes including RNA stability control, protein synthesis, and transcriptional regulation. Furthermore, accumulative evidence also implicates the role of RNA m5C in tumorigenesis. Here, we review the latest progresses in the biological roles of m5C modifications and how it is regulated by corresponding “writers”, “readers” and “erasers” proteins, as well as the potential molecular mechanism in tumorigenesis and cancer immunotherapy.
CRIS-Team Scopus Importer:2022-04-15
Keywords: 5-methylcytosine (m; cancer immunotherapy; Epigenetics; Non-coding RNAs; RNA methylation modification

Biology of Kaposi's sarcoma. - Ensoli, Barbara; Sgadari, Cecilia; Barillari, Giovanni; Sirianni, Maria Caterina; Stürzl, Michael; Monini, Paolo (European Journal of Cancer, 2001)
Kaposi's sarcoma (KS) is an angioproliferative disease occurring in several different clinical-epidemiological forms that, however, share the same histological traits and are all associated with infection by the human herpesvirus 8 (HHV8). KS initiates in a context of immune dysregulation characterised by CD8+ T cell activation and the production of Th1-type cytokines that induce a generalised activation of endothelial cells leading to adhesion and tissue extravasation of lympho-monocytes, spindle cell formation and angiogenesis. These phenomena are triggered or enhanced by infection with HHV8 that, in turn, is reactivated by the same cytokines. Productively-infected circulating cells are recruited into 'activated' tissue sites where HHV8 finds an optimal environment for establishing a persistent, latent infection of KS spindle cells (KSC). HHV8 dissemination is favoured by virus escape mechanisms and immune dysregulation, and leads to immune responses that are not effective against the virus but, paradoxically, exacerbates the reactive process. Although early KS is a reactive process of polyclonal nature that can regress, in time it can progress in to a true sarcoma. The progression of KS appears to be due to the deregulated expression of oncogenes and oncosuppressor genes, to the long-lasting expression of the HHV8 latency genes and, for AIDS-KS, is promoted by the proliferative and angiogenic effects of the HIV-1 Tat protein.
Keywords: KS; Spindle cells; Inflammatory cytokines; Angiogenic factors; AIDS; HIV-1 Tat; HHV8; Angiogenesis; bcl-2; Immune evasion

Biomimetic Magnetic Particles for the Removal of Gram-Positive Bacteria and Lipoteichoic Acid. - Friedrich, Bernhard; Eichermüller, Julia; Bogdan, Christian; Cunningham, Sarah; Hackstein, Holger; Strauss, Richard; Alexiou, Christoph; Lyer, Stefan; Tietze, Rainer (Pharmaceutics, 2022)
Gram+ bacteria are very common in clinical medicine and responsible for a large number of infectious diseases. For example, Gram+ bacteria play a major role in causing bloodstream infections and sepsis. Therefore, the detection of Gram+ bacteria is of great importance for the diagnosis and treatment of infectious diseases. Furthermore, these bacteria are often present in biofilms that cover implants. Recent research work has mainly focused on the biologic activity and removal of Gram-negative bacteria or bacterial components such as lipopolysaccharides (LPS). In contrast, the effects of lipoteichoic acid (LTA) have been less well studied so the relevance of their removal from body fluids is possibly underestimated. To address this topic, we evaluated superparamagnetic iron oxide particles (SPION) carrying different peptides derived from the innate immune receptor (GP-340) for their ability to bind and remove Gram+ bacteria and LTA from different media. Our results show that, beyond S. aureus, effective agglutinating and removing of S. pneumoniae was possible. Furthermore, we were able to show for the first time that this was possible with LTA alone and that the magnetic removal of bacteria was also efficient under flow conditions. We also found that this method was able to capture Stapyhylococcus aureus from platelet concentrates, which can help to enhance the sensitivity of microbiological diagnostics, quality control measures, and blood product safety.
EVALuna2:508460

Block of Voltage-Gated Sodium Channels by Aripiprazole in a State-Dependent Manner - Föhr, Karl Josef; Rapp, Michael; Fauler, Michael; Zimmer, Thomas; Jungwirth, Bettina; Messerer, David Alexander Christian (International Journal of Molecular Sciences, 2022)
Aripiprazole is an atypical antipsychotic drug, which is prescribed for many psychiatric diseases such as schizophrenia and mania in bipolar disorder. It primarily acts as an agonist of dopaminergic and other G-protein coupled receptors. So far, an interaction with ligand- or voltage-gated ion channels has been classified as weak. Meanwhile, we identified aripiprazole in a preliminary test as a potent blocker of voltage-gated sodium channels. Here, we present a detailed analysis about the interaction of aripiprazole with the dominant voltage-gated sodium channel of heart muscle (hNav1.5). Electrophysiological experiments were performed by means of the patch clamp technique at human heart muscle sodium channels (hNav1.5), heterologously expressed in human TsA cells. Aripiprazole inhibits the hNav1.5 channel in a state- but not use-dependent manner. The affinity for the resting state is weak with an extrapolated Kr of about 55 µM. By contrast, the interaction with the inactivated state is strong. The affinities for the fast and slow inactivated state are in the low micromolar range (0.5–1 µM). Kinetic studies indicate that block development for the inactivated state must be described with a fast (ms) and a slow (s) time constant. Even though the time constants differ by a factor of about 50, the resulting affinity constants were nearly identical (in the range of 0.5 µM). Besides this, aripirazole also interacts with the open state of the channel. Using an inactivation deficit mutant, an affinity of about 1 µM was estimated. In summary, aripiprazole inhibits voltage-gated sodium channels at low micromolar concentrations. This property might add to its possible anticancer and neuroprotective properties.
CRIS-Team Scopus Importer:2022-11-25
Keywords: aripiprazole; cardiotoxicity; electrophysiology; patch clamp; sodium channel

Blood Vessel-Targeted Therapy in Colorectal Cancer: Current Strategies and Future Perspectives - Jacobsen, Anne; Siebler, Jürgen; Grützmann, Robert; Stürzl, Michael; Naschberger, Elisabeth (Cancers, 2024)
The vasculature is a key player and regulatory component in the multicellular microenvironment of solid tumors and, consequently, a therapeutic target. In colorectal carcinoma (CRC), antiangiogenic treatment was approved almost 20 years ago, but there are still no valid predictors of response. In addition, treatment resistance has become a problem. Vascular heterogeneity and plasticity due to species-, organ-, and milieu-dependent phenotypic and functional differences of blood vascular cells reduced the hope of being able to apply a standard approach of antiangiogenic therapy to all patients. In addition, the pathological vasculature in CRC is characterized by heterogeneous perfusion, impaired barrier function, immunosuppressive endothelial cell anergy, and metabolic competition-induced microenvironmental stress. Only recently, angiocrine proteins have been identified that are specifically released from vascular cells and can regulate tumor initiation and progression in an autocrine and paracrine manner. In this review, we summarize the history and current strategies for applying antiangiogenic treatment and discuss the associated challenges and opportunities, including normalizing the tumor vasculature, modulating milieu-dependent vascular heterogeneity, and targeting functions of angiocrine proteins. These new strategies could open perspectives for future vascular-targeted and patient-tailored therapy selection in CRC.
CRIS-Team Scopus Importer:2024-03-22
Keywords: aflibercept; angiocrine; antiangiogenic treatment; bevacizumab; cancer; colorectal cancer; endothelial cells; fruquintinib; ramucirumab; regorafenib; tumor microenvironment; vascular heterogeneity; vasculature

Branch duct intraductal papillary mucinous neoplasm - contra resection - Brunner, Michaela; Kersting, S.; Grützmann, Robert; Weber, Georg (Chirurg, 2017)
Due to improvements in imaging modalities the diagnosis of branch duct intraductal papillary mucinous neoplasms (BD-IPMN) has been significantly increased in recent years. A BD-IPMN is frequently diagnosed as an incidental finding in asymptomatic patients. The optimal management of BD-IPMN is the subject of controversial discussions. Numerous studies have shown that an individualized therapeutic strategy with a follow-up observation of most BD-IPMNs is feasible and safe, considering age, comorbidities and patient preference. An accurate evaluation of BD-IPMN with a detailed anamnesis, high-resolution imaging techniques and endoscopic ultrasound is necessary. Symptomatic patients as well as patients with so-called high-risk stigmata should undergo resection. Asymptomatic patients with so-called worrisome features can either undergo surveillance or surgical resection, taking age and comorbidities into account. For BD-IPMN patients without high-risk stigmata and worrisome features and showing no symptoms, surveillance of the pancreatic lesion is the preferred approach. The high prevalence of BD-IPMN, limitations in differential diagnostics, an overestimation of the risk of malignancy due to an overrepresentation of symptomatic and suspected BD-IPMN in resected cohorts, an overestimated role of BD-IPMN as precursor lesions for pancreatic carcinoma and evidence of the safety of follow-up surveillance, underline the enormous importance of surveillance. Based on this and considering the background of a notable mortality and morbidity of pancreatic surgery, aggressive management with prophylactic surgical resection is not justified for all BD-IPMN, in particular for low-risk lesions.
EVALuna2:15288

Buffy coat volume reduction for optimization of leucapheresis harvests produced by the autoMNC program - Burk, Samaya; Erdmann, M.; Weiss, D.; Eckstein, Reinhold; Strasser, Erwin (Vox Sanguinis, 2015)
Buffy coat (BC) volume reduction was evaluated in leucapheresis (LA) harvests due to the target monocyte yield and the red blood cell (RBC) content. A packed erythrocyte volume (PEV) of 7.5 ml should not be exceeded to avoid RBC debulking with loss of leucocytes (WBCs) and the monocyte fraction during monocyte counterflow elutriation, a next step of monocyte enrichment prior to cell culture.Two hundred and fifty-three 5-l leucaphereses (autoMNC program) performed in 102 healthy blood donors (24 female and 78 male donors) were retrospectively analysed. Different categories of BC volumes were compared due to the quality of the LA products measured by blood counts and flow cytometry.Collection of maximum BC volume of 10 ml and more each collection cycle (product volume: 169 ± 21 ml) resulted in 1.58 ± 0·41 × 10e9 CD14(+) monocytes and high volume of packed erythrocyte (18.4 ± 8.8 ml). Low BC volume collection below 6 ml each collection cycle produced only 1.07 ± 0.40 × 10e9 CD14(+) monocytes but reduced PEV significantly by 64% (6.7 ± 4.1 ml).By reduction of the BC volume, the PEV in LA products could be reduced, which is a precondition for counterflow elutriation of monocytes. A BC volume between 7 and 8 ml per collection cycle should be adjusted to reduce PEV to 7.5 ml without relevant monocyte loss.
EVALuna2:15992

Cancer is associated with alterations in the three-dimensional organization of the genome - Li, Lifei; Barth, Nicolai; Pilarsky, Christian; Taher, Leila (Cancers, 2019)
The human genome is organized into topologically associating domains (TADs), which represent contiguous regions with a higher frequency of intra-interactions as opposed to inter-interactions. TADs contribute to gene expression regulation by restricting the interactions between their regulatory elements, and TAD disruption has been associated with cancer. Here, we provide a proof of principle that mutations within TADs can be used to predict the survival of cancer patients. Specifically, we constructed a set of 1467 consensus TADs representing the three-dimensional organization of the human genome and used Cox regression analysis to identify a total of 35 prognostic TADs in different cancer types. Interestingly, only 46% of the 35 prognostic TADs comprised genes with known clinical relevance. Moreover, in the vast majority of such cases, the prognostic value of the TAD was not directly related to the presence/absence of mutations in the gene(s), emphasizing the importance of regulatory mutations. In addition, we found that 34% of the prognostic TADs show strong structural perturbations in the cancer genome, consistent with the widespread, global epigenetic dysregulation often observed in cancer patients. In summary, this study elucidates the mechanisms through which non-coding variants may influence cancer progression and opens new avenues for personalized medicine.
CRIS-Team Scopus Importer:2019-12-10
Keywords: Biomarkers; Cancer; Copy number variants (CNVs); LASSO cox regression analysis; The cancer genome atlas (TCGA); Topologically associating domains (TADs)

Can clinicopathological parameters predict for lymph node metastases in ypT0-2 rectal carcinoma? Results of the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 phase 3 trials - Von Den Gruen, Jens Mueller; Hartmann, Arndt; Fietkau, Rainer; Ghadimi, Michael; Liersch, Torsten; Hohenberger, Werner; Weitz, Jurgen; Sauer, Rolf; Wittekind, Christian; Stroebel, Philipp; Roedel, Claus; Fokas, Emmanouil (Radiotherapy and Oncology, 2018)
BACKGROUND: The advent of less radical surgical approaches has generated concern about leaving locoregional lymph node metastases (LNM) unresected that could lead to adverse outcome. We examined the prognostic role of clinicopathological factors for ypN-positivity in patients with ypT0-2 rectal carcinoma treated within the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 randomized phase 3 trials. METHODS: The correlation of clinicopathological factors with ypN-status (ypN0 vs ypN1/2) was examined in n = 776 patients with ypT0-2 rectal carcinoma after preoperative CRT and total mesorectal excision surgery using Pearson's Chi-squared test for categorical variables and Kruskal-Wallis' test for continuous variables. Multivariable analysis was performed using binary logistic regression to identify independent prognosticators for ypN-positivity. RESULTS: Residual LNM (ypN+) were found in 6%, 20.8% and 21.4% of patients with ypT0, ypT1 and ypT2 carcinomas, respectively. Independent prognosticators for LNM were advanced ypT category (p = 0.002) and lymphatic invasion (p = 0.020). In a separate multivariable analysis performed upon exclusion of ypT-category due to multicollinearity with residual tumor diameter (RTD), lymphatic invasion (p = 0.015) and RTD ≥10 mm (p = 0.005) demonstrated strong correlation with LNM. CONCLUSION: Advanced ypT-stage, lymphatic invasion and RTD ≥10 mm were prognostic factors for LNM in patients ypT0-2 rectal carcinoma treated with CRT and surgery within both phase 3 trials. The high incidence of LNM in the ypT1-2 group needs to be taken into consideration in the context of oncological safety and indicate that LE should be advocated with great caution in this patient subgroup. The prognostic pathological factor identified here could help guide decision of LE vs TME after standard CRT.
EVALuna2:34854

Cap polyposis in children: case report and literature review - Brunner, Maximilian; Agaimy, Abbas; Atreya, Raja; Grützmann, Robert; Matzel, Klaus E. (International Journal of Colorectal Disease, 2019)
PURPOSE: Cap polyposis is a benign disease of the colon, characterized by inflammatory polyps with a "cap" of inflammatory granulation tissue. Its prevalence is very low, especially in children. METHODS AND RESULTS: A 16-year-old girl presented with frequent bowel movements with mucous discharge and bloody stool, leading to the initial suspicion of chronic inflammatory bowel disease. Results of further investigation by endoscopy and histological examination were consistent with a diagnosis of cap polyposis. Treatment with systemic steroids resulted in symptom improvement. CONCLUSION: A review of the literature shows that cap polyposis can occur at any age, including childhood, with a slight predilection for the male gender. Rectal bleeding and rectal polyps are consistent features in all reported cases. Other typical symptoms include constipation, diarrhea, and abdominal pain. Symptoms may be very similar to those of chronic inflammatory bowel disease, the most important differential diagnosis. The cause of cap polyposis is still unclear, and specific therapy has not as yet been established. Conservative therapeutic measures should be preferred, especially in children.
EVALuna2:52991

Case report: Tension pneumoperitoneum after diagnostic colonoscopy in an 11 y/o boy with Crohns disease - Seitz, Sigurd; Rückel, Aline; Siebenlist, Gregor; Besendörfer, Manuel; Schellerer, Vera (International Journal of Surgery Case Reports, 2020)
Introduction: Endoscopy is an established diagnostic and therapeutic tool in paediatric gastroenterology and a save method with rare complications. Presentation of case: We present the case of an 11-year-old Caucasian boy with a long history of inflammatory bowel disease. Three years prior an ileostomy was created and is still in position. After diagnostic panendoscopy (colonoscopy, gastroscopy, endoscopy of small intestine via ileostomy) the patient showed progressive abdominal distension and pain. After diagnosis of tension pneumoperitoneum by radiological proof of massive intraabdominal air and altered vital signs, we initiated emergency laparotomy. Surgical intervention ruled out a free gastrointestinal perforation as well as peritonitis. There was a gaseous insufflation of the mesenteric tissue of the sigmoid and upper rectum most likely according to microperforations to the mesentery. Due to the pre-existing ileostomy, we took no further surgical action. The abdomen was lavaged and drains inserted. Upon further conservative treatment with intravenous antibiotics, the patient showed quick recovery and was discharged on postoperative day 6. Discussion: With an incidence of 0.01%, perforation after diagnostic colonoscopy in children is very uncommon. The zone most frequently affected is the sigmoid colon due to direct penetration or indirect force due to flexure, or insufflation. Even without macroscopic perforation, the development of a tension pneumoperitoneum seems to be possible. Conclusion: Even though Colonoscopy in children is a safe tool, the treating physician must never underestimate the risks of such an intervention. Especially chronically altered intestine as in long-time persisting chronic inflammatory bowel disease demand special care and intensive observation of the patient after intervention.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Child; Colonoscopy; Crohns disease; Pneumoperitoneum

CD11c(+) dendritic cells mediate antigen-specific suppression in extracorporeal photopheresis - Hackstein, Holger; Kalina, A.; Dorn, B.; Keil, I. S.; Baal, N.; Michel, G.; Brendel, C.; Neubauer, A.; Jakob, T.; Bein, Gregor (Clinical and Experimental Immunology, 2020)
Extracorporeal photopheresis (ECP) represents one of the most widespread and effective cell therapies for graft-versus-host disease and other T cell-mediated disorders. However, the key factors affecting the therapeutic efficacy of ECP remain unclear. We hypothesized that therapeutic effects are mediated by ECP-treated antigen-presenting dendritic cells (DC). To test this hypothesis, we used the experimental model of contact hypersensitivity (CHS). The ECP's therapeutic activity improved when the total cell dose of the ECP-treated cells was increased. We used different haptens during sensitization to demonstrate that the anti-inflammatory activity of ECP is antigen-specific. This confirmed the hypothesis that professional antigen-presenting cells are involved in the mode of action. Also, the ECP's therapeutic activity was abrogated by the depletion of CD11c(+) DC, which represents fewer than 1% of all the ECP-exposed cells. Finally, we confirm the critical importance of CD11c(+) DC for ECP activity by showing that only a few purified CD11c(+) DC are sufficient to mediate its therapeutic effect. The finding that ECP-treated, physiological antigen-presenting DC alone mediate antigen-specific modulation of a pathological immune response may result in better-targeted interventions when treating patients.
CRIS-Team WoS Importer:2020-11-27

CD19 CAR-T cell treatment of CNS relapse of Burkitt's lymphoma: A case report - Aigner, Michael; Jacobs, Benedikt; Gary, Regina; Kretschmann, S.; Achenbach, Susanne; Mackensen, Andreas; Mougiakakos, Dimitrios; Völkl, Simon; Baur, Rebecca (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-10-23

