Checkpoint Inhibitors - Heinzerling, Lucie; De Toni, Enrico N.; Schett, Georg; Hundorfean, Gheorghe; Zimmer, Lisa (Deutsches Ärzteblatt international, 2019)
BACKGROUND: Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening. METHODS: This review is based on pertinent articles retrieved by a search in PubMed and on an evaluation of a side-effect registry. RESULTS: Checkpoint-inhibitor-induced autoimmune side effects manifest themselves in all organ systems, most commonly as skin lesions (46-62%), autoimmune colitis (22-48%), autoimmune hepatitis (7-33%), and endocrinopathies (thyroiditis, hypophysitis, adrenalitis, diabetes mellitus; 12-34%). Rarer side effects include pneumonitis (3-8%), nephritis (1-7%), cardiac side effects including cardiomyositis (5%), and neurological side effects (1-5%). Severe (sometimes lethal) side effects arise in 17-21%, 20-28%, and 59% of patients undergoing anti-PD-1 and anti- CTLA-4 antibody treatment and the approved combination therapy, respectively. With proper monitoring, however, these side effects can be recognized early and, usually, treated with success. Endocrine side effects generally require long-term hormone substitution. Patients who have stopped taking checkpoint inhibitors because of side effects do not show a poorer response of their melanoma or shorter survival in comparison to patients who continue to take checkpoint inhibitors. CONCLUSION: The complex management of checkpoint-inhibitor-induced side effects should be coordinated in experienced centers. The creation of an interdisciplinary "tox team" with designated experts for organ-specific side effects has proven useful. Prospective registry studies based on structured documentation of side effects in routine clinical practice are currently lacking and urgently needed.
EVALuna2:69389

Checkpoint Inhibitors The Diagnosis and Treatment of Side Effects - Heinzerling, Lucie; De Toni, Enrico N.; Schett, Georg; Hundorfean, Gheorghe; Zimmer, Lisa (Deutsches Ärzteblatt international, 2019)
Background: Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-Iymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening.
CRIS-Team WoS Importer:2019-04-12

Chemically induced mouse models of acute and chronic intestinal inflammation - Wirtz, Stefan; Popp, Vanessa; Kindermann, Markus; Gerlach, Katharina; Weigmann, Benno; Fichtner-Feigl, Stefan; Neurath, Markus (Nature Protocols, 2017)
Inflammatory bowel diseases (IBDs) result in diarrhea and abdominal pain with further potential complications such as tissue fibrosis and stenosis. Animal models help in understanding the immunopathogenesis of IBDs and in the design of novel therapeutic concepts. Here we present an updated version of a protocol we published in 2007 for key models of acute and chronic forms of colitis induced by 2,4,6-trinitro-benzene sulfonic acid (TNBS), oxazolone and dextran sulfate sodium (DSS). This protocol update describes an adaptation of the existing protocol that modifies the technique. This protocol has been used to generate improved mouse models that better reflect the nature of IBDs in humans. In TNBS and oxazolone colitis models, topical administration of hapten reagents results in T-cell-mediated immunity against haptenized proteins and luminal antigens. By contrast, to generate DSS colitis models, mice orally receive DSS, causing death of epithelial cells, compromising barrier function and causing subsequent inflammation. The analysis of the acute colitis models can be performed within 1-2 weeks, whereas that of the chronic models may take 2-4 months. The strengths of the acute models are that they are based on the analysis of short-lasting barrier alterations, innate immune effects and flares. The advantages of the chronic models are that they may offer better insight into adaptive immunity and complications such as neoplasia and tissue fibrosis. The protocol requires basic skills in laboratory animal research.
EVALuna2:33810