CD71 surface analysis of T cells: a simple alternative for extracorporeal photopheresis quality control - Schwab, Laura; Michel, Gabriela; Bein, Gregor; Hackstein, Holger (Vox Sanguinis, 2019)
Background: Extracorporeal photopheresis (ECP) is a leukapheresis-based cellular therapy that is used with increasing frequency worldwide to treat various T-cell-mediated diseases. Currently, the inhibition of T-cell proliferation after photopheresis is analysed frequently using time-consuming assays including radioactive thymidine assays or carboxyfluorescein succinimidyl ester (CFSE) staining. We investigated whether simple surface T-cell staining using surrogate markers of T-cell proliferation can replace time-consuming measurement of T-cell proliferation in ECP quality control. Study design and methods: T-cell activation markers were investigated by flow cytometry after ECP. Candidates were validated by direct comparison with the classical CFSE T-cell proliferation inhibition test and apoptosis staining. Finally, surface T-cell staining was performed in patient samples in comparison with classical methods. Results: CD71 expression exhibited the fastest and most robust upregulation, which was detectable as early as 6–8 h after T-cell stimulation and almost completely abrogated by ECP. In a direct comparison with the CFSE T-cell proliferation assay, suppression of CD71 expression after ECP was almost identical and detectable as early as 16 h after stimulation in peripheral blood mononuclear cells of healthy donors. Furthermore, in direct comparison with classical apoptosis staining, the inhibition delta of CD71 after ECP was significantly higher. Moreover, in patients under T-cell suppressive therapy, T-cell-dependent CFSE and CD71 assays exhibited decreased sensitivity to detect ECP treatment and were inferior in comparison to apoptosis staining. Conclusion: Surface CD71 analysis represents a very simple quality control alternative to detect ECP-mediated T-cell proliferation inhibition in normal PBMC samples devoid of T-cell suppressive drugs.
CRIS-Team Scopus Importer:2019-11-19
Keywords: CD71; extracorporeal photopheresis; flow cytometry

CD71 surface analysis of T cells: a simple alternative for extracorporeal photopheresis quality control - Schwab, Laura; Michel, Gabriela; Bein, Gregor; Hackstein, Holger (Vox Sanguinis, 2020)
BACKGROUND: Extracorporeal photopheresis (ECP) is a leukapheresis-based cellular therapy that is used with increasing frequency worldwide to treat various T-cell-mediated diseases. Currently, the inhibition of T-cell proliferation after photopheresis is analysed frequently using time-consuming assays including radioactive thymidine assays or carboxyfluorescein succinimidyl ester (CFSE) staining. We investigated whether simple surface T-cell staining using surrogate markers of T-cell proliferation can replace time-consuming measurement of T-cell proliferation in ECP quality control. STUDY DESIGN AND METHODS: T-cell activation markers were investigated by flow cytometry after ECP. Candidates were validated by direct comparison with the classical CFSE T-cell proliferation inhibition test and apoptosis staining. Finally, surface T-cell staining was performed in patient samples in comparison with classical methods. RESULTS: CD71 expression exhibited the fastest and most robust upregulation, which was detectable as early as 6-8 h after T-cell stimulation and almost completely abrogated by ECP. In a direct comparison with the CFSE T-cell proliferation assay, suppression of CD71 expression after ECP was almost identical and detectable as early as 16 h after stimulation in peripheral blood mononuclear cells of healthy donors. Furthermore, in direct comparison with classical apoptosis staining, the inhibition delta of CD71 after ECP was significantly higher. Moreover, in patients under T-cell suppressive therapy, T-cell-dependent CFSE and CD71 assays exhibited decreased sensitivity to detect ECP treatment and were inferior in comparison to apoptosis staining. CONCLUSION: Surface CD71 analysis represents a very simple quality control alternative to detect ECP-mediated T-cell proliferation inhibition in normal PBMC samples devoid of T-cell suppressive drugs.
EVALuna2:213423

CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer - Zeng, Siyuan; Lan, Bin; Ren, Xiaofan; Zhang, Shuman; Schreyer, Daniel; Eckstein, Markus; Yang, Hai; Britzen-Laurent, Nathalie; Dahl, Andreas; Mukhopadhyay, Debabrata; Chang, David; Kutschick, Isabella; et al. (Journal of Experimental & Clinical Cancer Research, 2022)
Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Although combined treatment with gemcitabine and albumin-bound paclitaxel has improved the prognosis of PDAC, both intrinsic and acquired chemoresistance remain as severe hurtles towards improved prognosis. Thus, new therapeutic targets and innovative strategies are urgently needed. Methods: In this study, we used the KPC mouse model-derived PDAC cell line TB32047 to perform kinome-wide CRISPR-Cas9 loss-of-function screening. Next-generation sequencing and MAGeCK-VISPR analysis were performed to identify candidate genes. We then conducted cell viability, clonogenic, and apoptosis assays and evaluated the synergistic therapeutic effects of cyclin-dependent kinase 7 (CDK7) depletion or inhibition with gemcitabine (GEM) and paclitaxel (PTX) in a murine orthotopic pancreatic cancer model. For mechanistic studies, we performed genome enrichment analysis (GSEA) and Western blotting to identify and verify the pathways that render PDAC sensitive to GEM/PTX therapy. Results: We identified several cell cycle checkpoint kinases and DNA damage-related kinases as targets for overcoming chemoresistance. Among them, CDK7 ranked highly in both screenings. We demonstrated that both gene knockout and pharmacological inhibition of CDK7 by THZ1 result in cell cycle arrest, apoptosis induction, and DNA damage at least predominantly through the STAT3-MCL1-CHK1 axis. Furthermore, THZ1 synergized with GEM and PTX in vitro and in vivo, resulting in enhanced antitumor effects. Conclusions: Our findings support the application of CRISPR-Cas9 screening in identifying novel therapeutic targets and suggest new strategies for overcoming chemoresistance in pancreatic cancer.
CRIS-Team Scopus Importer:2022-08-19
Keywords: CDK7; CRISPR-Cas9; FOLFIRINOX; Gemcitabine; Paclitaxel; THZ1

Cell death inhibition by KSHV - Murtadak, Vinay; Becker, Christoph; Stürzl, Michael (Aging-Us, 2015)
EVALuna2:1975

Cellular and molecular features of HIV-associated Kaposi's sarcoma. - Roth, Willi Kurt; Brandstetter, Heinz; Stürzl, Michael (Aids, 1992)

Centralization as the key survival benefit in acute neonatal surgery - Besendörfer, Manuel; Günster, Simone; Linz, Katja; Reutter, Heiko Martin; Diez, Sonja (Frontiers in Pediatrics, 2024)
Introduction: Centralization of neonatal surgical care for congenital malformations is already under discussion. Acute care of neonatal emergencies in perinatal centers with affiliated hospitals is not uniformly regulated in Germany. Materials and methods: Analyses are based on acute pediatric surgical care at four affiliated hospitals of a perinatal center. Epidemiologic data and outcome parameters “survival”, “intracerebral hemorrhage”, and “revision of surgical indication” are assessed. Comparison is made between patients receiving surgical treatment at affiliated hospitals (group A) and patients with transfer to the university center for therapy in case of surgical indication for gastrointestinal diseases (group B). Results: 17 group A-patients are compared to 40 group B-patients. Comparison of epidemiological data reveals no significant differences. There is a survival advantage with transfer to the university center (mortality of 29% in group A vs. 2% in group B, p = 0.007). Intracerebral hemorrhage occurred more frequently in externally treated patients (group A 24% vs. group B 2%, p = 0.024). Surgical indication was revised in 30% of group B at the university center (p = 0.011) with consecutive successful conservative treatment. Conclusion: Transfer of patients at the beginning of the acute phase of gastrointestinal diseases is key to optimize the quality of neonatal surgical care. However, larger population studies should confirm the presented results, discuss restricting factors of real care structures and should rule out bias in triage of patients.
CRIS-Team Scopus Importer:2024-04-05
Keywords: centralization; German medical system; neonatal emergency; neonatal surgery; perinatal center

Centrosomal protein TRIM43 restricts herpesvirus infection by regulating nuclear lamina integrity - Full, Florian; Van Gent, Michiel; Sparrer, Konstantin M. J.; Chiang, Cindy; Zurenski, Matthew A.; Scherer, Myriam; Brockmeyer, Norbert H.; Heinzerling, Lucie; Stürzl, Michael; Korn, Klaus; Stamminger, Thomas; Enßer, Armin; et al. (Nature Microbiology, 2019)
Tripartite motif (TRIM) proteins mediate antiviral host defences by either directly targeting viral components or modulating innate immune responses. Here we identify a mechanism of antiviral restriction in which a TRIM E3 ligase controls viral replication by regulating the structure of host cell centrosomes and thereby nuclear lamina integrity. Through RNAi screening we identified several TRIM proteins, including TRIM43, that control the reactivation of Kaposi's sarcoma-associated herpesvirus. TRIM43 was distinguished by its ability to restrict a broad range of herpesviruses and its profound upregulation during herpesvirus infection as part of a germline-specific transcriptional program mediated by the transcription factor DUX4. TRIM43 ubiquitinates the centrosomal protein pericentrin, thereby targeting it for proteasomal degradation, which subsequently leads to alterations of the nuclear lamina that repress active viral chromatin states. Our study identifies a role of the TRIM43-pericentrin-lamin axis in intrinsic immunity, which may be targeted for therapeutic intervention against herpesviral infections.
EVALuna2:35255

Change of the metabolomic profile during short-term mononuclear cell storage - Steininger, Philipp; Strasser, Erwin; Ziehe, Bettina; Eckstein, Reinhold; Rauh, Manfred (Vox Sanguinis, 2017)
BACKGROUND AND OBJECTIVES: Short-term storage of leukapheresis products used for immunotherapeutic mononuclear cell (MNC) products is a frequent event. The analysis of time-related metabolic patterns enables the characterization of storage-related effects in MNCs and the hypothesis-based optimization of the MNC medium. MATERIALS AND METHODS: The MNC products from seven leukapheresis procedures were stored within a closed bag system for 48 h. Concentrations of amino acids, biogenic amines, phospho- and sphingolipids and hexoses in the medium were measured by targeted metabolomics. The viability of MNC subpopulations was assayed by Annexin V (AnV) and JC-1 staining. RESULTS: Glucose depletion and a significant change of the acylcarnitine profile are early events within the first 24 h of storage. In contrast, for most amino acids, the maximum increase was observed at 48 h of storage as mirrored by an increase in the amino acid levels by a mean factor of 1·2 (1·3, 2·0) after 6 h (24 h, 48 h, respectively). This was except for the concentrations of glutamine and lysine, which did not change significantly. The taurine concentration showed a twofold increase within the first 24 h and remained constant thereafter. The steepest increase in AnV+and 7-AAD+CD4+T cells was found between 24 and 48 h. CONCLUSION: The time-course of apoptosis and metabolic patterns in the MNC products demonstrate that 24 h of storage is a decisive time-point, as afterwards key metabolic pathways showed nonlinear detrimental changes. Optimization of storage by supplementation of specific substrates demands therefore an early intervention.
EVALuna2:32783

Changing paradigm of sacral neuromodulation and external anal sphincter repair for faecal incontinence in specialist centres - Ong, Kelly; Bordeianou, L.; Brunner, Maximilian; Buntzen, S.; Collie, M. H. S.; Hanly, A.; Hunt, C. W.; Matzel, Klaus; O'Connell, P. R.; Rydningen, M.; Savitt, L.; Totaro, A.; et al. (Colorectal Disease, 2020)
Aim: The aim of this study was to determine whether the paradigm of surgical intervention for faecal incontinence (FI) has changed between 2000 and 2013. Method: This was a multi-centre retrospective study of patients who had undergone either sacral neuromodulation (SNM) or delayed sphincter repair or sphincteroplasty (SR) as a primary surgical intervention for FI in five centres in Europe and one in the United States. The flow of patients according to the intervention, sustainability of the treatment at a minimum follow-up of 5 years, complications and requirement for further interventions were recorded. Results: A total of 461 patients (median age 56 years, range 24–90 years, 41 men) had either SNM or SR as an index operation during the study period [SNM 284 (61.6%), SR 177 (38.4%)]. Among SNM patients, there were 169 revisional operations (change of battery and/or lead, re-siting or removal). At the time of last follow-up 203 patients (71.4%) continued to use SNM. Among SR patients, 30 (16.9%) had complications, most notably wound infection (22, 12.4%). During follow-up 32 patients (18.1%) crossed over to SNM. Comparing two 4-year periods (2000–2003 and 2007–2010), the proportion of patients operated on who had a circumferential sphincter defect of less than 90° was 48 (68%) and 45 (46%), respectively (P = 0.03), while those who had SNM as the primary intervention increased from 29% to 89% (P < 0.05). Conclusion: The paradigm of surgical intervention for FI has changed with increasing use of SNM.
CRIS-Team Scopus Importer:2020-10-02
Keywords: faecal incontinence; sacral nerve stimulation; sacral neuromodulation; sphincter repair; sphincteroplasty

Characterization of mast cell-derived rRNA-containing microvesicles and their inflammatory impact on endothelial cells - Elsemueller, Ann-Kathrin; Tomalla, Vanessa; Gaertner, Ulrich; Troidl, Kerstin; Jeratsch, Sylvia; Graumann, Johannes; Baal, Nelli; Hackstein, Holger; Lasch, Manuel; Deindl, Elisabeth; Preissner, Klaus T.; Fischer, Silvia (The FASEB Journal, 2019)
Tissue-resident mast cells (MCs) are well known for their role in inflammatory responses and allergic and anaphylactic reactions, but they also contribute to processes of arterial remodeling. Although ribosomes and cytosolic RNAs are located around secretory granules in mature MCs, their functional role in MC responses remains unexplored. Previous studies by our group characterized extracellular RNA (eRNA) as an inflammatory and pathogenetic factor in vitro and in vivo. In the present study, RNA-containing MCs and eRNA were located in close proximity to growing collateral arteries in vivo. In vitro, various agonists were found to induce the degranulation of MCs and the concomitant release of eRNA in association with microvesicles (MVs). The liberation of eRNA from MCs was abolished by MC stabilizers or by preventing the increase of intracellular Ca2+ in MCs. eRNA was found to be mainly contained inside MVs, as demonstrated by electron microscopy and immunocytochemistry. The exposure to and the uptake of MC-released MVs by cultured endothelial cells increased their expression of cytokines, such as monocyte chemoattractant protein or IL-6, in a dose- and time-dependent manner. These results indicate that RNA-containing MC-derived MVs are likely to be involved in inflammatory responses, relevant, for example, to processes of vascular remodeling.
CRIS-Team WoS Importer:2019-04-12

Characterization of the impact of immune checkpoint inhibitors on platelet activation and aggregation - Schlüter, Julian; Cunningham, Sarah; Zimmermann, Robert; Achenbach, Susanne; Kramer, Rafaela; Erdmann, Michael; Beckmann, Matthias; Heinzerling, Lucie; Hackstein, Holger (Immunobiology, 2023)
Immune checkpoint inhibitors (ICIs) are effective oncological drugs which block cellular check-point receptors typically targeted by tumor immune evasion strategies. Despite their benefits, clinicians have reported treatment-associated thromboembolism during ICI therapy in recent years. Though several theories on this ICI-associated pathogenesis exist, the direct effects of ICIs on platelets remains unknown. We therefore investigated the potential direct and indirect effect of PD-1, PD-L1 and CTLA-4-targeting ICIs on platelet functionality in multifaceted in vitro experiments. Interestingly, we could not observe a clear effect of ICI on platelet aggregation and primary hemostasis in whole blood and platelet concentrate-based assays. Furthermore, the presence of ICIs in toll-like receptor stimulation had no significant impact on platelet surface marker expression. In a second approach, we investigated the indirect immunological impact of ICIs on platelet activation by exposing platelets to supernatants from ICI- and Staphylococcal enterotoxin B-exposed PBMCs. Whereas ICIs affected IL-2 levels in supernatants, we could not detect clear differences in the secretion of pro-thrombogenic factors and platelet responses. The obtained data suggest that the direct influence of ICIs on platelet activation or the influence of altered T cell function on platelet activation cannot be considered a major factor in the development of thrombotic events.
CRIS-Team Scopus Importer:2023-01-13
Keywords: Immune checkpoint inhibitors; Platelet activation; Platelet function tests; Platelets; Thrombosis

Chemoradiotherapy plus hyperthermia (CRTH) versus chemoradiotherapy (CRT) alone in neoadjuvant treatment of soft tissue sarcoma: tumor response, treatment toxicity and disease control - Willner, Alexander; Agaimy, Abbas; Fechner, Katja; Ott, Oliver; Denz, Axel; Weissmann, Thomas; Meidenbauer, Norbert; Höfler, Daniel; Gaipl, Udo; Frey, Benjamin; Schmidt, Manfred; Haller, Florian; et al. (International Journal of Hyperthermia, 2023)
Introduction: Neoadjuvant chemotherapy and radiotherapy for the management of soft tissue sarcomas (STS) are still preferably delivered sequentially, with or without concurrent hyperthermia. Concurrent delivery of chemo-, radio- and thermotherapy may produce synergistic effects and reduce chemotherapy-free intervals. The few available studies suggest that concurrent chemoradiation (CRT) has a greater local effect. Data on the efficacy and toxicity of adding hyperthermia to CRT (CRTH) are sparse. Materials and methods: A cohort of 101 patients with STS of the extremities and trunk who received CRT (n = 33) or CRTH (n = 68) before resection of macroscopic tumor (CRT: n = 19, CRTH: n = 49) or re-resection following a non-oncological resection, so called ‘whoops procedure’, (CRT: n = 14, CRTH: n = 19) were included in this retrospective study. CRT consisted of two cycles of doxorubicine (50 mg/m2 on d2) plus ifosfamide (1500 mg/m2 on d1-5, q28) plus radiation doses of up to 60 Gy. Hyperthermia was delivered in two sessions per week. Results: All patients received the minimum dose of 50 Gy. Median doses of ifosfamide and doxorubicin were comparable between CRT (75%/95%) and CRTH (78%/97%). The median number of hyperthermia sessions was seven. There were no differences in acute toxicities. Major wound complications occurred in 15% (CRT) vs. 25% (CRTH) (p = 0.19). In patients with macroscopic disease, the addition of hyperthermia resulted in a tendency toward improved remission: regression ≥90% occurred in 21/48 (CRTH) vs. 4/18 (CRT) patients (p = 0.197). With a median postoperative follow-up of 72 months, 6-year local control and overall survival rates for CRTH vs. CRT alone were 85 vs. 78% (p = 0.938) and 79 vs. 71% (p = 0.215). Conclusions: Both CRT and CRTH are well tolerated with an expected rate of wound complications. The results suggest that adding hyperthermia may improve tumor response.
CRIS-Team Scopus Importer:2023-09-01
Keywords: chemoradiotherapy; chemotherapy; hyperthermia; neoadjuvant; radiotherapy; Sarcoma; soft-tissue sarcoma; toxicity

Chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: Final results of the CAO/ARO/AIO-12 randomized phase 2 trial - Fokas, E.; Schlenska-Lange, A.; Polat, B.; Klautke, G.; Grabenbauer, G.; Fietkau, Rainer; Kuhnt, T.; Staib, L.; Brunner, T.; Grosu, A. -L.; Kirste, S.; Jacobasch, L.; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial - Fokas, Emmanouil; Schlenska-Lange, Anke; Polat, Buelent; Klautke, Gunther; Grabenbauer, Gerhard G.; Fietkau, Rainer; Kuhnt, Thomas; Staib, Ludger; Brunner, Thomas; Grosu, Anca-Ligia; Kirste, Simon; Jacobasch, Lutz; et al. (JAMA Oncology, 2021)
IMPORTANCE Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established.
CRIS-Team WoS Importer:2021-12-10

Chemoradiotherapy plus induction versus consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-12 multicentre, open-label, randomised, phase 2 trial - Fokas, E.; Allgaeuer, M.; Polat, B.; Klautke, G.; Grabenbauer, G.; Fietkau, Rainer; Kuhnt, T.; Staib, L.; Brunner, T.; Grosu, A-L; Schmiegel, W.; Jacobasch, L.; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus - Ott, Oliver J.; Schmidt, Manfred; Semrau, Sabine; Strnad, Vratislav; Matzel, Klaus E.; Schneider, Ignaz Hans Friedrich; Raptis, Dimitrios; Uter, Wolfgang; Grützmann, Robert; Fietkau, Rainer (Strahlentherapie und Onkologie, 2018)
PURPOSE: To compare results after chemoradiotherapy with and without deep regional hyperthermia in patients with anal cancer. METHODS: Between 2000 and 2015, a total of 112 consecutive patients with UICC stage I-IV anal cancer received chemoradiotherapy with 5‑fluororuracil and mitomycin C (CRT). In case of insufficient tumor response 4-6 weeks after chemoradiotherapy, patients received an interstitial pulsed-dose-rate brachytherapy boost. Additionally, 50/112 patients received hyperthermia treatments (HCRT). RESULTS: Median follow-up was 41 (2-165) months. After 5 years follow-up, overall (95.8 vs. 74.5%, P = 0.045), disease-free (89.1 vs. 70.4%, P = 0.027), local recurrence-free (97.7 vs. 78.7%, P = 0.006), and colostomy-free survival rates (87.7 vs. 69.0%, P = 0.016) were better for the HCRT group. Disease-specific, regional failure-free, and distant metastasis-free survival rates showed no significant differences. The adjusted hazard ratios for death were 0.25 (95% CI, 0.07 to 0.92; P = 0.036) and for local recurrence 0.14 (95% CI, 0.02 to 1.09; P = 0.06), respectively. Grades 3-4 early toxicities were comparable with the exception of hematotoxicity, which was higher in the HCRT group (66 vs. 43%, P = 0.032). Incidences of late side effects were similar with the exception of a higher telangiectasia rate in the HCRT group (38.0 vs. 16.1%, P = 0.009). CONCLUSION: Additional regional hyperthermia improved overall survival, local control, and colostomy rates. Its potential beneficial role has to be confirmed in a prospective randomized setting. Therefore, the HyCAN trial has already been established by our group and is currently recruiting patients (Clinicaltrials.gov identifier: NCT02369939).
EVALuna2:36451

Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus - Ott, O. J.; Schmidt, M.; Semrau, S.; Strnad, Vratislav; Matzel, K. E.; Schneider, I.; Raptis, D.; Uter, Wolfgang; Grützmann, Robert; Fietkau, Rainer (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Chemoresistance in Pancreatic Cancer - Zeng, Siyuan; Pöttler, Marina; Lan, Bin; Grützmann, Robert; Pilarsky, Christian; Yang, Hai (International Journal of Molecular Sciences, 2019)
Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While the incidence of pancreatic cancer is displaying a rising tendency every year, the mortality rate has not decreased significantly because of late diagnosis, early metastasis, and limited reaction to chemotherapy or radiotherapy. Adjuvant chemotherapy after surgical resection is typically the preferred option to treat early pancreatic cancer. Although 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel can profoundly improve the prognosis of advanced pancreatic cancer, the development of chemoresistance still leads to poor clinical outcomes. Chemoresistance is multifactorial as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. Therefore, we outline new perspectives for enhancing the efficacy of gemcitabine after reviewing the related factors of gemcitabine metabolism, mechanism of action, and chemoresistance.
CRIS-Team Scopus Importer:2019-09-20
Keywords: chemoresistance; FOLFIRINOX; gemcitabine; pancreatic cancer; PDAC

Chemo-RT plus induction or consolidation chemotherapy for rectal cancer: a randomised phase 2 trial - Fokas, E.; Allgaeuer, M.; Polat, B.; Klautke, G.; Grabenbauer, G.; Fietkau, Rainer; Kuhnt, T.; Staib, L.; Brunner, T.; Grosu, A. L.; Schmiegel, W.; Jacobasch, L.; et al. (RADIOTHERAPY AND ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-06-18

Cholelithiasis and cholecystitis in children and adolescents: Does this increasing diagnosis require a common guideline for pediatricians and pediatric surgeons? - Diez, Sonja; Mueller, Hanna; Weiss, Christel; Schellerer, Vera; Besendörfer, Manuel (BMC Gastroenterology, 2021)
Background: In contrast to adults, for whom guidelines on the cholelithiasis treatment exist, there is no consistent treatment of pediatric patients with cholelithiasis throughout national and international departments, most probably due to the lack of evidence-based studies. Methods: We evaluated the German management of pediatric cholelithiasis in a dual approach. Firstly, a retrospective, inter-divisional study was established, comparing diagnostics and therapy of patients of the pediatric surgery department with the management of patients aged < 25 years of the visceral surgery department in our institution over the past ten years. Secondarily, a nation-wide online survey was implemented through the German Society of Pediatric Surgery. Results: Management of pediatric patients with cholelithiasis was primarily performed by pediatricians in the retrospective analysis (p < 0.001). Pediatric complicated cholelithiasis was not managed acutely in the majority of cases with a median time between diagnosis and surgery of 22 days (range 4 days–8 months vs. 3 days in visceral surgery subgroup (range 0 days–10 months), p = 0.003). However, the outcome remained comparable. The hospital’s own results triggered a nation-wide survey with a response rate of 38%. Primary pediatric medical management of patients was confirmed by 36 respondents (71%). In case of acute cholecystitis, 22% of participants perform a cholecystectomy within 24 h after diagnosis. Open questions revealed that complicated cholelithiasis is managed individually. Conclusions: The management of pediatric cholelithiasis differs between various hospitals and between pediatricians and pediatric surgeons. Evidence-based large-scale population studies as well as a common guideline may represent very important tools for treating this increasing diagnosis.
CRIS-Team Scopus Importer:2021-05-07
Keywords: Cholecystitis; Pediatric gallstones; Symptomatic cholecystolithiasis

Chronic critical limb ischemia in octogenarian patients Advantages and disadvantages of endovascular and surgical procedures - Uhl, C.; Behrendt, C.; Goertz, H.; Ruemenapf, G.; Boeckler, D.; Rother, Ulrich (Gefässchirurgie, 2021)
Vascular surgery patients older than 80 years have been seen more frequently in the clinical routine over the last years. This demographic change poses a challenge to medicine and will accompany us in the future. Many studies in recent years have provided evidence of a positive impact of revascularization in chronic critical limb ischemia; however, technically possible does not always mean reasonable for the patient. Endovascular and open vascular surgical procedures are known modalities for revascularization. Good results can be achieved by using the eligible revascularization procedures, taking the comorbidities, the life expectancy and the expected patient mobility into consideration. This review article with a selective literature search aims to sensitize to the important topic of treatment options for critical limb ischemia in patients >80 years old. It also shows that each revascularization procedure has advantages and disadvantages. The treatment should be individualized for each patient.
CRIS-Team WoS Importer:2021-01-29

Chronic intestinal inflammation in mice expressing viral Flip in epithelial cells - Ruder, Barbara; Murtadak, Vinay; Stürzl, Michael; Wirtz, Stefan; Distler, Ute; Tenzer, Stefan; Mahapatro, Mousumi; Greten, Florian R.; Hu, Yinling; Neurath, Markus; Cesarman, Ethel; Ballon, Gianna; et al. (Mucosal Immunology, 2018)
Viruses are present in the intestinal microflora and are currently discussed as a potential causative mechanism for the development of inflammatory bowel disease. A number of viruses, such as Human Herpesvirus-8, express homologs to cellular FLIPs, which are major contributors for the regulation of epithelial cell death. In this study we analyzed the consequences of constitutive expression of HHV8-viral FLIP in intestinal epithelial cells (IECs) in mice. Surprisingly, expression of vFlip disrupts tissue homeostasis and induces severe intestinal inflammation. Moreover vFlipIEC-tg mice showed reduced Paneth cell numbers, associated with excessive necrotic cell death. On a molecular level vFlip expression altered classical and alternative NFκB activation. Blocking of alternative NFκB signaling by deletion of Ikka in vivo largely protected mice from inflammation and Paneth cell loss induced by vFLIP. Collectively, our data provide functional evidence that expression of a single viral protein in IECs can be sufficient to disrupt epithelial homeostasis and to initiate chronic intestinal inflammation.
EVALuna2:35131

Chronic popliteal entrapment with calcified lesions results in an acute occlusion after blunt knee trauma in a 17-year-old soccer player - Regus, Susanne; Söder, Stephan; Janka, Rolf Matthias; Lang, Werner (Journal of Vascular Surgery, 2015)
EVALuna2:6687

Cinematic Rendering in Anatomy: A Crossover Study Comparing a Novel 3D Reconstruction Technique to Conventional Computed Tomography - Binder, Johannes; Scholz, Michael; Ellmann, Stephan; Uder, Michael; Grützmann, Robert; Krautz, Christian; Weber, Georg (Anatomical Sciences Education, 2020)
Integration of medical imaging into preclinical anatomy courses is already underway in many medical schools. However, interpretation of two-dimensional grayscale images is difficult and conventional volume rendering techniques provide only images of limited quality. In this regard, a more photorealistic visualization provided by Cinematic Rendering (CR) may be more suitable for anatomical education. A randomized, two-period crossover study was conducted from July to December 2018, at the University Hospital of Erlangen, Germany to compare CR and conventional computed tomography (CT) imaging for speed and comprehension of anatomy. Sixteen students were randomized into two assessment sequences. During each assessment period, participants had to answer 15 anatomy-related questions that were divided into three categories: parenchymal, musculoskeletal, and vascular anatomy. After a washout period of 14 days, assessments were crossed over to the respective second reconstruction technique. The mean interperiod differences for the time to answer differed significantly between the CR-CT sequence (-204.21 +/- 156.0 seconds) and the CT-CR sequence (243.33 +/- 113.83 seconds;P < 0.001). Overall time reduction by CR was 65.56%. Cinematic Rendering visualization of musculoskeletal and vascular anatomy was higher rated compared to CT visualization (P P = 0.003), whereas CT visualization of parenchymal anatomy received a higher scoring than CR visualization (P < 0.001). No carryover effects were observed. A questionnaire revealed that students consider CR to be beneficial for medical education. These results suggest that CR has a potential to enhance knowledge acquisition and transfer from medical imaging data in medical education.
CRIS-Team WoS Importer:2020-07-17

Circadian and circaseptan rhythms in implant-based thoracic impedance - Kirchner, J.; Paule, S.; Beckendorf, C.; Achenbach, Susanne; Arnold, Martin (Physiological Measurement, 2015)
Thoracic impedance (TI) denotes the electrical resistance that is measured between the right ventricular lead and the can of an implantable cardioverter-defibrillator. It is used in medical diagnostics for fluid load monitoring in heart failure patients. We analysed TI for diurnal and weekly components that go along with the recurrent patterns of daily life.TI was measured in 53 patients over 280 d each with a resolution of 1 h. Information about the patients' professional occupation and typical sleeping rhythm was sought. Periodic signal components were identified in the amplitude spectrum, and their main characteristics were derived by cosinor analysis. The typical daily and weekly pattern were reconstructed by Fourier filtering.The Fourier spectrum indicates a strong circadian and a weaker circaseptan component in TI. The latter is significantly elevated in patients who regularly go to work, on error level [Formula: see text]. Cosinor analysis states a significant circadian rhythm in all patients ([Formula: see text]), with MESOR 61.8 [Formula: see text], amplitude 1.9 [Formula: see text], and acrophase 17.5 h. A significant weekly rhythm is found in 25 patients ([Formula: see text]), with amplitude 0.31 [Formula: see text] and acrophase typically on Wednesday. Both rhythms typically obtain their maximum during the 'active' phase of the period in daily life, i.e. in the afternoon and on working days, respectively, while the minimum is reached in the 'recreative' phase.Circadian and circaseptan variation are hence prevalent components of TI, which can induce impedance changes of several Ohms and thus be an error source for daily TI measurements.
EVALuna2:12074

Circulating Monocytes Serve as Novel Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma Patients - Hansen, Frederik; David, Paul; Akram, Marina; Knoedler, Samuel; Mittelstädt, Anke; Merkel, Susanne; Podolska, Malgorzata; Swierzy, Izabela; Roßdeutsch, Lotta; Klösch, Bettina; Kouhestani, Dina; Anthuber, Anna; et al. (Cancers, 2023)
Pancreatic ductal adenocarcinoma (PDAC) ranks among the most fatal cancer diseases, widely accepted to have the most dismal prognoses. Although immunotherapy has broadly revolutionized cancer treatment, its value in PDAC appears to be relatively low. Exhibiting protumoral effects, monocytes have recently been proposed as potential targets of such immunotherapeutic regimens. However, to date, the body of evidence on monocytes’ role in PDAC is scarce. Therefore, we analyzed monocytes in the peripheral blood of 58 PDAC patients prior to surgery and compared them to healthy individuals. PDAC patients showed increased levels of monocytes when compared to healthy controls In addition, patients with perineural infiltration demonstrated a higher percentage of monocytes compared to non-infiltrating tumors and PDAC G3 was associated with higher monocyte levels than PDAC G2. Patients with monocyte levels > 5% were found to have an 8.9-fold increased risk for a G3 and perineural infiltrated PDAC resulting in poorer survival compared to patients with <5% monocyte levels. Furthermore, PDAC patients showed increased expressions of CD86 and CD11c and decreased expressions of PD-L1 on monocytes compared to healthy individuals. Finally, levels of monocytes correlated positively with concentrations of IL-6 and TNF-α in plasma of PDAC patients. Based on our findings, we propose monocytes as a novel prognostic biomarker. Large-scale studies are needed to further decipher the role of monocytes in PDAC and investigate their potential as therapeutic targets.
CRIS-Team Scopus Importer:2023-02-03
Keywords: grading; liquid biopsy; monocytes; pancreatic ductal adenocarcinoma; perineural invasion; prognostic biomarker

Clearance of human herpesvirus 8 from blood and regression of leukopenia-associated aggressive classic Kaposi's sarcoma during interferon-alpha therapy: a case report. - Monini, Paolo; Sirianni, Maria Caterina; Franco, Marina; Vincenzi, Laura; Topino, Simone; Goletti, Delia; Leone, Patrizia; Leone, Pasqualina; Chiozzini, Chiara; Nicastri, Emanuele; Andreoni, Massimo; Borduagni, Osvaldo; et al. (Clinical Infectious Diseases, 2001)
A human immunodeficiency virus-negative woman with severe classic Kaposi's sarcoma, idiopathic leukopenia, and massive spread of human herpesvirus 8 (HHV-8) in circulating cells showed stable disease remission in response to systemic interferon-alpha treatment that was accompanied by increased CD3(+) and CD4(+) T cell numbers and complete clearance of HHV-8 from the circulation. These results suggest a direct relationship between HHV-8 clearance from blood and regression of Kaposi's sarcoma and are consistent with the in vitro inhibitory effects of interferon-alpha on HHV-8 infection.

Clinical Characteristics of Necrotizing Enterocolitis in Preterm Patients With and Without Persistent Ductus Arteriosus and in Patients With Congenital Heart Disease - Diez, Sonja; Tielesch, Lea; Weiss, Christel; Halbfass, Julia; Mueller, Hanna; Besendörfer, Manuel (Frontiers in Pediatrics, 2020)
Background: Diagnosis and management of NEC is based on clinical, radiological, and laboratory findings. Discrimination of pathogens for an improved understanding of NEC in preterm infants and NEC in infants with congenital heart disease has been previously discussed and enables evaluation of further NEC biomarkers. Patients and Methods: Within a study period of 11 years (2008–2019), we identified 107 patients with a diagnosis of NEC at our primary care center. Thirty-six out of 54 patients suffering from NEC in high Bell stages who underwent surgery met inclusion criteria. These patients were classified according to their cardiac status, and analyses of clinical factors influencing NEC were conducted. Additionally, clinical factors associated with a fulminant course of NEC were examined. Univariable and multivariable analyses were performed. Results: The study populations consisted of 12 preterm infants with NEC but without patent ductus arteriosus (PT-NEC), seven preterm infants with NEC and patent ductus arteriosus (PDA-NEC), and 17 infants with NEC and congenital heart disease (CHD-NEC). Blood flow in intestinal vessels was impaired in infants with PDA-NEC and CDH-NEC. Therefore, we used logistic regression to compare PDA-NEC and CDH-NEC infants with PT-NEC infants: positive bacterial culture of intraoperative swabs (p = 0.0199; odds ratio: 21.9) and macroscopic intestinal necrosis (p = 0.0033; odds ratio: 43.5) were observed more frequently in the first group. Furthermore, multiple regression analysis determined the NEC localization (p = 0.0243) as a significant factor correlated with a fulminant course. Compared to a NEC exclusively localized in the colon, there is a 5.8-fold increased risk of a fulminant course when the small intestine is affected and a 42-fold increase of risk when both small intestine and colon were affected. Conclusion: An early diagnosis and timely surgical intervention of NEC, especially in infants with PDA and CDH may be considered to avoid major bowel necrosis (resulting in loss of intestinal tissue) and multiple operations.
CRIS-Team Scopus Importer:2020-07-10
Keywords: congenital heart disease; fulminant NEC; NEC; necrotizing enterocolitis; patent ductus arteriosus