Chronic intestinal inflammation drives colorectal tumor formation triggered by dietary heme iron in vivo - Seiwert, Nina; Adam, Janine; Steinberg, Pablo; Wirtz, Stefan; Schwerdtle, Tanja; Adams-Quack, Petra; Hovelmeyer, Nadine; Kaina, Bernd; Foersch, Sebastian; Fahrer, Jorg (Archives of Toxicology, 2021)
The consumption of red meat is associated with an increased risk for colorectal cancer (CRC). Multiple lines of evidence suggest that heme iron as abundant constituent of red meat is responsible for its carcinogenic potential. However, the underlying mechanisms are not fully understood and particularly the role of intestinal inflammation has not been investigated. To address this important issue, we analyzed the impact of heme iron (0.25 mu mol/g diet) on the intestinal microbiota, gut inflammation and colorectal tumor formation in mice. An iron-balanced diet with ferric citrate (0.25 mu mol/g diet) was used as reference. 16S rRNA sequencing revealed that dietary heme reduced alpha-diversity and caused a persistent intestinal dysbiosis, with a continuous increase in gram-negative Proteobacteria. This was linked to chronic gut inflammation and hyperproliferation of the intestinal epithelium as attested by mini-endoscopy, histopathology and immunohistochemistry. Dietary heme triggered the infiltration of myeloid cells into colorectal mucosa with an increased level of COX-2 positive cells. Furthermore, flow cytometry-based phenotyping demonstrated an increased number of T cells and B cells in the lamina propria following heme intake, while gamma delta-T cells were reduced in the intraepithelial compartment. Dietary heme iron catalyzed formation of fecal N-nitroso compounds and was genotoxic in intestinal epithelial cells, yet suppressed intestinal apoptosis as evidenced by confocal microscopy and western blot analysis. Finally, a chemically induced CRC mouse model showed persistent intestinal dysbiosis, chronic gut inflammation and increased colorectal tumorigenesis following heme iron intake. Altogether, this study unveiled intestinal inflammation as important driver in heme iron-associated colorectal carcinogenesis.
CRIS-Team WoS Importer:2021-05-28

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 Pruritus in the Absence of Skin Disease: Pathophysiology, Diagnosis and Treatment - Pereira, Manuel P.; Kremer, Andreas; Mettang, Thomas; Staender, Sonja (American Journal of Clinical Dermatology, 2016)
Chronic pruritus arises not only from dermatoses, but also, in up to half of cases, from extracutaneous origins. A multitude of systemic, neurological, psychiatric, and somatoform conditions are associated with pruritus in the absence of skin disease. Moreover, pruritus is a frequently observed side effect of many drugs. It is therefore difficult for physicians to make a correct diagnosis. Chronic pruritus patients frequently present to the dermatologist with skin lesions secondary to a long-lasting scratching behavior, such as lichenification and prurigo nodularis. A structured clinical history and physical examination are essential in order to evaluate the pruritus, along with systematic, medical history-adapted laboratory and radiological tests carried out according to the differential diagnosis. For therapeutic reasons, a symptomatic therapy should be promptly initiated parallel to the diagnostic procedures. Once the underlying factor(s) leading to the pruritus are identified, a targeted therapy should be implemented. Importantly, the treatment of accompanying disorders such as sleep disturbances or mental symptoms should be taken into consideration. Even after successful treatment of the underlying cause, pruritus may persist, likely due to chronicity processes including peripheral and central sensitization or impaired inhibition at spinal level. A vast arsenal of topical and systemic agents targeting these pathophysiological mechanisms has been used to deter further chronicity. The therapeutic options currently available are, however, still insufficient for many patients. Thus, future studies aiming to unveil the complex mechanisms underlying chronic pruritus and develop new therapeutic agents are urgently needed.
EVALuna2:2197

Chronic pruritus represents a major burden in non-cholestatic hepatobiliary disorders - Düll, Miriam; Karlen, Vanessa; Vetter, Marcel; Dietrich, Peter; Kupfer, Joerg; Neurath, Markus; Kremer, Andreas (JOURNAL OF HEPATOLOGY, 2022)
CRIS-Team WoS Importer:2022-08-12

Chronischer Pruritus - Kremer, Andreas (Medizinische Monatsschrift für Pharmazeuten, 2019)
Chronic pruritus is an agonizing Symptom accompanying various diseases which often represents an interdisciplinary diagnostic and therapeutic challenge. Approxi-mately 15 % of the population suffers from this symptom. Aside general measures such as a cold surrounding and topical treatment, several systemic therapies such as anticonvulsives and antidepressants may be used in different pruritus-associated diseases due to similar chronification mechanisms. Novel insights into the neuro-biological mechanisms of chronic pruritus have led to new therapeutic approaches. Still we are currently far away from an optimal care of patients suffering from chronic pruritus.
CRIS-Team Scopus Importer:2021-04-20