Clinical-grade generation of peptide-stimulated CMV/EBV-specific T cells from G-CSF mobilized stem cell grafts - Gary, Regina; Aigner, Michael; Moi, Stephanie; Gottmann, Anja; Maas, Stefanie; Zimmermann, Robert; Zingsem, Jürgen; Strobel, Joachim; Mackensen, Andreas; Mautner, Josef; Moosmann, Andreas; Gerbitz, Armin; et al. (Journal of Translational Medicine, 2018)
BACKGROUND: A major complication after allogeneic hematopoietic stem cell transplantation (aSCT) is the reactivation of herpesviruses such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Both viruses cause significant mortality and compromise quality of life after aSCT. Preventive transfer of virus-specific T cells can suppress reactivation by re-establishing functional antiviral immune responses in immunocompromised hosts. METHODS: We have developed a good manufacturing practice protocol to generate CMV/EBV-peptide-stimulated T cells from leukapheresis products of G-CSF mobilized and non-mobilized donors. Our procedure selectively expands virus-specific CD8+ und CD4+ T cells over 9 days using a generic pool of 34 CMV and EBV peptides that represent well-defined dominant T-cell epitopes with various HLA restrictions. For HLA class I, this set of peptides covers at least 80% of the European population. RESULTS: CMV/EBV-specific T cells were successfully expanded from leukapheresis material of both G-CSF mobilized and non-mobilized donors. The protocol allows administration shortly after stem cell transplantation (d30+), storage over liquid nitrogen for iterated applications, and protection of the stem cell donor by avoiding a second leukapheresis. CONCLUSION: Our protocol allows for rapid and cost-efficient production of T cells for early transfusion after aSCT as a preventive approach. It is currently evaluated in a phase I/IIa clinical trial.
EVALuna2:34166

Clinical outcome after total neoadjuvant treatment (CAO/ARO/AIO-12) versus intensified neoadjuvant and adjuvant treatment (CAO/ARO/AIO 04) a comparison between two multicenter randomized phase II/III trials - Diefenhardt, Markus; Fleischmann, Maximillian; Martin, Daniel; Hofheinz, Ralf-Dieter; Piso, Pompiliu; Germer, Christoph-Thomas; Hambsch, Peter; Grützmann, Robert; Kirste, Simon; Schlenska-Lange, Anke; Ghadimi, Michael; Roedel, Claus; et al. (Radiotherapy and Oncology, 2023)
Background: Total neoadjuvant therapy (TNT) can enhance local tumor regression, but its survival bene-fits compared to intensified chemoradiotherapy (CRT) followed by adjuvant chemotherapy (CT) remain unclear.Methods: This is a secondary comparison between 607 patients treated with intensified 5-FU/Oxaliplatin neoadjuvant CRT and adjuvant CT within the experimental arm of the CAO/ARO/AIO-04 phase III trial, and 306 patients treated with TNT within the CAO/ARO/AIO-12 phase II trial. Comparison between clinical-pathological characteristics, surgical quality, and post-surgical complications were analyzed using the Pearson's Chi-squared or Mann-Whitney U test. Oncological outcome was examined with log-rank, Gray's test, and multivariate cox regression. In addition, further subgroup analyses and propensity score matching were performed to optimize the balance of baseline covariates.Findings: Patients treated with CRT followed by consolidation CT had a significantly higher rate of patho-logical complete remission (pCR) compared to patients treated within the experimental arm of the CAO/ ARO/AIO-04 trial (25.3 % vs 17.3 %, P = 0.04). Post-surgical complications were less common in the CAO/ ARO/AIO-12 trial. After a median follow-up of 46 months, clinical outcome did not differ significantly in the overall cohort, in any subgroup or after propensity score matching. In multivariate analysis, disease-free survival (DFS) was similar between the experimental arm of the CAO/ARO/AIO-04 trial and treat-ments arms of the CAO/ARO/AIO-12 trial (vs arm A: HR 0.92 [95 % CI 0.62-1.37], P = 0.69; vs arm B: HR 1.06 [95 % CI 0.72-1.58], P = 0.76).Interpretation: Notwithstanding the limitations of intertrial comparison, TNT did not improve long term oncological outcome in our study compared to the intensified neoadjuvant CRT and adjuvant CT treat-ment in the CAO/ARO/AIO-04 trial. Improved response rates after TNT offers an attractive option to explore organ preservation in selective patients with locally advanced rectal cancer.(c) 2022 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 179 (2023) 109455
CRIS-Team WoS Importer:2023-03-03

Clinical Outcome and Quality of Life of Multimodal Treatment of Extracranial Arteriovenous Malformations: The APOLLON Study Protocol - Schmidt, Vanessa F.; Masthoff, Max; Vielsmeier, Veronika; Seebauer, Caroline T.; Cangir, Ozlem; Meyer, Lutz; Muekke, Antje; Lang, Werner; Schmid, Axel; Sporns, Peter B.; Brill, Richard; Wohlgemuth, Walter A.; et al. (Cardiovascular and Interventional Radiology, 2022)
Purpose Arteriovenous malformations (AVMs) as rare diseases are diagnostically and therapeutically challenging. Due to the limited evidence regarding treatment outcome, prospective data are needed on how different treatment regimens affect outcome. The aims of this prospective trial are to determine effectiveness, safety, and clinical outcome of multimodal treatment in patients with extracranial AVMs.
CRIS-Team WoS Importer:2022-11-04

Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study - Mlecnik, Bernhard; Torigoe, Toshihiko; Bindea, Gabriela; Popivanova, Boryana; Xu, Mingli; Fujita, Tomonobu; Hazama, Shoichi; Suzuki, Nobuaki; Nagano, Hiroaki; Okuno, Kiyotaka; Hirohashi, Yoshihiko; Furuhata, Tomohisa; et al. (Cancers, 2022)
BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I–III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I–III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75−30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10–4.55) p = 0.0269) of the patient’s gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27−9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35−5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21−5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39−6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.
CRIS-Team Scopus Importer:2022-10-07
Keywords: Asian; classification; colon cancer; immune response; Immunoscore; MSI; prognostic markers; risk stratification; T cell; tumor microenvironment

Clinical Response to Vedolizumab in Ulcerative Colitis Patients Is Associated with Changes in Integrin Expression Profiles - Fuchs, Florian; Schillinger, Daniela; Atreya, Raja; Hirschmann, Simon; Fischer, Sören; Neufert, Clemens; Atreya, Imke; Neurath, Markus; Zundler, Sebastian (Frontiers in Immunology, 2017)
BACKGROUND: Despite large clinical success, deeper insights into the immunological effects of vedolizumab therapy for inflammatory bowel diseases are scarce. In particular, the reasons for differential clinical response in individual patients, the precise impact on the equilibrium of integrin-expressing T cell subsets, and possible associations between these issues are not clear. METHODS: Blood samples from patients receiving clinical vedolizumab therapy were sequentially collected and analyzed for expression of integrins and chemokine receptors on T cells. Moreover, clinical and laboratory data from the patients were collected, and changes between homing marker expression and clinical parameters were analyzed for possible correlations. RESULTS: While no significant correlation of changes in integrin expression and changes in outcome parameters were identified in Crohn's disease (CD), increasing α4β7 levels in ulcerative colitis (UC) seemed to be associated with favorable clinical development, whereas increasing α4β1 and αEβ7 correlated with negative changes in outcome parameters. Changes in α4β1 integrin expression after 6 weeks were significantly different in responders and non-responders to vedolizumab therapy as assessed after 16 weeks with a cutoff of +4.2% yielding 100% sensitivity and 100% specificity in receiver-operator-characteristic analysis. DISCUSSION: Our data show that clinical response to vedolizumab therapy in UC but not in CD is associated with specific changes in integrin expression profiles opening novel avenues for mechanistic research and possibly prediction of response to therapy.
EVALuna2:33807

Clotting factor activity in fresh frozen plasma after thawing with a new radio wave thawing device - Kuta, Piotr; Melling, Nathaniel; Zimmermann, Robert; Achenbach, Susanne; Eckstein, Reinhold; Strobel, Joachim (Transfusion, 2019)
BACKGROUND: Massive hemorrhage usually results in rapid need of blood products. Patients in need of fresh frozen plasma (FFP) might benefit from shorter thawing times using a novel radio wave device. So far, only one study on the prototype has been published. Activities of clotting factors after thawing FFP with the radio wave device and with a system using water cushions were compared. This is the first study analyzing the quality of FFP using the fully developed radio wave thawing device UFT100. STUDY DESIGN AND METHODS: Thirty FFP units were thawed with the UFT100 and the Plasmatherm machine. Various clotting factors and inhibitors were analyzed before freezing, immediately after thawing, and after a 48-hour storage period at +4°C. RESULTS: After thawing, all factor activities were within normal ranges regardless of the thawing procedure. We observed significant differences in nearly all clotting factor activities regarding time as effector, whereas thawing with the Plasmatherm machine led to a significant decrease (>10%) only in factor V activity compared to the UFT100. CONCLUSIONS: Immediately after rapid thawing with the UFT100, all FFP units contained adequate coagulation factor activities to maintain hemostatic activity. The UFT100 does not deteriorate FFP quality compared to a conventional system. Regardless of the thawing system, the postthaw refrigerated storage caused a decrease in several clotting factors and inhibitors (factors V, VIII, and IX; von Willebrand factor activity; protein S and C activity) and a significant increase of factor XI.
CRIS-Team Scopus Importer:2019-05-14

c-Met and PD-L1 on Circulating Exosomes as Diagnostic and Prognostic Markers for Pancreatic Cancer - Lux, Alexander; Kahlert, Christoph; Grützmann, Robert; Pilarsky, Christian (International Journal of Molecular Sciences, 2019)
Exosomes are membrane vesicles which offer potential as blood derived biomarkers for malign tumors in clinical practice. Pancreatic cancer is counted among cancer diseases with the highest mortality. The present work seeks to assess whether pancreatic carcinomas release exosomes which express c-Met (proto-oncogene mesenchymal-epithelial transition factor) and PD-L1 (programmed cell death 1 ligand 1), and whether the detection of such expression in serum has diagnostic or prognostic meaning for the affected patients. Exosome isolation was performed on culture media of one benign pancreatic cell line and ten pancreatic carcinoma cell lines as well as on serum samples from 55 patients with pancreatic ductal adenocarcinoma (PDAC), 26 patients with chronic pancreatitis and 10 patients with benign serous cyst adenoma of the pancreas. Exosomes were bound to latex beads and stained with antibodies against c-Met or PD-L1. Analysis of fluorescence intensity was performed by flow cytometry. In terms of c-Met, the mean fluorescence intensity of PDAC-patients was significantly higher than the fluorescence intensity of the comparative patients with benign disease (p < 0.001). A diagnostic test based on c-Met resulted in a sensitivity of 70%, a specificity of 85% and a diagnostic odds ratio of 13:2. The specificity of the test can be further improved by combining it with the established tumor marker carbohydrate antigen 19-9 (CA 19-9). In addition, c-Met-positive patients showed a significantly shorter postoperative survival time (9.5 vs. 21.7 months, p < 0.001). In terms of PD-L1, no significant difference between fluorescence intensity of PDAC-patients and comparative patients was detectable. However, PD-L1-positive PDAC-patients also showed a significantly shorter postoperative survival time (7.8 vs. 17.2 months, p = 0.043). Thus, both markers can be considered as negative prognostic factors.
CRIS-Team Scopus Importer:2019-07-30
Keywords: c-Met; chronic pancreatitis; exosomes; pancreatic cancer; PD-L1; PDAC; serous cyst adenoma

Cocultivation of Mesenchymal Stem Cells and Endothelial Progenitor Cells Reveals Antiapoptotic and Proangiogenic Effects - Steiner, Dominik; Köhn, Katrin; Beier, Justus; Stürzl, Michael; Horch, Raymund E.; Arkudas, Andreas (Cells Tissues Organs, 2017)
Integrating bioartificial tissues into the host vasculature is a prerequisite for tissue engineering applications. Endothelial progenitor cells (EPCs) display a high angiogenic potential and a low donor-site morbidity, making them ideal for tissue engineering applications. In our study we used a murine EPC cell line (T17b) and rat mesenchymal stem cells (MSCs) for cocultivation experiments. MSCs were cocultured with increasing T17b EPC amounts. Furthermore, MSCs in monoculture were treated with conditioned medium (CM) from T17b EPCs and T17b EPCs were treated with CM from MSCs. Proliferation and apoptosis were quantified with a bromodeoxyuridine ELISA and a DNA fragmentation ELISA, respectively. Osteogenic differentiation was detected with an alkaline phosphatase assay and bone morphogenetic protein-2 ELISA. The production of proangiogenic molecules was measured with a matrix metalloproteinase-3 and vascular endothelial growth factor ELISA as well as nitric oxide assay. We could show that T17b EPCs stimulated MSC proliferation but not vice versa. On the other hand, MSCs promoted the cell survival of EPCs. The growth-inducing and antiapoptotic effects were dependent on heterotypic cell contacts and paracrine mediators. Moreover, proangiogenic growth factors were found in the coculture. Collectively, our results indicate that the coapplication of MSCs and T17b EPCs provides new perspectives for tissue engineering applications.
EVALuna2:15306

Coexistence of gastrointestinal stromal tumours (GIST) and malignant neoplasms of different origin: prognostic implications - Vassos, Nikolaos; Agaimy, Abbas; Hohenberger, Werner; Croner, Roland S. (International Journal of Surgery, 2014)
Over the past decade, several changes occurred in diagnostics, treatment and understanding of pathogenesis of gastrointestinal stromal tumours (GIST). However, their coexistence with other malignancies of different histogenetic origin remains a challenging issue.Patients diagnosed with GIST in a 10-years period were identified retrospectively and clinical history and findings thoroughly explored for the presence of associated other malignancies. Follow up data were obtained and analysed for prognostic impact of the concurrent malignancy and/or GIST.Thirty seven (27 males, 10 females) of 86 GIST-patients (43%) had another malignancy. Mean age was 70 years. Associated malignancies were gastrointestinal (n = 29; 69%), renal-/urological (n = 5; 12%), haematological (n = 4; 9.5%), cutaneous (n = 3; 7%) and thyroid (n = 1; 2.5%) in origin. Majority of GISTs occurred in stomach (65%) and small intestine (30.6%) and most (78%) were asymptomatic incidental findings during diagnostic or therapeutic procedures for associated malignancies. GIST size ranged from 0.1 cm to 9 cm (mean, 2.2 cm) and all of them had a low (<5/50 HPFs) or no mitotic activity. Thirty-one tumours (84%) were of no/very low/low risk and 6 were of intermediate risk. During follow-up (range 3-160 months, mean; 60 months), one patient suffered from distant metastases of GIST. Seven patients (19%) died of associated malignancies and three patients (8%) of other non-tumour-associated cause, but none died of GIST.Coexistence of GIST with other malignancies is higher than previously reported and should draw attention of clinicians towards these incidental findings. Prognosis in these patients is usually determined by other malignancy and not significantly influenced by GIST. Therefore treatment algorithms should be focused on prognostically relevant malignancy.
EVALuna2:6572

Collateral effects of the SARS-CoV-2 pandemic on oncologic surgery in Bavaria - Dienemann, Thomas; Brennfleck, Frank; Dejaco, Alexander; Grützmann, Robert; Binder, Johannes; Krautz, Christian; Stoess, Christian; Jaeger, Carsten; Friess, Helmut; Schlitt, Hans Juergen; Brunner, Stefan M. (BMC Surgery, 2021)
Background: The ongoing SARS-COV-2 pandemic has severe implications for people and healthcare systems everywhere. In Germany, worry about the consequences of the pandemic led to the deferral of non-emergency surgeries. Tumor surgery accounts for a large volume in the field of visceral surgery and cannot be considered purely elective. It is not known how the SARS-COV-2 pandemic has changed the surgical volume in tumor patients. Methods: Retrospective analysis of the amount of oncological surgeries in three academic visceral surgery departments in Bavaria, Germany, in 2020. Procedures were split into subgroups: Upper Gastrointestinal (Upper GI), Colorectal, Hepato-Pancreato-Biliary (HPB), Peritoneal and Endocrine. Procedures in 2020 were compared to a reference period from January 1st, 2017 to December 31st 2019. Surgical volume was graphically merged with SARS-COV-2 incidence and the number of occupied ICU beds. Results: Surgical volume decreased by 7.6% from an average of 924 oncologic surgeries from 2017 to 2019 to 854 in 2020. The decline was temporally associated with the incidence of infections and ICU capacity. Surgical volume did not uniformly increase to pre-pandemic levels in the months following the first pandemic wave with lower SARS-COV-2 incidence and varied according to local incidence levels. The decline was most pronounced in colorectal surgery where procedures declined on average by 26% following the beginning of the pandemic situation. Conclusion: The comparison with pre-pandemic years showed a decline in oncologic surgeries in 2020, which could have an impact on lost life years in non-COVID-19 patients. This decline was very different in subgroups which could not be solely explained by the pandemic.
CRIS-Team Scopus Importer:2021-12-17
Keywords: COVID-19; Oncologic surgery; Oncology; Patient care; SARS-CoV-2

Colon Cancer Microbiome Landscaping: Differences in Right- and Left-Sided Colon Cancer and a Tumor Microbiome-Ileal Microbiome Association - Kneis, Barbara; Wirtz, Stefan; Weber, Klaus; Denz, Axel; Gittler, Matthias; Geppert, Carol-Immanuel; Brunner, Maximilian; Krautz, Christian; Siebenhuener, Alexander Reinhard; Schierwagen, Robert; Tyc, Olaf; Agaimy, Abbas; et al. (International Journal of Molecular Sciences, 2023)
In the current era of precision oncology, it is widely acknowledged that CRC is a heterogeneous disease entity. Tumor location (right- or left-sided colon cancer or rectal cancer) is a crucial factor in determining disease progression as well as prognosis and influences disease management. In the last decade, numerous works have reported that the microbiome is an important element of CRC carcinogenesis, progression and therapy response. Owing to the heterogeneous nature of microbiomes, the findings of these studies were inconsistent. The majority of the studies combined colon cancer (CC) and rectal cancer (RC) samples as CRC for analysis. Furthermore, the small intestine, as the major site for immune surveillance in the gut, is understudied compared to the colon. Thus, the CRC heterogeneity puzzle is far from being solved, and more research is necessary for prospective trials that separately investigate CC and RC. Our prospective study aimed to map the colon cancer landscape using 16S rRNA amplicon sequencing in biopsy samples from the terminal ileum, healthy colon tissue, healthy rectal tissue and tumor tissue as well as in preoperative and postoperative stool samples of 41 patients. While fecal samples provide a good approximation of the average gut microbiome composition, mucosal biopsies allow for detecting subtle variations in local microbial communities. In particular, the small bowel microbiome has remained poorly characterized, mainly because of sampling difficulties. Our analysis revealed the following: (i) right- and left-sided colon cancers harbor distinct and diverse microbiomes, (ii) the tumor microbiome leads to a more consistent cancer-defined microbiome between locations and reveals a tumor microbiome-ileal microbiome association, (iii) the stool only partly reflects the microbiome landscape in patients with CC, and (iv) mechanical bowel preparation and perioperative antibiotics together with surgery result in major changes in the stool microbiome, characterized by a significant increase in the abundance of potentially pathogenic bacteria, such as Enterococcus. Collectively, our results provide new and valuable insights into the complex microbiome landscape in patients with colon cancer.
CRIS-Team Scopus Importer:2023-03-10
Keywords: colon cancer; gut microbiome; left-sided colon cancer; microbiome; right-sided colon cancer; tumor microbiome

Colorectal cancer - Heading to the future - Hohenberger, Werner (Innovative Surgical Science, 2020)
CRIS-Team Scopus Importer:2020-02-04