Circadian profiling reveals higher histamine plasma levels and lower diamine oxidase serum activities in 24% of patients with suspected histamine intolerance compared to food allergy and controls - Pinzer, T. C.; Tietz, E.; Waldmann, Elisabeth; Schink, Monic; Neurath, Markus; Zopf, Yurdagül (Allergy, 2018)
BACKGROUND: Histamine intolerance is thought to trigger manifold clinical symptoms after ingesting histamine-rich food due to reduced activity of diamine oxidase (DAO). No study has hitherto systematically assessed daily fluctuations of histamine levels and DAO activities in symptomatic patients. The aim of the study was to investigate the presence of histamine intolerance, to therefore establish day profiles of histamine levels and DAO activities, and to compare the results between patients with suspected histamine intolerance, food allergy and healthy controls. METHODS: We determined day profiles of histamine plasma levels and DAO serum activities in 33 patients with suspected histamine intolerance, in 21 patients with proven food allergy and in 10 healthy control patients. Clinical symptoms, food intolerances and further clinical and laboratory chemical parameters were evaluated. RESULTS: Twenty-four percent (8 of 33) suspected histamine-intolerant patients showed elevated histamine levels during the day. That might be caused by constantly and significantly reduced DAO activities in these patients compared to food-allergic and control patients. The remaining 25 patients presented normal histamine levels and DAO activities, but an increased prevalence of multiple food intolerances compared to the other subgroup of suspected histamine-intolerants. There was no correlation between subjective complaints and serological histamine parameters in patients with suspected histamine intolerance. CONCLUSIONS: We determined by daily profiling that decreased DAO activities correlated with elevated histamine levels in a subgroup of suspected histamine-intolerants. This finding discriminates these patients from food intolerant individuals with similar clinical symptoms and strongly suggests the presence of histamine intolerance.
EVALuna2:34072

Circulating Adaptive Immune Cells Expressing the Gut Homing Marker α4β7 Integrin Are Decreased in COVID-19 - Müller, Tanja; Becker, Elisabeth; Wiendl, Maximilian; Schulze, Lisa; Voskens, Caroline; Kremer, Andreas; Neurath, Markus; Zundler, Sebastian; Völkl, Simon (Frontiers in Immunology, 2021)
Background: Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide range of symptoms including gastrointestinal manifestations, and intestinal epithelial cells are a target of the virus. However, it is unknown how the intestinal immune system contributes to systemic immune responses in coronavirus disease 2019 (COVID-19). Methods: We characterized peripheral blood lymphocytes from patients with active COVID-19 and convalescent patients as well as healthy controls by flow cytometry. Results: The frequency and absolute number of circulating memory T and B cells expressing the gut homing integrin α4β7 integrin was reduced during COVID-19, whether gastrointestinal symptoms were present or not. While total IgA-expressing B cells were increased, gut-imprinted B cells with IgA expression were stable. Conclusion: COVID-19 is associated with a decrease in circulating adaptive immune cells expressing the key gut homing marker α4β7 suggesting that these cells are preferentially recruited to extra-intestinal tissues independently of α4β7 or that the systemic immune response against SARS-CoV-2 is at least numerically dominated by extraintestinal, particularly pulmonary, immune cell priming.
CRIS-Team Scopus Importer:2021-05-21
Keywords: COVID-19; gut homing; integrins; SARS-CoV-2 infection; T cell trafficking

Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection - Torcellan, Tommaso; Friedrich, Christin; Doucet-Ladevèze, Rémi; Ossner, Thomas; Solé, Virgínia Visaconill; Riedmann, Sofie; Ugur, Milas; Imdahl, Fabian; Rosshart, Stephan Patrick; Arnold, Sebastian J.; Gomez de Agüero, Mercedes; Gagliani, Nicola; et al. (Immunity, 2024)
Natural killer (NK) cells are present in the circulation and can also be found residing in tissues, and these populations exhibit distinct developmental requirements and are thought to differ in terms of ontogeny. Here, we investigate whether circulating conventional NK (cNK) cells can develop into long-lived tissue-resident NK (trNK) cells following acute infections. We found that viral and bacterial infections of the skin triggered the recruitment of cNK cells and their differentiation into Tcf1hiCD69hi trNK cells that share transcriptional similarity with CD56brightTCF1hi NK cells in human tissues. Skin trNK cells arose from interferon (IFN)-γ-producing effector cells and required restricted expression of the transcriptional regulator Blimp1 to optimize Tcf1-dependent trNK cell formation. Upon secondary infection, trNK cells rapidly gained effector function and mediated an accelerated NK cell response. Thus, cNK cells redistribute and permanently position at sites of previous infection via a mechanism promoting tissue residency that is distinct from Hobit-dependent developmental paths of NK cells and ILC1 seeding tissues during ontogeny.
CRIS-Team Scopus Importer:2024-01-19
Keywords: infection; innate immune memory; innate lymphoid cells; natural killer cells; Staphylococcus aureus; tissue immunity; tissue-resident lymphocytes; trained immunity; vaccination; vaccinia virus