Colorectal cancer in Crohn’s colitis is associated with advanced tumor invasion and a poorer survival compared with ulcerative colitis: a retrospective dual-center study - Vetter, Leonie E.; Merkel, Susanne; Bénard, Alan; Krautz, Christian; Brunner, Maximilian; Mittelstädt, Anke; Schlegel, Nicolas; Wiegering, Armin; Germer, Christoph Thomas; Weber, Klaus; Grützmann, Robert; Weber, Georg (International Journal of Colorectal Disease, 2020)
Purpose: Colorectal cancer is a well-recognized complication of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn’s colitis (CC). In this study, we assess the clinico-pathological features and outcomes of patients with colorectal cancer from UC in comparison with CC. Methods: Data of all patients with colitis-associated cancer (CAC) who underwent surgery at Erlangen or Würzburg University Clinic between 1995 and 2015 were selected. Clinical, histopathological, and survival data were analyzed retrospectively. Results: Of all 88 patients with CAC, 20 patients had Crohn’s colitis and 68 patients had ulcerative colitis. We observed a young median age at tumor diagnosis (49.5 years UC; 45.5 years CC, p = 0.208) in both diseases and a long median disease duration before CAC (19 years UC; 18 years CC; p = 0.840). Patients with CC suffered more often from rectal cancer (14 (70.0%) in CC; 23 (33.8%) in UC; p = 0.005) and advanced tumor stages (8 (47.0%) pT4 in CC; 14 (25.0%) pT4/ypT4 in UC; p = 0.008). Five-year overall survival rate was 39.3% for CC and 67.1% for UC (p = 0.009 for difference between the groups). Survival did not differ significantly between UC and CC in the multivariate analysis after correction for UICC tumor stage. Conclusion: CAC in CC showed advanced tumor stages associated with reduced survival compared with CAC in UC. This may be explained by less intense surveillance in patients with CC leading to delayed cancer diagnosis.
CRIS-Team Scopus Importer:2020-09-25
Keywords: Colorectal cancer; Crohn’s colitis; Ulcerative colitis

Colorectal Carcinoma in Young Patients - Is Age a Prognostic Factor? - Schellerer, Vera; Croner, R.; Langheinrich, M.; Hohenberger, Werner; Merkel, Susanne (Zentralblatt für Chirurgie, 2015)
Concerning younger patients with colorectal carcinoma (CRC) controversies still exist regarding outcome. The aim of this study was to evaluate possible differences between patients suffering from CRC at a younger age (< 40 years) and at an age over 40 years.Data of 51 younger patients (< 40 years) and 2122 older patients (>= 40 years) were prospectively collected and retrospectively evaluated according to clinical parameters, treatment and prognosis. Patients with a CRC arising from familial adenomatous polyposis, ulcerative colitis or Crohn's disease have been excluded.The younger patients presented significantly more often with mucinous adenocarcinomas (p = 0.033). There were no differences between the groups concerning gender, localisation, elective and emergency surgery, UICC (Union internationale contre le cancer) stages and residual tumour classification. Postoperative therapy - in adjuvant, therapeutic or palliative intent - was applied significantly more often in younger patients, especially in those with colon carcinoma (p = 0.001). After curative resection of colon carcinoma a significantly better observed (5 year rate 94 vs. 76 %; p = 0.024) and disease-free (88 vs. 69 %; p = 0.013) survival were found. This trend was similar in patients with rectal carcinoma (84 vs. 75 % and 72 vs. 65 %) without reaching the level of significance (p = 0.155 and 0.269). Taking into account differences in life expectancy, just minor differences were detected in relative survival (colon carcinoma, 5 year rate 94 vs. 89 %; rectal carcinoma, 84 % both).The general assumption of a poorer prognosis in younger patients with CRC could not be confirmed. Younger patients have a poorer histological subtype of carcinoma. But this is compensated by the better overall condition, less comorbidities, faster postoperative recovery and an optimally organised post-operative (adjuvant, therapeutic or palliative) therapy. In summary, younger patients have a better observed survival but - considering differences in life expectancy - a similar relative survival.
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Combined Clagett procedure, negative pressure therapy, and thoracomyoplasty for treatment of late-onset postpneumonectomy empyema necessitatis - Schreiner, Waldemar; Dudek, Wojciech; Sirbu, Horia (Kardiochirurgia I Torakochirurgia Polska, 2015)
Late-onset post-pneumonectomy empyema necessitatis can occur many years after the surgery and is a life-threatening condition. A 58-year-old male presented with empyema necessitatis 18 years after undergoing pneumonectomy. He was successfully treated with a modified two-stage Clagett procedure and ambulatory negative pressure as the bridge between the stages. The 72-month follow-up was uneventful. The complete obliteration of the rigid and wide residual postpneumonectomy cavity was necessary to avoid re-recurrence of the infection.
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Combined free flaps with arteriovenous loops for reconstruction of extensive thoracic defects after sternal osteomyelitis - Taeger, Christian; Horch, Raymund E.; Arkudas, Andreas; Schmitz, Marweh; Stübinger, Axel; Lang, Werner; Meyer, Alexander; Seitz, Tatjana; Weyand, Michael; Beier, Justus (Microsurgery, 2016)
Various local flaps have been described for patients suffering from sternal osteomyelitis and are regarded as a standard procedure for defect reconstruction. In contrast, the use of microsurgical free flaps has been reported anecdotally only. We present our experiences with the combination of an arteriovenous loop and a free flap transfer in defects larger than half of the sternum.Between January 2012 and October 2014, eight patients with a mean age of 68 years who suffered from extensive deep sternal osteomyelitis were operated in a consecutive series. After radical surgical debridement, the defect size comprised all three thirds of the sternum. Defect reconstruction was achieved by means of free flap transplantation using the vastus lateralis myocutaneous flap, rectus abdominis, and bipedicled latissimus dorsi/parascapular flap. As local recipient vessels were depleted in all patients, the pedicle of the flap was anastomosed to a high-flow and short-length subclavian arteriovenous loop as recipient vessel in all cases.The immediate postoperative course in all patients was uneventful despite one axonal injury to the femoral nerve at the donor site. There was no partial or total flap loss. During a mean follow-up of 9 months, one patient suffered from a local infection at the donor site. In all patients, a successful defect reconstruction could be achieved.Depletion of local recipient vessels as an obstacle for free flap reconstruction can be overcome by creating an arteriovenous loop. Even extensive defects are adequate for defect reconstruction using a single or, in extreme cases, bipedicled free flap. © 2015 Wiley Periodicals, Inc. Microsurgery 36:121-127, 2016.
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Combined recurrent laryngeal nerve monitoring and one-lung ventilation using the EZ-Blocker and an electromyographic endotracheal tube - Moritz, Andreas; Schmidt, Joachim; Schreiner, Waldemar; Birkholz, Torsten; Sirbu, Horia; Irouschek, Andrea (Journal of Cardiothoracic Surgery, 2019)
Background: Intraoperative neuromuscular monitoring (IONM) is a widespread procedure to identify and protect the recurrent laryngeal nerve (RLN) during thyroid surgery. However, for left thoracic surgery with high risk of RLN injury, both reliable recurrent laryngeal nerve monitoring and one-lung ventilation could interfere. Methods: In this prospective study, a new method for IONM during one-lung ventilation combining RLN monitoring with an electromyographic (EMG) endotracheal tube (ETT) and lung separation using the EZ-Blocker (EZB) is described and its clinical feasibility and effectiveness were assessed. Results: A total of 14 patients undergoing left upper lobe surgery and left upper mediastinal lymph node dissection were enrolled. The EZB was introduced and positioned without any problems and sufficient lung collapse was achieved in all patients. No tracheobronchial injuries or immediate complications occurred. A stable EMG signal was present in all patients and no RLN palsy and no negative side effects of the NIM EMG ETT or the EZB were observed postoperatively. Conclusions: The described method is technically feasible, easy to apply and save. It provides both reliable IONM and independent lung separation for optimal surgical exposure. The combined use of the EZB and the NIM EMG ETT might reduce the risk for RLN palsy and impaired lung separation during left thoracic surgery with high risk for RLN injury.
CRIS-Team Scopus Importer:2019-07-02
Keywords: EZ-Blocker; Intraoperative monitoring; One-lung ventilation; Recurrent laryngeal nerve; Thoracic surgery

Comment on: Complete mesocolic excision for right colonic cancer: prospective multicentre study - Bertelsen, Claus Anders; Bianchi, Paolo Pietro; Croner, Roland; Kleif, Jakob; Matzel, Klaus; Merkel, Susanne; Miskovic, Danilo; Gomez Ruiz, Marcos; Stearns, Adam T.; Storli, Kristian Eeg (British Journal of Surgery, 2023)
CRIS-Team WoS Importer:2023-04-14

Common variants in glyoxalase I do not inease chronic pancreatitis risk - Kaune, Tom; Hollenbach, Marcus; Keil, Bettina; Chen, Jian Min; Masson, Emmanuelle; Becker, Carla; Damm, Marko; Ruffert, Claudia; Grützmann, Robert; Hoffmeister, Albrecht; Te Morsche, Rene H.M.; Cavestro, Giulia Martina; et al. (PLoS ONE, 2019)
Introduction Chronic pancreatitis (CP) may be caused by oxidative stress. An important source of reactive oxygen species (ROS) is the methylglyoxal-derived formation of advanced glycation endproducts (AGE). Methylglyoxal is detoxified by Glyoxalase I (GLO1). A reduction in GLO1 activity results in increased ROS. Single nucleotide polymorphisms (SNPs) of GLO1 have been linked to various inflammatory diseases. Here, we analyzed whether common GLO1 variants are associated with alcoholic (ACP) and non-alcoholic CP (NACP). Methods Using melting curve analysis, we genotyped a screening cohort of 223 ACP, 218 NACP patients, and 328 controls for 11 tagging SNPs defined by the SNPinfo LD TAG SNP Selection tool and the functionally relevant variant rs4746. For selected variants the cohorts were extended to up to 1,441 patient samples. Results In the ACP cohort, comparison of genotypes for rs1937780 between patients and controls displayed an ambiguous result in the screening cohort (p = 0.08). However, in the extended cohort of 1,441 patients no statistically significant association was found for the comparison of genotypes (p = 0.11), nor in logistic regression analysis (p = 0.214, OR 1.072, 95% CI 0.961-1.196). In the NACP screening cohort SNPs rs937662, rs1699012, and rs4746 displayed an ambiguous result when patients were compared to controls in the recessive or dominant model (p = 0.08, 0.08, and 0.07, respectively). Again, these associations were not confirmed in the extended cohorts (rs937662, dominant model: P = 0.07, logistic regression: P = 0.07, OR 1.207, 95% CI 0.985-1.480) or in the replication cohorts for rs4746 (Germany, p = 0.42, OR 1.080, 95% CI 0.673-1.124; France, p = 0.19, OR 0.90, 95% CI 0.76-1.06; China, p = 0.24, OR 1.18, 95% CI 0.90-1.54) and rs1699012 (Germany, Munich; p = 0.279, OR 0.903, 95% CI 0.750-1.087). Conclusions Common GLO1 variants do not increase chronic pancreatitis risk.
CRIS-Team Scopus Importer:2019-11-08

Comparable Cerebral Blood Flow in Both Hemispheres During Regional Cerebral Perfusion in Infant Aortic Arch Surgery - Rueffer, Andre; Tischer, Philip; Münch, Frank; Purbojo, Ariawan; Toka, Okan; Rascher, Wolfgang; Cesnjevar, Robert; Juengert, Joerg (Annals of Thoracic Surgery, 2017)
Cerebral protection during aortic arch repair can be provided by regional cerebral perfusion (RCP) through the innominate artery. This study addresses the question of an adequate bilateral blood flow in both hemispheres during RCP.Fourteen infants (median age 11 days [range, 3 to 108]; median weight, 3.6 kg [range, 2.8 to 6.0 kg]) undergoing RCP (flow rate 54 to 60 mL · kg(-1) · min(-1)) were prospectively included. Using combined transfontanellar/transtemporal two- and three-dimensional power/color Doppler sonography, cerebral blood flow intensity in the main cerebral vessels was displayed. Mean time average velocities were measured with combined pulse-wave Doppler in the basilar artery, and both sides of the internal carotid, anterior, and medial cerebral arteries. In addition, bifrontal regional cerebral oximetry (rSO2) was assessed. Comparing both hemispheres, measurements were performed at target temperature (28°C) during full-flow total body perfusion (TBP) and RCP.A regular circle of Willis with near-symmetric blood flow intensity to both hemispheres was visualized in all infants during both RCP and TBP. In the left internal carotid artery, blood flow direction was mixed (retrograde, n = 5; antegrade, n = 8) during TBP and retrograde during RCP. Comparison between sides showed comparable cerebral time average velocities and rSO2, except for higher time average velocities in the right internal carotid artery (TBP p = 0.019, RCP p = 0.09). Unilateral comparison between perfusion methods revealed significantly higher rSO2 in the right hemisphere during TBP (82% ± 9%) compared with RCP (74% ± 11%, p = 0.036).Bilateral assessment of cerebral rSO2 and time average velocity in the main great cerebral vessels suggests that RCP is associated with near-symmetric blood flow intensity to both hemispheres. Further neurodevelopmental studies are necessary to verify RCP for neuroprotection during aortic arch repair.
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Comparative studies of different types of osteosynthesis on the human corpse preparation in bilateral antero-lateral flail chest - Grupp, Sina; Fürst, Veronika; Buder, Thomas; Fichte, Alexander; Krinner, Sebastian; Carbon, Roman T.; Hennig, Friedrich; Langenbach, Andreas; Schulz-Drost, Stefan (Injury-International Journal of the Care of the Injured, 2017)
Bilateral flail chest injuries are challenging in treatment and comparatively often require an operative stabilization of the anterior chest wall to re-establish normal physiological conditions of the chest wall in shape and statics. Various procedures have been described which are technically sophisticated for the surgeon. Consequently there is an increasing interest in potentials of operative care and their effectiveness on the anterolateral chest wall.12 Human cadavers were prepared and the natural Sternum Position (NP) was marked. A digital probe was fixed to the sternum at the height of the 4th intercostal space in order to measure and compare the stability of the thorax. Readings were taken of the sternal displacement at 1-5cm sagittal distance from NP in starting conditions and from every combination of materials. Serial osteotomies were performed on 2 locations on ribs 2-8 to induce bilateral flail chest. Afterwards the stabilization was achieved with different implants: RESULTS: The osteotomies lead to a subsidence of the sternum occurred to almost 75 mm from NP which corresponds to a maximal unstable situation. The unstable chest wall showed substantially more stabilization through the use of locking plates. Our materialcombinations showed a stability of up to 60% of normal. The more ribs were treated osteosynthetically, the higher the stability of the chest wall.Locking plate fixation offers anatomically realignment of the ribs whereas metal strut support only lifts up the chest wall, but could not provide realignment of the dislocated ribs.
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Comparative whole genome analysis of three consecutive Salmonella diarizonae isolates - Gerlach, Roman G.; Walter, Steffi; McClelland, Michael; Schmidt, Christiane; Steglich, Matthias; Prager, Rita; Bender, Jennifer K.; Fuchs, Stephan; Schoerner, Christoph; Rabsch, Wolfgang; Lang, Werner; Jantsch, Jonathan (International Journal of Medical Microbiology, 2017)
Infections of very young children or immunocompromised people with Salmonella of higher subspecies are a well-known phenomenon often associated with contact to cold-blooded animals. We describe the molecular characterization of three S. enterica subsp. diarizonae strains, isolated consecutively over a period of several months from a hospital patient suffering from diarrhea and sepsis with fatal outcome. With the initial isolate the first complete genome sequence of a member of subsp. diarizonae is provided and based on this reference we revealed the genomic differences between the three isolates by use of next-generation sequencing and confirmed by phenotypical tests. Genome comparisons revealed mutations within gpt, hfq and purK in the first isolate as a sign of clonal variation rather than host-directed evolution. Furthermore, our work demonstrates that S. enterica subsp. diarizonae possess, besides a conserved set of known Salmonella Pathogenicity Islands, a variable portfolio of additional genomic islands of unknown function.
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Comparison between open and pharmacomechanical repair of acutely thrombosed arteriovenous hemodialysis fistulae within a decade - Regus, Susanne; Almási-Sperling, Veronika; Rother, Ulrich; Meyer, Alexander; Schmid, Axel; Uder, Michael; Lang, Werner (Hemodialysis International, 2018)
INTRODUCTION: Different declotting techniques are available for acutely thrombosed arteriovenous hemodialysis fistulae (AVF). The aim of this single-center study was to compare immediate and follow-up results between surgical repair and a modified interventional lyse-and-wait technique characterized by prolonged local reaction times of recombinant tissue-plasminogen activator (rtPA). MATERIALS AND METHODS: We retrospectively analyzed medical records of 110 consecutively treated patients between the years 2003 and 2013. All patients were on hemodialysis (HD) and suffered from an acutely thrombosed AVF. The treatment standards changed in the course of time, wherefore we compared 2 groups: the open repair (OR) (N = 50) and the endovascular repair (ER) group (N = 60). FINDINGS: We found no significant differences in success rates (OR 92%/ER 96.7%; P = 0.28), immediate failures (IFs) (OR 8%/ER 10%; P = 0.71), and temporary catheter placements (TCPs) (OR 10%/ER 6.7%; P = 0.52). Furthermore, there were no differences in cumulative primary patency rates (P = 0.42) and secondary patency rates (P = 0.97).The infection rate was significantly increased after OR (8%) compared to ER (0%); P = 0.026. The hospital stay in days was shorter after ER (5.2 ±2.8) vs. OR (9.0 ± 3.5); P < 0.001. CONCLUSION: The modified lyse-and-wait technique with prolonged local reaction times is a successful alternative to surgical repair for acutely thrombosed AVF. Clear benefits are less infections and significant shorter hospital stays after ER. However, OR remains the preferred treatment for aneurysms and anastomotic stenoses.
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Comparison of a new microscopic system for the measurement of residual leucocytes in apheresis platelets with flow cytometry and manual counting - Strobel, Joachim; Antos, U.; Zimmermann, Rüdiger; Eckstein, Reinhold; Zingsem, Jürgen (Vox Sanguinis, 2014)
Since 2001, all blood components in Germany must be leucocyte depleted. Recently, a new method for quality control of depletion was introduced. Our study aimed at the validation of the method for routine use in apheresis platelet concentrates.We compared the new ADAM-rWBC device with manual counting in the Nageotte chamber and flow cytometry, two standard methods, by measuring residual leucocytes in 40 units of apheresis platelet concentrates and in six geometrical dilution series.Cell counts of residual leucocytes in the 40 units were below 10(6) cells per component with all methods, although mean cell counts were approximately 5 and 6 times higher in flow cytometry and ADAM-rWBC, respectively, compared to the Nageotte chamber. No unit with <10(6) leucocytes was regarded as contaminated. The dilution series showed acceptable accuracy, especially in the range around the cut-off (approximately 4·5 cells/?l in components with a volume of 220 ml) for regarding a concentrate as contaminated with leucocytes. No sample spiked with more than 4·5 cells/?l was counted as having less.In comparison with manual counting and flow cytometry, the ADAM-rWBC device performed equally. The method is suitable for routine screening of leucocyte contamination of apheresis platelets.
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Comparison of automated differential blood cell counts from abbott sapphire, siemens advia 120, beckman coulter DxH 800, and sysmex XE-2100 in normal and pathologic samples - Meintker, Lisa; Ringwald, Juergen; Rauh, Manfred; Krause, Stefan (American Journal of Clinical Pathology, 2013)
Reliable automated blood cell characterization and quantification remain challenging in pathologic samples, whereas slide reviews due to unnecessary flagging should be avoided. We compared 4 modern hematology analyzers-Abbott Sapphire, Siemens Advia 120, Sysmex XE-2100, and Beckman Coulter DxH 800-regarding complete blood cell count (CBC), leukocyte differential count, and flagging efficacy in a total of 202 samples from hematology patients and normal controls. Manual differential count was used as reference. The analyzers exhibited very good correlation for CBC parameters. Neutrophils and eosinophils also showed very good correlations, whereas lymphocytes and monocytes correlated fairly. The Advia 120 displayed notably lower measurements for both parameters, which is attributable to classification of some events as large unstained cells. Basophil counts were unreliable with all analyzers. Flagging for blasts and immature granulocytes showed moderate sensitivity and specificity. Operators must not rely on blast flagging alone to detect leukemic samples with any analyzer. © American Society for Clinical Pathology.
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Keywords: Automated blood cell count; Blasts; Flag; Immature granulocytes; Leukocyte differential count