Citrullination licenses calpain to decondense nuclei in neutrophil extracellular trap formation - Goesswein, Stefanie; Lindemann, Aylin; Mahajan, Aparna; Maueröder, Christian; Martini, Eva; Patankar, Jay; Schett, Georg; Becker, Christoph; Wirtz, Stefan; Naumann-Bartsch, Nora; Bianchi, Marco E.; Greer, Peter A.; et al. (Frontiers in Immunology, 2019)
Neutrophils respond to various stimuli by decondensing and releasing nuclear chromatin characterized by citrullinated histones as neutrophil extracellular traps (NETs). This achieves pathogen immobilization or initiation of thrombosis, yet the molecular mechanisms of NET formation remain elusive. Peptidyl arginine deiminase-4 (PAD4) achieves protein citrullination and has been intricately linked to NET formation. Here we show that citrullination represents a major regulator of proteolysis in the course of NET formation. Elevated cytosolic calcium levels trigger both peptidylarginine deiminase-4 (PAD4) and calpain activity in neutrophils resulting in nuclear decondensation typical of NETs. Interestingly, PAD4 relies on proteolysis by calpain to achieve efficient nuclear lamina breakdown and chromatin decondensation. Pharmacological or genetic inhibition of PAD4 and calpain strongly inhibit chromatin decondensation of human and murine neutrophils in response to calcium ionophores as well as the proteolysis of nuclear proteins like lamin B1 and high mobility group box protein 1 (HMGB1). Taken together, the concerted action of PAD4 and calpain induces nuclear decondensation in the course of calcium-mediated NET formation.
CRIS-Team Scopus Importer:2019-11-15
Keywords: Calpain; Cell death; Chromatin; Citrullination; Neutrophil; Nucleus; PAD4

CLARINET FORTE Baseline Characteristics: Lanreotide Autogel 120 mg (LAN) Every 14 Days in Patients With Progressive Pancreatic or Midgut Neuroendocrine Tumors During a Standard First-Line LAN Regimen - Ruszniewski, Philippe; Cwikla, Jaroslaw; Lombard-Bohas, Catherine; Borbath, Ivan; Shah, Tahir; Pape, Ulrich -Frank; Xuan-Mai Truong Thanh,; Houchard, Aude; Pavel, Marianne Ellen (PANCREAS, 2020)
CRIS-Team WoS Importer:2020-05-02

Classification of Confocal Laser Endomicroscopic Images of the Oral Cavity to Distinguish Pathological from Healthy Tissue - Jaremenko, Christian; Maier, Andreas; Steidl, Stefan; Hornegger, Joachim; Oetter, Nicolai; Knipfer, Christian; Stelzle, Florian; Neumann, Helmut (Bildverarbeitung für die Medizin 2015, 2015)
Confocal laser endomicroscopy is a recently introduced advanced imaging technique which enables microscopic imaging of the mucosa in-vivo. This technique has already been applied successfully during diagnosis of gastrointestinal diseases. Whereas for this purpose several computer aided diagnosis approaches exist, we present a classification system that is able to differentiate between healthy and pathological images of the oral cavity. Varying textural features of small rectangular regions are evaluated using random forests and support vector machines. Preliminary results reach up to 99.2% classification rate. This indicates that an automatic classification system to differentiate between healthy and pathological mucosa of the oral cavity is feasible.
UnivIS-Import:2017-12-18:Pub.2015.tech.IMMD.IMMD5.classi_8