Comparison of Cinematic Rendering and Computed Tomography for Speed and Comprehension of Surgical Anatomy - Elshafei, Moustafa; Binder, Johannes; Baecker, Justus; Brunner, Maximilian; Uder, Michael; Grützmann, Robert; Krautz, Christian; Weber, Georg (JAMA Surgery, 2019)
Importance: Three-dimensional (3-D) volume rendering has been shown to improve visualization in general surgery. Cinematic rendering (CR), a novel 3-D visualization technology for postprocessing of computed tomographaphy (CT) images, provides photorealistic images with the potential to improve visualization of anatomic details. Objective: To determine the value of CR for the comprehension of the surgical anatomy. Design, Setting, and Participants: This preclinical, randomized, 2-sequence crossover study was conducted from February to November 1, 2018, at University Hospital of Erlangen, Germany. The 40 patient cases were evaluated by 18 resident and attending surgeons using a prepared set of CT and CR images. The patient cases were randomized to 2 assessment sequences (CR-CT and CT-CR). During each assessment period, participants answered 1 question per case that addressed crucial issues of anatomic understanding, preoperative planning, and intraoperative strategies. After a washout period of 2 weeks, case evaluations were crossed over to the respective second image modality. Main Outcomes and Measures: The primary outcome measure was the correctness of answers. Secondary outcome was the time needed to answer. Results: The mean (SD) interperiod differences for the percentage of correct answers in the CR-CT sequence (8.5% [7.0%]) differed significantly from those in the CT-CR sequence (-13.1% [6.3%]) (P <.001). The mean (SD) interperiod differences for the time spent to answer the questions in the CR-CT sequence (-18.3 [76.9] seconds) also differed significantly from those in the CT-CR sequence (52.4 [88.5] seconds) (P <.001). Subgroup analysis revealed that residents as well as attending physicians benefitted from CR visualization. Analysis of the case assessment questionnaire showed that CR added significant value to the comprehension of the surgical anatomy (overall mean [SD] score, 4.53 [0.75]). No carryover or period effects were observed. Conclusions and Relevance: The visualization with CR allowed a more correct and faster comprehension of the surgical anatomy compared with conventional CT imaging, independent of level of surgeon experience. Therefore, CR may assist general surgeons with preoperative preparation and intraoperative guidance..
CRIS-Team Scopus Importer:2019-06-18

Comparison of Open vs. Laparoscopic Techniques in Complete Mesocolic Excision (CME) During Right Hemicolectomy - Croner, R.; Hohenberger, Werner; Strey, C. W. (Zentralblatt für Chirurgie, 2015)
The technique of open complete mesocolic excision (CME) has improved the outcomes of patients with colon carcinoma. Meanwhile it has become an established international standard procedure. It remains unclear if laparoscopic procedures are able to match the high quality of open resections. A video comparison of the two methods gives insight into the different dissection techniques.Open CME is demonstrated in a 79-year-old female patient with an asymptomatic carcinoma of the ascending colon verified by histopathology. The tumour was diagnosed during routine colonoscopy. No distant metastases were identified during the staging procedure. Laparoscopic CME is performed in a 72-year-old female patient with a biopsy-proven carcinoma of the ascending colon. Similarly this patient was diagnosed during a screening colonoscopy and had no distant metastasis.During open CME the ascending colon and the duodenum are mobilised by sharp dissection between the parietal and visceral layer of the mesentery. Afterwards the ascending and transverse mesocolon are dissected from the duodenum and pancreas. The parietal and the visceral mesentery are strictly preserved during these procedures. After the exposure of the superior mesenteric artery and vein, a central dissection of the vessels follows. The colon is cut 10 cm distal to the carcinoma. An ileotransversostomy is performed with a running suture. The hole in the mesentery is closed. The laparoscopic CME is performed using the 4-trocar technique with an umbilical camera position following a medial to lateral approach with primary dissection of the superior mesenteric vein. Radicular vessel ligation opens the space dorsal to the mesocolon with the border lamella remaining intact. The space is widened until the ascending colon is entirely mobilised. The mobilised colon is eventrated through an enlarged umbilical midline incision. Colon resection and the subsequent two-layered side-to-side ileotransversostomy are performed in a standard open surgical fashion.Open and laparoscopic CME enable central vessel dissection while preserving the mesenteric layers. However, the laparoscopic procedure is technically demanding and should therefore only be performed by surgeons experienced in laparoscopy.
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Comparison of Simultaneous CD34+ and CD3+ Quantification with a Modified Stem Cell Enumeration Kit on Two Different Flow Cytometers - Strobel, Joachim; Hauck-Dlimi, Barbara; Weisbach, Volker Günter; Eckstein, Reinhold; Zingsem, Jürgen; Strasser, Erwin (Clinical Laboratory, 2016)
BACKGROUND: Quantification of CD34+ cells in peripheral blood stem cell apheresis is normally performed by single platform flow cytometric measurements according to the ISHAGE protocol. Peripheral blood stem cell concentrates (PBSC) produced by apheresis normally contain many T cells. Those T cells can be used for production of donor lymphocyte infusion doses, if abundant amounts of CD34+ cells have been collected. Therefore, it is of interest to know both the CD3+ and the CD34+ cell count of allogeneic PBSC. This is the first study comparing the performance of a modified ISHAGE protocol allowing additional quantification of CD3+ cells on two different flow cytometers, the FACSCalibur and the FACSVerse, respectively. METHODS: CD45+ and CD34+ cell concentrations were measured using a standard and a modified ISHAGE protocol including CD3+ cell quantification on both machines. All cell concentrations were measured using a Trucount bead based stem cell enumeration kit. The FACSVerse machine can additionally be equipped with a sample volume sensor allowing cell quantification without using beads. The samples analysed were taken from granulocyte-colony-stimulating factor mobilized peripheral blood stem cell apheresis procedures (pre- and post-apheresis, and apheresis concentrate). RESULTS: There were no significant differences in cell concentrations measured by the standard and modified ISHAGE protocol, regardless of which machine had been used when using bead quantification. No significant differences between the results of the two flow cytometers using the modified ISHAGE protocol were observed. Pearson´s correlation was always > 0.96, and regression coefficients were higher than 0.93. The only significant differences were observed between bead quantification and volume sensor quantification on the FACSVerse machine. CONCLUSIONS: The modified ISHAGE protocol can effectively be used on both flow cytometers tested, especially if bead quantification is used.
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Comparison of Six Different Cryoprotective Agents Used for Deep Freezing and Storage of CD34+ Cells Derived from Cord Blood and Peripheral Blood Stem Cell Concentrates - Strobel, Joachim; Hohensee, Friederike; Kuta, Piotr; Eckstein, Reinhold; Zingsem, Jürgen (Clinical Laboratory, 2017)
BACKGROUND: For cryopreservation of stem cells, a cryoprotective agent is essential. Dimethyl sulfoxide is commonly used, but has deleterious effects on cell vitality in the warmth and for the recipients of stem cells. The aim of the study was to reduce DMSO and find one cryoprotective solution suitable for stem cells of different origin. Materials: Small volumes of both stem cell apheresis products and cord blood derived stem cells were frozen using six different cryoprotective solutions. Suitability of these solutions was tested by comparing cell vitalities and recovery rates of CD45 and CD34 positive cells and colony forming unit recovery rates. RESULTS: No single cryoprotective solution being significantly superior regarding all cell qualities and recovery rates could be identified. However, mixing approximately 5% DMSO with hydroxyethyl starch with a molecular weight of 450,000 Dalton showed better results for most qualities examined than DMSO alone, especially when looking at cord blood derived stem cells. CONCLUSIONS: There might not be an all-in-one cryoprotective solution suitable for every purpose regarding the cryopreservation of stem cell concentrates produced from different cell sources. However, when trying to reduce the DMSO amount used, hydroxyethyl starch of a molecular weight of 450,000 Dalton is a suitable option.
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Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial - Leiter, Ulrike; Stadler, Rudolf; Mauch, Cornelia; Hohenberger, Werner; Brockmeyer, Norbert; Sunderkoetter, Cord; Kaatz, Martin; Schulte, Klaus-Werner; Lehmann, Percy; Vogt, Thomas; Ulrich, Jens; Herbst, Rudolf; et al. (Lancet Oncology, 2016)
Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation.In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients.Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20-54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9-82·1; 55 events) in the observation group and 74·9% (69·5-80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported.Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller.German Cancer Aid.
EVALuna2:15232

Complete mesocolic excision for right colonic cancer: prospective multicentre study - Benz, Stefan R.; Feder, Inke S.; Vollmer, Saskia; Tam, Yu; Reinacher-Schick, Anke; Denz, Robin; Hohenberger, Werner; Lippert, Hans; Tannapfel, Andrea; Stricker, Ingo (British Journal of Surgery, 2022)
Background Complete mesocolic excision (CME) for right colonic cancer is a more complex operation than standard right hemicolectomy but evidence to support its routine use is still limited. This prospective multicentre study evaluated the effect of CME on long-term survival in colorectal cancer centres in Germany (RESECTAT trial). The primary hypothesis was that 5-year disease-free survival would be higher after CME than non-CME surgery. A secondary hypothesis was that there would be improved survival of patients with a mesenteric area greater than 15 000 mm(2). Methods Centres were asked to continue their current surgical practices. The surgery was classified as CME if the superior mesenteric vein was dissected; otherwise it was assumed that no CME had been performed. All specimens were shipped to one institution for pathological analysis and documentation. Clinical data were recorded in an established registry for quality assurance. The primary endpoint was 5-year overall survival for stages I-III. Multivariable adjustment for group allocation was planned. Using a primary hypothesis of an increase in disease-free survival from 60 to 70 per cent, a sample size of 662 patients was calculated with a 50 per cent anticipated drop-out rate. Results A total of 1004 patients from 53 centres were recruited for the final analysis (496 CME, 508 no CME). Most operations (88.4 per cent) were done by an open approach. Anastomotic leak occurred in 3.4 per cent in the CME and 1.8 per cent in the non-CME group. There were slightly more lymph nodes found in CME than non-CME specimens (mean 55.6 and 50.4 respectively). Positive central mesenteric nodes were detected more in non-CME than CME specimens (5.9 versus 4.0 per cent). One-fifth of patients had died at the time of study with recorded recurrences (63, 6.3 per cent), too few to calculate disease-free survival (the original primary outcome), so overall survival (not disease-specific) results are presented. Short-term and overall survival were similar in the CME and non-CME groups. Adjusted Cox regression indicated a possible benefit for overall survival with CME in stage III disease (HR 0.52, 95 per cent c.i. 0.31 to 0.85; P = 0.010) but less so for disease-free survival (HR 0.66; P = 0.068). The secondary outcome (15 000 mm(2) mesenteric size) did not influence survival at any stage (removal of more mesentery did not alter survival). Conclusion No general benefit of CME could be established. The observation of better overall survival in stage III on unplanned exploratory analysis is of uncertain significance.
CRIS-Team WoS Importer:2022-12-02

Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis - Palumbo-Zerr, Katrin; Soare, Alina; Zerr, Pawel; Liebl, Andrea; Mancuso, Rossella; Tomcik, Michal; Sumova, Barbora; Dees, Clara; Chen, Chih-Wei; Wohlfahrt, Thomas; Mallano, Tatjana; Distler, Alfiya; et al. (Annals of the Rheumatic Diseases, 2017)
TWIST1 is a member of the class B of basic helix-loop-helix transcription factors that regulates cell lineage determination and differentiation and has been implicated in epithelial-to-mesenchymal transition. Here, we aimed to investigate the role of TWIST1 for the activation of resident fibroblasts in systemic sclerosis (SSc).The expression of Twist1 in fibroblasts was modulated by forced overexpression or siRNA-mediated knockdown. Interaction of Twist1, E12 and inhibitor Of differentiation (Id) was analysed by co-immunoprecipitation. The role of Twist1 in vivo was evaluated using inducible, conditional knockout mice with either ubiquitous or fibroblast-specific depletion of Twist1. Mice were either challenged with bleomycin or overexpressing a constitutively active transforming growth factor (TGF)? receptor I.The expression of TWIST1 was increased in fibroblasts in fibrotic human and murine skin in a TGF?/SMAD3-dependent manner. TWIST1 in turn enhanced TGF?-induced fibroblast activation in a p38-dependent manner. The stimulatory effects of TWIST1 on resident fibroblasts were mediated by TWIST1 homodimers. TGF? promotes the formation of TWIST1 homodimers by upregulation of TWIST1 and by induction of inhibitor of DNA-binding proteins, which have high affinity for E12/E47 and compete against TWIST1 for E12/E47 binding. Mice with selective depletion of Twist1 in fibroblasts are protected from experimental skin fibrosis in different murine models to a comparable degree as mice with ubiquitous depletion of Twist1.Our data identify TWIST1 as a central pro-fibrotic factor in SSc, which facilitates fibroblast activation by amplifying TGF? signalling. Targeting of TWIST1 may thus be a novel approach to normalise aberrant TGF? signalling in SSc.
EVALuna2:13273

Comprehensive screening for mutations associated with colorectal cancer in unselected cases reveals penetrant and nonpenetrant mutations - Kraus, Cornelia; Rau, Tilman; Lux, Philipp; Erlenbach-Wuensch, Katharina; Loehr, Sabine; Krumbiegel, Mandy; Thiel, Christian; Stoehr, Robert; Agaimy, Abbas; Croner, Roland S.; Stürzl, Michael; Hohenberger, Werner; et al. (International Journal of Cancer, 2015)
Germline mutation testing in patients with colorectal cancer (CRC) is offered only to a subset of patients with a clinical presentation or tumor histology suggestive of familial CRC syndromes, probably underestimating familial CRC predisposition. The aim of our study was to determine whether unbiased screening of newly diagnosed CRC cases with next generation sequencing (NGS) increases the overall detection rate of germline mutations. We analyzed 152 consecutive CRC patients for germline mutations in 18 CRC-associated genes using NGS. All patients were also evaluated for Bethesda criteria and all tumors were investigated for microsatellite instability, immunohistochemistry for mismatch repair proteins and the BRAF*V600E somatic mutation. NGS based sequencing identified 27 variants in 9 genes in 23 out of 152 patients studied (18%). Three of them were already reported as pathogenic and 12 were class 3 germline variants with an uncertain prediction of pathogenicity. Only 1 of these patients fulfilled Bethesda criteria and had a microsatellite instable tumor and an MLH1 germline mutation. The others would have been missed with current approaches: 2 with a MSH6 premature termination mutation and 12 uncertain, potentially pathogenic class 3 variants in APC, MLH1, MSH2, MSH6, MSH3 and MLH3. The higher NGS mutation detection rate compared with current testing strategies based on clinicopathological criteria is probably due to the large genetic heterogeneity and overlapping clinical presentation of the various CRC syndromes. It can also identify apparently nonpenetrant germline mutations complicating the clinical management of the patients and their families.
EVALuna2:6598

Computed Tomography-Guided Percutaneous Gastrostomy/Jejunostomy for Feeding and Decompression - Albrecht, Heinz; Hagel, Alexander; Schlechtweg, Philipp; Förtsch, Thomas; Neurath, Markus; Mudter, Jonas (Nutrition in Clinical Practice, 2017)
An effective method for long-term enteral feeding or stomach decompression is the use of a percutaneous gastrostomy (PEG) or sometimes jejunostomy (PEJ). Under certain circumstances (eg, inadequate transillumination), endoscopic placement of PEG/PEJ tubes is impossible. In these cases, computed tomography (CT)-guided PEG/PEJ may represent an alternative technique. In this study, we evaluate indications, results, and complications of CT-guided PEG/PEJ.A total of 102 consecutive referred patients were enrolled in the study. Patients came to the endoscopy unit of our department to undergo a CT-guided PEG/PEJ for long-term intragastric/intrajejunal feeding (n = 57) or decompression (n = 45). The majority (n = 98) received a pull-through PEG/PEJ with simultaneous gastroscopy/jejunoscopy. Dose length product and the effective dose for every patient were calculated.PEG/PEJ tube placement was successful in 87.3% (89 of 102). Feeding PEG/PEJ tube placement was successfully completed in 91.2% (52 of 57); decompressive PEG/PEJ tube placement was likewise successfully completed in 82.2% (37 of 45). No procedure-related mortality was observed. Minor complications (eg, tube dysfunction, local bleeding, minimal leakage, local skin infection) were observed in 13 patients. The complication rate was similar between the feeding and decompression groups ( P = .9).CT-guided PEG/PEJ is a feasible and safe method with a low procedure-related morbidity rate for patients where endoscopic placement via transillumination is not successful. Thus, the procedure is an attractive alternative to surgical tube placement. Long-term complications, mainly tube disturbances, can be treated easily.
EVALuna2:14587

Computed Tomography-Guided Wire-Marking for Thoracoscopic Resection of Small Lung Nodules in Children - Seitz, Sigurd T.; Schellerer, Vera; Schmid, Axel; Metzler, Markus; Besendörfer, Manuel (Journal of Laparoendoscopic & Advanced Surgical Techniques, 2019)
Introduction: In pediatric patients, thoracoscopic wedge-resection of pulmonary nodules is an established therapy. However, intraoperative localization of small lesions is still challenging. Purpose of this study was to evaluate the efficacy of preoperative computed tomography (CT)-guided wire-marking of small lung nodules. Materials and Methods: Between 2012 and 2017 a total of six cases receiving thoracoscopic resection of CT-marked lung nodules were analyzed. The nodules were preoperatively tagged by a wire, which was attached to the thoracic wall by sterile dressing. Characteristics of interest were stability of wire, complete resection, and prevention of open thoracotomy. Results: Six procedures were performed on five patients, including four men and one woman. Median age at intervention was 16 years (range 11-19 years). All patients had a history of primary malignancies, including osteosarcoma (n = 4) and synovial sarcoma (n = 1). A total of 10 nodules were visualized in CT of which 9 were marked by wire. The median expected size of nodules was 6 mm (range 2-23 mm). Two patients had bilateral, two left-sided and two right-sided lung lesions. There was no wire slippage. In five procedures wedge resection was possible; one case needed a near total lobe resection. In one case a mini-thoracotomy at port insertion site was performed to extract the specimen. There was no conversion to thoracotomy. Histopathology showed R0 resection in all patients. Malignancy was found in all specimens. In one patient postoperative hemorrhagic anemia necessitated transfusion. Conclusions: Preoperative wire-localization of small lung nodules is a safe and effective tool to enable thoracoscopic resection in children and to avoid thoracotomic interventions.
CRIS-Team WoS Importer:2019-04-18

CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial - Sinn, Marianne; Bahra, Marcus; Liersch, Torsten; Gellert, Klaus; Messmann, Helmut; Bechstein, Wolf; Waldschmidt, Dirk; Jacobasch, Lutz; Wilhelm, Martin; Rau, Bettina M.; Grützmann, Robert; Weinmann, Arndt; et al. (Journal of Clinical Oncology, 2017)
Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m2 days 1, 8, 15, every 4 weeks plus erlotinib 100 mg once per day (GemErlo) or gemcitabine (Gem) alone for six cycles. The primary end point of the study was to improve disease-free survival (DFS) from 14 to 18 months by adding erlotinib to gemcitabine. Results In all, 436 patients were randomly assigned at 57 study centers between April 2008 and July 2013. A total of 361 instances (83%) of disease recurrence were observed after a median follow-up of 54 months. Median treatment duration was 22 weeks in both arms. There was no difference in median DFS (GemErlo 11.4 months; Gem 11.4 months) or median overall survival (GemErlo 24.5 months; Gem 26.5 months). There was a trend toward long-term survival in favor of GemErlo (estimated survival after 1, 2, and 5 years for GemErlo was 77%, 53%, and 25% v 79%, 54%, and 20% for Gem, respectively). The occurrence or the grade of rash was not associated with a better survival in the GemErlo arm. Conclusion To the best of our knowledge, CONKO-005 is the first study to investigate the combination of chemotherapy and a targeted therapy in the adjuvant treatment of PDAC. GemErlo for 24 weeks did not improve DFS or overall survival over Gem.
EVALuna2:15299

Consensus in determining the resectability of locally progressed pancreatic ductal adenocarcinoma - results of the Conko-007 multicenter trial - Wittel, U. A.; Lubgan, Dorota; Ghadimi, M.; Belyaev, O.; Uhl, W.; Bechstein, W. O.; Grützmann, Robert; Hohenberger, Werner; Schmid, Andrea; Jacobasch, L.; Croner, R. S.; Reinacher-Schick, A.; et al. (BMC Cancer, 2019)
BACKGROUND: One critical step in the therapy of patients with localized pancreatic cancer is the determination of local resectability. The decision between primary surgery versus upfront local or systemic cancer therapy seems especially to differ between pancreatic cancer centers. In our cohort study, we analyzed the independent judgement of resectability of five experienced high volume pancreatic surgeons in 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer. METHODS: Pretherapeutic CT or MRI scans of 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer were evaluated by 5 independent pancreatic surgeons. Resectability and the degree of abutment of the tumor to the venous and arterial structures adjacent to the pancreas were reported. Interrater reliability and dispersion indices were compared. RESULTS: One hundred ninety-four CT scans and 6 MRI scans were evaluated and all parameters were evaluated by all surgeons in 133 (66.5%) cases. Low agreement was observed for tumor infiltration of venous structures (κ = 0.265 and κ = 0.285) while good agreement was achieved for the abutment of the tumor to arterial structures (interrater reliability celiac trunk κ = 0.708 P < 0.001). In patients with vascular tumor contact indicating locally advanced disease, surgeons highly agreed on unresectability, but in patients with vascular tumor abutment consistent with borderline resectable disease, the judgement of resectability was less uniform (dispersion index locally advanced vs. borderline resectable p < 0.05). CONCLUSION: Excellent agreement between surgeons exists in determining the presence of arterial abutment and locally advanced pancreatic cancer. The determination of resectability in borderline resectable patients is influenced by additional subjective factors. TRIAL REGISTRATION: EudraCT:2009-014476-21 (2013-02-22) and NCT01827553 (2013-04-09).
CRIS-Team Scopus Importer:2019-10-29
Keywords: Borderline resectable; Determination of resectability; Locally advanced; Pancreatic cancer; Prospective randomized multicenter trial

Consensus Statement on Mandatory Measurements for Pancreatic Cancer Trials for Patients With Resectable or Borderline Resectable Disease (COMM-PACT-RB) A Systematic Review and Delphi Consensus Statement - Pijnappel, Esther N.; Suurmeijer, J. Annelie; Koerkamp, Bas Groot; Kos, Milan; Siveke, Jens T.; Salvia, Roberto; Ghaneh, Paula; Van Eijck, Casper H. J.; Van Etten-Jamaludin, Faridi S.; Abrams, Ross; Brasiuniene, Birute; Buechler, Markus W.; et al. (JAMA Oncology, 2022)
IMPORTANCE Pancreatic cancer is the third most common cause of cancer death; however, randomized clinical trials (RCTs) of survival in patients with resectable pancreatic cancer lack mandatory measures for reporting baseline and prognostic factors, which hampers comparisons between outcome measures.
CRIS-Team WoS Importer:2022-05-13

Consensus statements on complete mesocolic excision for right-sided colon cancer—technical steps and training implications - Tejedor, Patricia; Francis, Nader; Jayne, David; Hohenberger, Werner; Khan, Jim (Surgical Endoscopy, 2022)
Background: CME is a radical resection for colon cancer, but the procedure is technically demanding with significant variation in its practice. A standardised approach to the optimal technique and training is, therefore, desirable to minimise technical hazards and facilitate safe dissemination. The aim is to develop an expert consensus on the optimal technique for Complete Mesocolic Excision (CME) for right-sided and transverse colon cancer to guide safe implementation and training pathways. Methods: Guidance was developed following a modified Delphi process to draw consensus from 55 international experts in CME and surgical education representing 18 countries. Domain topics were formulated and subdivided into questions pertinent to different aspects of CME practice. A three-round Delphi voting on 25 statements based on the specific questions and 70% agreement was considered as consensus. Results: Twenty-three recommendations for CME procedure were agreed on, describing the technique and optimal training pathway. CME is recommended as the standard of care resection for locally advanced colon cancer. The essential components are central vascular ligation, exposure of the superior mesenteric vein and excision of an intact mesocolon. Key anatomical landmarks to perform a safe CME dissection include identification of the ileocolic pedicle, superior mesenteric vein and root of the mesocolon. A proficiency-based multimodal training curriculum for CME was proposed including a formal proctorship programme. Conclusions: Consensus on standardisation of technique and training framework for complete mesocolic excision was agreed upon by a panel of experts to guide current practice and provide a quality control framework for future studies.
CRIS-Team Scopus Importer:2022-08-12
Keywords: Complete mesocoloc excision; Expert consensus; Right colon cancer; Standardisation; Survival

Construction and analysis of tissue microarrays in the era of digital pathology: a pilot study targeting CDX1 and CDX2 in a colon cancer cohort of 612 patients - Nolte, Sarah; Zlobec, Inti; Lugli, Alessandro; Hohenberger, Werner; Croner, Roland; Merkel, Susanne; Hartmann, Arndt; Geppert, Carol-Immanuel; Rau, Tilman (Journal of Pathology: Clinical Research, 2017)
CDX1 and CDX2 are possibly predictive biomarkers in colorectal cancer. We combined digitally-guided (next generation) TMA construction (ngTMA) and the utility of digital image analysis (DIA) to assess accuracy, tumour heterogeneity and the selective impact of different combined intensity-percentage levels on prognosis.CDX1 and CDX2 immunohistochemistry was performed on ngTMAs covering normal tissue, tumour centre and invasive front. The percentages of all epithelial cells per staining intensity per core were analysed digitally. Beyond classical prognosis analysis following REMARK guidelines, we investigated pre-analytical conditions, three different types of heterogeneity (mosaic-like, targeted and haphazard) and influences on cohort segregation and patient selection. The ngTMA-DIA approach produced robust biomarker data with infrequent core loss and excellent on-target punching. The detailed assessment of tumour heterogeneity could - except for a certain diffuse mosaic-like heterogeneity - exclude differences between the invasive front and tumour centre, as well as detect haphazard clonal heterogeneous elements. Moreover, lower CDX1 and CDX2 counts correlated with mucinous histology, higher TNM stage, higher tumour grade and worse survival (p < 0.01, all). Different protein expression intensity levels shared comparable prognostic power and a great overlap in patient selection. The combination of ngTMA with DIA enhances accuracy and controls for biomarker analysis. Beyond the confirmation of CDX1 and CDX2 as prognostically relevant markers in CRC, this study highlights the greater robustness of CDX2 in comparison to CDX1. For the assessment of CDX2 protein loss, cut-points as percentage data of complete protein loss can be deduced as a recommendation.
EVALuna2:15290

Context Matters—Why We Need to Change From a One Size Fits all Approach to Made-to-Measure Therapies for Individual Patients With Pancreatic Cancer - Sankarasubramanian, Sushmitha; Pfohl, Ulrike; Regenbrecht, Christian R. A.; Reinhard, Christoph; Wedeken, Lena (Frontiers in Cell and Developmental Biology, 2021)
Pancreatic cancer is one of the deadliest cancers and remains a major unsolved health problem. While pancreatic ductal adenocarcinoma (PDAC) is associated with driver mutations in only four major genes (KRAS, TP53, SMAD4, and CDKN2A), every tumor differs in its molecular landscape, histology, and prognosis. It is crucial to understand and consider these differences to be able to tailor treatment regimens specific to the vulnerabilities of the individual tumor to enhance patient outcome. This review focuses on the heterogeneity of pancreatic tumor cells and how in addition to genetic alterations, the subsequent dysregulation of multiple signaling cascades at various levels, epigenetic and metabolic factors contribute to the oncogenesis of PDAC and compensate for each other in driving cancer progression if one is tackled by a therapeutic approach. This implicates that besides the need for new combinatorial therapies for PDAC, a personalized approach for treating this highly complex cancer is required. A strategy that combines both a target-based and phenotypic approach to identify an effective treatment, like Reverse Clinical Engineering® using patient-derived organoids, is discussed as a promising way forward in the field of personalized medicine to tackle this deadly disease.
CRIS-Team Scopus Importer:2021-12-03
Keywords: 3D cell culture models; combined targeted and phenotypic approach; KRAS; pancreatic ductal adenocarcinoma (PDAC); patient-derived tumor organoids; personalized medicine; reverse clinical engineering; tumor heterogeneity

Continuous or interrupted suture technique for hepaticojejunostomy? A national survey - Brunner, Maximilian; Stockheim, Jessica; Krautz, Christian; Raptis, Dimitrios; Kersting, Stephan; Grützmann, Robert; Weber, Georg (BMC Surgery, 2018)
BACKGROUND: Hepaticojejunostomy is commonly used in hepato-bilio-pancreatic surgery and a crucial step in many surgical procedures, including pancreaticoduodenectomy. The most frequently used techniques are the interrupted suture and the continuous suture technique. Currently, there is no data available in regard to the utilization of these techniques. METHODS: In total, 102 hospitals in Germany were invited between September and November 2017 to participate in this survey. Using a paper-based questionnaire, data were collected on surgical technique and complication rates of hepaticojejunostomies. RESULTS: A total of 77 of the 102 addressed hospitals (76%) participated in the survey. On average, each hospital performed 71 hepaticojejunostomies per year - most often in the context of pancreaticoduodenectomy (71%). 24 (31%) hospitals exclusively use an interrupted suture technique, 7 (9%) hospitals solely a continuous suture technique, 3 (4%) hospitals perform a combination of continuous and interrupted suture technique and 43 (56%) hospitals decide on one of both techniques depending on intraoperative findings. According to the participants in this survey, the continuous suture technique is significantly faster than the interrupted suture technique in hepaticojejunostomy (p = 0,015). There were no significant differences in the overall complication rate (p = 0,902) and insufficiency rate (p = 1,000). CONCLUSIONS: In Germany, there is a heterogeneity in the technique used to create a hepaticojejunostomy. As our survey suggests that the use of continuous suture technique may offer an advantage in time without jeopardizing patient outcomes, the different techniques should be compared in a randomized controlled study.
EVALuna2:210706

Continuous or interrupted suture technique for hepaticojejunostomy during pancreatoduodenectomy (HEKTIK trial): study protocol of a randomized controlled multicenter trial - Brunner, Maximilian; Golcher, Henriette; Krautz, Christian; Kersting, Stephan; Grützmann, Robert; Weber, Georg (Trials, 2022)
Background: Hepaticojejunostomy is commonly performed in hepato-bilio-pancreatic surgery, particularly during pancreaticoduodenectomy. The purpose of this study is to evaluate the safety and efficiency of two commonly applied suture techniques (the interrupted versus the continuous suture technique) in patients undergoing a hepaticojejunostomy during pancreatoduodenectomy.
CRIS-Team WoS Importer:2022-06-24

Contrast-Enhanced Multispectral Optoacoustic Tomography for Functional Assessment of the Gastrointestinal Tract - Paulus, Lars-Philip; Bühler, Adrian; Wagner, Alexandra; Raming, Roman; Jüngert, Jörg; Simon, David; Tascilar, Koray; Schnell, Alexander; Rother, Ulrich; Eckstein, Markus; Lang, Werner; Hörning, André; et al. (Advanced Science, 2023)
Real-time imaging and functional assessment of the intestinal tract and its transit pose a significant challenge to conventional clinical diagnostic methods. Multispectral optoacoustic tomography (MSOT), a molecular-sensitive imaging technology, offers the potential to visualize endogenous and exogenous chromophores in deep tissue. Herein, a novel approach using the orally administered clinical-approved fluorescent dye indocyanine green (ICG) for bedside, non-ionizing evaluation of gastrointestinal passage is presented. The authors are able to show the detectability and stability of ICG in phantom experiments. Furthermore, ten healthy subjects underwent MSOT imaging at multiple time points over eight hours after ingestion of a standardized meal with and without ICG. ICG signals can be visualized and quantified in different intestinal segments, while its excretion is confirmed by fluorescent imaging of stool samples. These findings indicate that contrast-enhanced MSOT (CE-MSOT) provides a translatable real-time imaging approach for functional assessment of the gastrointestinal tract.
CRIS-Team Scopus Importer:2023-06-30
Keywords: indocyanine green; intestine; multispectral optoacoustic tomography; optoacoustics; photoacoustics

Contribution of Blood Vessel Activation, Remodeling and Barrier Function to Inflammatory Bowel Diseases - Britzen-Laurent, Nathalie; Weidinger, Carl; Stürzl, Michael (International Journal of Molecular Sciences, 2023)
Inflammatory bowel diseases (IBDs) consist of a group of chronic inflammatory disorders with a complex etiology, which represent a clinical challenge due to their often therapy-refractory nature. In IBD, inflammation of the intestinal mucosa is characterized by strong and sustained leukocyte infiltration, resulting in the loss of epithelial barrier function and subsequent tissue destruction. This is accompanied by the activation and the massive remodeling of mucosal micro-vessels. The role of the gut vasculature in the induction and perpetuation of mucosal inflammation is receiving increasing recognition. While the vascular barrier is considered to offer protection against bacterial translocation and sepsis after the breakdown of the epithelial barrier, endothelium activation and angiogenesis are thought to promote inflammation. The present review examines the respective pathological contributions of the different phenotypical changes observed in the microvascular endothelium during IBD, and provides an overview of potential vessel-specific targeted therapy options for the treatment of IBD.
CRIS-Team Scopus Importer:2023-04-07
Keywords: angiogenesis; gut vascular barrier; inflammatory bowel diseases (IBDs); vasculature; vessel permeability

Contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression - Hartmann, Philipp; Trufa, Denis; Hohenberger, Katja; Tausche, Patrick; Trump, Sonja; Mittler, Susanne; Geppert, Carol-Immanuel; Rieker, Ralf; Schieweck, Oliver; Sirbu, Horia; Hartmann, Arndt; Neurath-Finotto, Susetta (Scientific Reports, 2023)
Neoplasms of the lungs are the leading cause of cancer incidence and mortality worldwide. Although immunotherapy has increased the overall survival of patients with lung cancer, there is the need to improve this treatment. At this regard, blood lipid levels are thought to be linked to cancer risk and thus a preventive intervention through regulation of the nutrition of patients with lung cancer is gaining much attention. In this study, we therefore asked about the contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression. We measured different serum lipids and analyzed cholesterol synthesis enzymes 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) and acetyl-coenzyme A cholesterol acetyltransferase 1 (ACAT1) as well as the cholesterol cellular export protein ATP-binding cassette (ABC) A-1 mRNA by quantitative PCR (qPCR) in the control and tumoral regions of post-surgery lung tissues to analyze the accumulation of cholesterol in cancer cells in a cohort of patients with lung adenocarcinoma (LUAD). We found that triglycerides in serum directly correlated with the body mass index (BMI) in patients with LUAD. By contrast, we found that high-density lipoprotein (HDL) cholesterol inversely correlated with the BMI, C-reactive protein (CRP) and overall survival and total cholesterol inversely correlated with the tumor diameter, serum CRP and overall survival in these LUAD patients. Functionally, the role of cholesterol is indispensable for the growth and development of normal animal cells where it is tightly regulated. Excess of cellular cholesterol regulated by HMGCR is converted to cholesteryl esters by the enzyme ACAT1 and exported extracellularly by the cholesterol transporter ABCA1. Here we found HMGCR and ACAT1 upregulated and ABCA1 downregulated in the lung's tumoral region of our LUAD cohort, indicating cholesterol dysregulated cellular export in lung tumor cells.
CRIS-Team Scopus Importer:2023-04-21

Conventional and three-dimensional photography as a tool to map distribution patterns of in-transit melanoma metastases on the lower extremity - Müller, Kilian; Berking, Carola; Voskens, Caroline; Heppt, Markus; Heinzerling, Lucie; Koch, Elias; Kramer, Rafaela; Merkel, Susanne; Schuler-Thurner, Beatrice; Schellerer, Vera; Steeb, Theresa; Wessely, Anja; et al. (Frontiers in Medicine, 2023)
Background: In melanoma, in-transit metastases characteristically occur at the lower extremity along lymphatic vessels. Objectives: The objective of this study was to evaluate conventional or three-dimensional photography as a tool to analyze in-transit metastasis pattern of melanoma of the lower extremity. In addition, we assessed risk factors for the development of in-transit metastases in cutaneous melanoma. Methods: In this retrospective, monocentric study first we compared the clinical data of all evaluable patients with in-transit metastases of melanoma on the lower extremity (n = 94) with melanoma patients without recurrence of disease (n = 288). In addition, based on conventional (n = 24) and three-dimensional photography (n = 22), we defined the specific distribution patterns of the in-transit metastases on the lower extremity. Results: Using a multivariate analysis we identified nodular melanoma, tumor thickness, and ulceration as independent risk factors to develop in-transit metastases ITM (n = 94). In patients with melanoma on the lower leg (n = 31), in-transit metastases preferentially developed along anatomically predefined lymphatic pathways. In contrast when analyzing in-transit metastases of melanoma on the foot (n = 15) no clear pattern could be visualized. In addition, no difference in distance between in-transit metastases and primary melanoma on the foot compared to the lower leg was observed using three-dimensional photography (n = 22). Conclusion: A risk-adapted follow-up of melanoma patients to detect in-transit metastases can be applied by knowledge of the specific lymphatic drainage of the lower extremity. Our current analysis suggests a more complex lymphatic drainage of the foot.
CRIS-Team Scopus Importer:2023-02-10
Keywords: 3D photography; in-transit metastasis; lower extremity; lymphatic pathways; melanoma

Cord-blood-derived professional antigen-presenting cells: Functions and applications in current and prospective cell therapies - Cunningham, Sarah; Hackstein, Holger (International Journal of Molecular Sciences, 2021)
Human umbilical cord blood (UCB) represents a valuable source of hematopoietic stem cells, particularly for patients lacking a matching donor. UCB provides practical advantages, including a lower risk of graft-versus-host-disease and permissive human leukocyte antigen mismatching. These advantageous properties have so far been applied for stem cell, mesenchymal stromal cell, and chimeric antigen receptor T cell therapies. However, UCB-derived professional antigen-presenting cells are increasingly being utilized in the context of immune tolerance and regenerative therapy. Here, we review the cell-specific characteristics as well as recent advancements in UCB-based cell therapies focusing on dendritic cells, monocytes, B lymphocytes, innate lymphoid cells, and macrophages.
CRIS-Team Scopus Importer:2021-06-11
Keywords: Antigen presentation; Cell therapy; Immune reconstitution; Umbilical cord blood

Coronary CT angiography in the elderly - Nijveldt, R.; Pflederer, T.; Achenbach, Susanne (Netherlands Heart Journal, 2014)
People over 75 years of age represent a specific group of patients for which the clinician is often in doubt about what to do, whether additional diagnostic workup is helpful or a primary medical approach would suffice. However, this patient population is less prone to the long-term effects of radiation burden or contrast medium-induced nephropathy, and therefore it may be especially worthwhile to use advanced imaging techniques such as contrast-enhanced CT in these patients. The following cases illustrate two common diagnostic problems, in which coronary CT angiography decided the clinical course.
EVALuna2:12009

Correction:Decreased Thymic Output Contributes to Immune Defects in Septic Patients(J. Clin. Med. (2020), 9, (2695), 10.3390/jcm9092695) - Sommer, Natascha; Noack, Steffen; Hecker, Andreas; Hackstein, Holger; Bein, Gregor; Weissmann, Norbert; Seeger, Werner; Mayer, Konstantin; Hecker, Matthias (Journal of Clinical Medicine, 2022)
In the original article, there were errors in Figure 1D (panel CD8-Control). Changes are below. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated.
CRIS-Team Scopus Importer:2022-09-30

Correction: Medikamentenfreisetzende Koronarstents/-scaffolds und medikamentenbeschichtete Ballonkatheter - Nef, H. M.; Abdel-Wahab, M.; Achenbach, Susanne; Joner, M.; Levenson, B.; Mehilli, J.; Moellmann, H.; Thiele, Holger; Zahn, R.; Zeus, T.; Elsaesser, A. (Der Kardiologe, 2018)
CRIS-Team Scopus Importer:2023-03-08

Correction to: Diagnostic performance of four SARS-CoV-2 antibody assays in patients with COVID-19 or with bacterial and non-SARS-CoV-2 viral respiratory infections (European Journal of Clinical Microbiology & Infectious Diseases, (2021), 10.1007/s10096-021-04285-4) - Huber, Timo; Steininger, Philipp; Irrgang, Pascal; Korn, Klaus; Tenbusch, Matthias; Diesch, Katharina; Achenbach, Susanne; Kremer, Andreas; Werblow, Marissa; Vetter, Marcel; Bogdan, Christian; Held, Jürgen (European Journal of Clinical Microbiology & Infectious Diseases, 2021)
In the originally published version of the article, captions of Figures 1, 2, 3, 4, and 5 have missing figure denominations. The figures are presented here with correct captions. Layout adjustments are also made to Tables 2-5 for readability. The original article has been corrected. (Figure presented.).
CRIS-Team Scopus Importer:2021-07-30

Correction to: Outcomes After Distal Pancreatectomy with Celiac Axis Resection for Pancreatic Cancer: A Pan-European Retrospective Cohort Study - Klompmaker, Sjors; Van Hilst, Jony; Gerritsen, Sarah L.; Adham, Mustapha; Albiol Quer, M. Teresa; Bassi, Claudio; Berrevoet, Frederik; Boggi, Ugo; Busch, Olivier R.; Cesaretti, Manuela; Dalla Valle, Raffaele; Darnis, Benjamin; et al. (Annals of Surgical Oncology, 2018)
In the original article, the institutional author the E-AHPBA DP-CAR study group was misspelled. It is correct as reflected here. The original article has also been corrected.
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Correlation of retinal vascular characteristics with laboratory and ocular findings in Fabry disease: exploring ocular diagnostic biomarkers - Lindziute, Migle; Kaufeld, Jessica; Hufendiek, Karsten; Volkmann, Ingo; Brockmann, Dorothee; Hosari, Sami; Hohberger, Bettina; Christian, Mirko; Framme, Carsten; Jan, Tode; Hufendiek, Katerina (Orphanet Journal of Rare Diseases, 2023)
Background: The goal of this study was to evaluate macular microvascular changes in patients with Fabry disease (FD) using optical coherence tomography angiography (OCTA) and to explore their correlation with laboratory and ocular findings. Methods: A total of 76 eyes (38 patients) and 48 eyes of 24 healthy controls were enrolled in this prospective study. Vessel Area Density (VAD) and Foveal Avascular Zone (FAZ) area were calculated on 2.9 × 2.9 mm OCTA images scanned with the Heidelberg Spectralis II (Heidelberg, Germany). VAD was measured in three layers: Superficial Vascular Plexus (SVP), Intermediate Capillary Plexus (ICP), and Deep Capillary Plexus (DCP). All scans were analyzed with the EA-Tool (Version 1.0), which was coded in MATLAB (The MathWorks Inc, R2017b). FAZ area was manually measured in full-thickness, SVP, ICP and DCP scans. Results: Average VAD in SVP, ICP and DCP was higher in Fabry disease patients than in controls (49.4 ± 11.0 vs. 26.5 ± 6.2, 29.6 ± 7.4 vs. 20.2 ± 4.4, 32.3 ± 8.8 vs. 21.7 ± 5.1 respectively, p < 0.001). Patients with cornea verticillata (CV) had a higher VAD in ICP and DCP compared to patients without CV (p < 0.01). Patients with increased lysoGb3 concentration had a higher VAD in DCP when compared to patients with normal lysoGb3 concentration (p < 0.04). There was no difference in VAD in patients with and without vascular tortuosity. However, a significantly higher VAD was observed in patients with vascular tortuosity compared to controls (p < 0.03). Conclusions: Increased lysoGb3 and VAD in DCP could be reliable biomarkers of disease activity. Cornea verticillata could be adopted as a predictive biomarker for VAD changes and disease progression. The combination of cornea verticillata and increased VAD may serve as a diagnostic biomarker for Fabry disease, however due to the discrepancies in VAD values in various studies, further research has to be done to address this claim.
CRIS-Team Scopus Importer:2023-10-20
Keywords: Biomarkers; Fabry disease; OCT angiography; Vascular remodelling; Vessel area density

Correlation of the hypotonic shock response and extent of shape change with the new ThromboLUX (TM) - Kraemer, L.; Raczat, Tatjana; Weiss, D. R.; Strobel, Joachim; Eckstein, Reinhold; Ringwald, J. (Vox Sanguinis, 2015)
ThromboLUX (TLX)-Score was compared with hypotonic shock response (HSR) and extent of shape change (ESC) in 99 samples from 42 platelet concentrates. Tests were performed in parallel and duplicate. Mean values for TLX Score, HSR and ESC were 30.3 ± 3.8%, 69.0 ± 12.2% and 23.2 ± 4.9%, respectively. We found no significant correlation between TLX Score and HSR or ESC (r = -0.158, P = 0.118 and r = -115, P = 0.255, respectively), whereas HSR and ESC correlated significantly (r = 0.351, P < 0.001). As TLX Score did not show significant correlation with HSR and ESC, the value of TLX for platelet quality testing remains unclear. Studies comparing these parameters with transfusion outcome are needed.
EVALuna2:15993

COVID-19: Proper dosing of Convalescent Plasma in Studies Comment - Hackstein, Holger (Transfusionsmedizin, 2022)
CRIS-Team WoS Importer:2022-05-27

CRISPR Cas9 in Pancreatic Cancer Research - Yang, Hai; Bailey, Peter; Pilarsky, Christian (Frontiers in Cell and Developmental Biology, 2019)
Pancreatic cancer is now becoming a common cause of cancer death with no significant change in patient survival over the last 10 years. The main treatment options for pancreatic cancer patients are surgery, radiation therapy and chemotherapy, but there is now considerable effort to develop new and effective treatments. In recent years, CRISPR/Cas9 technology has emerged as a powerful gene editing tool with promise, not only as an important research methodology, but also as a new and effective method for targeted therapy. In this review, we summarize current advances in CRISPR/Cas9 technology and its application to pancreatic cancer research, and importantly as a means of selectively targeting key drivers of pancreatic cancer.
CRIS-Team Scopus Importer:2019-11-15
Keywords: CRISPR/Cas9; gene editing; knock out and knock in; library screening; pancreatic cancer

CRISPR/Cas9-mediated knock-out of krasG12D mutated pancreatic cancer cell lines - Lentsch, Eva; Li, Lifei; Pfeffer, Sina; Ekici, Arif Bülent; Taher, Leila; Pilarsky, Christian; Grützmann, Robert (International Journal of Molecular Sciences, 2019)
In 90% of pancreatic ductal adenocarcinoma cases, genetic alteration of the proto-oncogene Kras has occurred, leading to uncontrolled proliferation of cancerous cells. Targeting Kras has proven to be difficult and the battle against pancreatic cancer is ongoing. A promising approach to combat cancer was the discovery of the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system, which can be used to genetically modify cells. To assess the potential of a CRISPR/CRISPR-associated protein 9 (Cas9) method to eliminate Kras mutations in cells, we aimed to knock-out the c.35G>A (p.G12D) Kras mutation. Therefore, three cell lines with a heterozygous Kras mutation (the human cell lines SUIT-2 and Panc-1 and the cell line TB32047 from a KPC mouse model) were used. After transfection, puromycin selection and single-cell cloning, proteins from two negative controls and five to seven clones were isolated to verify the knock-out and to analyze changes in key signal transduction proteins. Western blots showed a specific knock-out in the KrasG12D protein, but wildtype Kras was expressed by all of the cells. Signal transduction analysis (for Erk, Akt, Stat3, AMPKα, and c-myc) revealed expression levels similar to the wildtype. The results described herein indicate that knocking-out the KrasG12D mutation by CRISPR/Cas9 is possible. Additionally, under regular growth conditions, the knock-out clones resembled wildtype cells.
CRIS-Team Scopus Importer:2019-11-26
Keywords: CRISPR/Cas9 system; G12D; Kras; Panc-1; Suit-2; TB32047

CRISPR-Cas9 Screen Identifies DYRK1A as a Target for Radiotherapy Sensitization in Pancreatic Cancer - Lan, Bin; Zeng, Siyuan; Zhang, Shuman; Ren, Xiaofan; Xing, Yuming; Kutschick, Isabella; Pfeffer, Sina; Frey, Benjamin; Britzen-Laurent, Nathalie; Grützmann, Robert; Cordes, Nils; Pilarsky, Christian (Cancers, 2022)
Although radiation therapy has recently made great advances in cancer treatment, the majority of patients diagnosed with pancreatic cancer (PC) cannot achieve satisfactory outcomes due to intrinsic and acquired radioresistance. Identifying the molecular mechanisms that impair the efficacy of radiotherapy and targeting these pathways are essential to improve the radiation response of PC patients. Our goal is to identify sensitive targets for pancreatic cancer radiotherapy (RT) using the kinome-wide CRISPR-Cas9 loss-of-function screen and enhance the therapeutic effect through the development and application of targeted inhibitors combined with radiotherapy. We transduced pancreatic cancer cells with a protein kinase library; 2D and 3D library cells were irradiated daily with a single dose of up to 2 Gy for 4 weeks for a total of 40 Gy using an X-ray generator. Sufficient DNA was collected for next-generation deep sequencing to identify candidate genes. In this study, we identified several cell cycle checkpoint kinases and DNA damage related kinases in 2D-and 3D-cultivated cells, including DYRK1A, whose loss of function sensitizes cells to radiotherapy. Additionally, we demonstrated that the harmine-targeted suppression of DYRK1A used in conjunction with radiotherapy increases DNA double-strand breaks (DSBs) and impairs homologous repair (HR), resulting in more cancer cell death. Our results support the use of CRISPR-Cas9 screening to identify new therapeutic targets, develop radiosensitizers, and provide novel strategies for overcoming the tolerance of pancreatic cancer to radiotherapy.
CRIS-Team Scopus Importer:2022-01-14
Keywords: CRISPR-Cas9; DNA damage repair; DNA double-strand break; DYRK1A; Harmine; Pancreatic cancer; Radioresistance; Radiotherapy

CT analysis of left ventricular function predicts short term survival in patients following transcatheter aortic valve implantation: 1-year outcome data - Ijgua, Mohamed Cherif; Arnold, Martin; Eckstein, Markus; Smolka, S.; Bittner, Daniel O.; Ammon, Fabian; Kondruweit, Markus; Moshage, Maximilian; Achenbach, Susanne; Marwan, Mohamed (European Heart Journal, 2022)
CRIS-Team WoS Importer:2023-03-03

Cue reactivity towards bodies in anorexia nervosa - common and differential effects in adolescents and adults - Horndasch, Stefanie; Kratz, Oliver; Van Doren, Jessica; Graap, Holmer; Kramer, Robert; Moll, Gunther; Heinrich, Hartmut (Psychological Medicine, 2018)
BACKGROUND: Aberrant reward mechanisms with regard to slim body shapes are discussed in patients with anorexia nervosa (AN). The aim of the present study was to examine of cue reactivity toward body shapes in AN via the late positive potential (LPP), an event-related electroencephalography (EEG) component. By including adolescents and adults, aspects of development and chronification could be studied (2 × 2 design). METHODS: Thirty-two female AN patients (19 adolescents and 13 adults) and 37 control participants (16 adolescents and 21 adults) were included. Standardized photographic stimuli showing women's bodies in underwear from five body mass index (BMI) categories (extremely underweight to extremely overweight) were presented. During picture evaluation, EEG activity was recorded (10-20 system). The LPP was measured in two time windows characterized by different topographies (450-700 ms: posterior; 1000-1300 ms: central). RESULTS: Regarding the posterior component, LPP amplitudes were clearly reduced in adult but not in adolescent patients; for both time windows the LPP showed differential patterns over BMI categories for patients and controls. Regarding the central component, a highly significant linear decrease from extremely underweight to extremely overweight body shapes was revealed in patients and no significant modulation in control participants. CONCLUSIONS: Adolescent and adult patients show increased sustained attention toward extremely underweight bodies. In chronically ill patients, this bias appears to be accompanied by generally reduced automatic attention. The LPP findings provide a differentiated picture of aberrant cue reactivity which could be interpreted as motivated attention toward body shapes in AN.
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Cu-releasing bioactive glass/polycaprolactone coating on Mg with antibacterial and anticorrosive properties for bone tissue engineering - Yang, Yuyun; Zheng, Kai; Liang, Ruifang; Mainka, Astrid; Taccardi, Nicola; Roether, Judith; Detsch, Rainer; Goldmann, Wolfgang; Virtanen, Sannakaisa; Boccaccini, Aldo R. (Biomedical Materials, 2017)
Copper (Cu)-containing bioactive glass nanoparticles (Cu-BGNs) were introduced in polycaprolactone (PCL) coating systems to improve the bioactivity, antibacterial property, and corrosion resistance of vulnerable magnesium matrices under physiological conditions. The influence of different amounts of Cu-BGNs in PCL coatings was thoroughly investigated determining the wettability, electrochemical properties, and antibacterial effects against Staphylococcus carnosus and Escherichia coli, as well as their cyto-compatibility. Cu-BGNs were observed randomly scattered in PCL coatings. Increasing concentration of Cu-BGNs resulted in slightly decreasing water contact angle, and reducing anti-corrosion properties of the Cu-BGNs composite coatings. Yet higher Cu-BGNs content in coatings led to more calcium phosphate formation on the surface after 7 days of immersion in DMEM, which was confirmed by FTIR and XPS. The growth of S. carnosus and E. coli was inhibited by Cu2+ ion released from Cu-BGN coatings. In addition, both direct and indirect cyto-compatibility experiments showed that the viability and proliferation of MG-63 cells on Cu-BGN coatings were highly increased compared to pure magnesium; however, an additional increase of Cu-BGNs concentration showed a slight decrease of cell proliferation and cell activity. In summary, Cu-BGN/PCL composite coatings impart magnesium-based biomaterials antibacterial and anticorrosive properties for clinical applications.
EVALuna2:13499

Current Applications of Liquid Biopsy in Gastrointestinal Cancer Disease—From Early Cancer Detection to Individualized Cancer Treatment - David, Paul; Mittelstädt, Anke; Kouhestani, Dina; Anthuber, Anna; Kahlert, Christoph; Sohn, Kai; Weber, Georg (Cancers, 2023)
Worldwide, gastrointestinal (GI) cancers account for a significant amount of cancer-related mortality. Tests that allow an early diagnosis could lead to an improvement in patient survival. Liquid biopsies (LBs) due to their non-invasive nature as well as low risk are the current focus of cancer research and could be a promising tool for early cancer detection. LB involves the sampling of any biological fluid (e.g., blood, urine, saliva) to enrich and analyze the tumor’s biological material. LBs can detect tumor-associated components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs). These components can reflect the status of the disease and can facilitate clinical decisions. LBs offer a unique and new way to assess cancers at all stages of treatment, from cancer screenings to prognosis to management of multidisciplinary therapies. In this review, we will provide insights into the current status of the various types of LBs enabling early detection and monitoring of GI cancers and their use in in vitro diagnostics.
CRIS-Team Scopus Importer:2023-04-28
Keywords: circulating tumor cells (CTCs); circulating tumor DNA (ctDNA); gastrointestinal cancer; liquid biopsy; organoids; tumor exosomes; tumor-educated blood platelets (TEPs)