Clearance of primary necrotic cells by non-professional phagocytes - Schwegler, Manuela; Wirsing, Anna Maria; Dollinger, Alena J.; Abendroth, Benjamin; Putz, Florian; Fietkau, Rainer; Distel, Luitpold (Biology of the Cell, 2015)
Homotypic internalisation of tumour cells has frequently been observed in tumour tissue sections. Events of non-professional phagocytosis, however, may also occur in normal tissue if the number of dying cells exceeds the phagocytic capacity of professional phagocytes such as macrophages and dendritic cells. The aim of this study was to investigate the molecular background of non-professional phagocytosis of primary necrotic cells by neighbouring tumour cells and normal skin fibroblasts.We demonstrate that homotypic and heterotypic uptake of necrotic cells is a feature common to various cell types. Investigating critical stimuli of necrotic cell clearance we found that non-professional phagocytes require cytoskeleton rearrangement, recognition of phosphatidylserine and GTPase activity of dynamin II, which is normally engaged in endocytosis. Additionally, we have observed an accumulation of adhesion molecule E-cadherin, phosphorylated actin-linker protein ezrin, lysosomal-associated membrane protein 1 and microtubule-associated protein 1 light chain 3 at the site of engulfment. Loss of membrane integrity and an increase in the intracellular level of heat-shock protein 70 in the necrotic cells have also been observed.Our results shed light on the mechanism of necrotic cell removal by tumour cells and normal skin fibroblasts in vitro. It is reasonable to assume that this process has a physiological relevance in inflammation and autoimmune disease in normal tissue as well as in tumours regarding immune cell infiltration. We conclude that necrotic cell clearance by non-professional phagocytes contributes to the phagocytic activity by macrophages and that this process may prevent release of proinflammatory damage-associated molecular pattern molecules.
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CLINICAL AND VIROLOGICAL CHARACTERISTICS AND RETREATMENT OF HCV-INFECTED PATIENTS WITH FAILURE TO MULTIPLE SUBSEQUENT DAA THERAPIES - Dietz, Julia; Vermehren, Johannes; Peiffer, Kai-Henrik; Wietzke-Braun, Perdita; Muellhaupt, Beat; Schattenberg, Joern; Antoni, Christoph; Hametner, Stephanie; Mauss, Stefan; Heinzow, Hauke; Graf, Christiana; Port, Kerstin; et al. (HEPATOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-25

Clinical Characteristics of Influenza in Season 2017/2018 in a German Emergency Department: A Retrospective Analysis - Mohammad, Sonia; Korn, Klaus; Schellhaas, Barbara; Neurath, Markus; Görtz, Rüdiger (Microbiology Insights, 2019)
Introduction: Influenza infection is a viral disease with significant morbidity and mortality during the cold months. Clinical presentation typically includes cough, fever, and pain. Influenza disease is hardly diagnosed only on the basis of clinical symptoms due to similar clinical presentation of other diseases such as a typical cold or other flu-like diseases. We evaluated patients with proven influenza who presented at an emergency department of internal medicine in a university hospital according to the clinical presentation and different age groups. Materials and Methods: From October 2017 to April 2018, 723 reverse transcription-polymerase chain reaction (RT-PCR) tests for influenza were performed in the emergency department on patients with suspected influenza diagnosed clinically. A total of 240 influenza-positive patients were retrospectively assessed for documented main symptoms, vital parameters, risk factors for an unfavorable course, hospitalization, and death. Results: The mean age of influenza patients was 65 years. Overall, 30 patients were aged 18 to 39 years, 48 patients 40 to 59 years, and 162 patients ⩾60 years. Influenza B in 168 (70%) was predominant to 72 influenza A (mostly H1N1). In only 30% of the patients all three typical symptoms (cough, fever, and headache/myalgia) were documented. Headache or myalgia (with 34%) was rather uncommon in influenza B. Sudden onset was cited in only 5.4%; 57% of all influenza patients were in hospital for a mean of 7.1 days, and 5.8% of all influenza patients died. Patients aged above 60 years had more risk factors, showed typical symptoms less frequently, and were hospitalized longer than younger patients (<60 and <40 years). Conclusions: At an emergency department of internal medicine, influenza-diseased patients are of higher age, show an increased number of comorbidities, and are more likely to have milder symptoms documented. Elderly patients with influenza have a higher hospitalization rate with a longer hospital stay as compared with younger patients.
EVALuna2:212379

Clinical Effects of a Topically Applied Toll-like Receptor 9 Agonist in Active Moderate-to-Severe Ulcerative Colitis - Atreya, Raja; Bloom, Stuart; Scaldaferri, Franco; Gerardi, Viviana; Admyre, Charlotte; Karlsson, Asa; Knittel, Thomas; Kowalski, Jan; Lukas, Milan; Lofberg, Robert; Nancey, Stephane; Petryka, Robert; et al. (Journal of Crohns & Colitis, 2016)
Toll-like receptors [TLRs] are potential drug targets for immunomodulation. We determined the safety and efficacy of the TLR-9 agonist DNA-based immunomodulatory sequence 0150 [DIMS0150] in ulcerative colitis [UC] patients refractory to standard therapy.In this randomized, double-blind, placebo-controlled trial, 131 patients with moderate-to-severe active UC were randomized to receive two single doses of the oligonucleotide DIMS0150 [30 mg] or placebo administered topically during lower GI endoscopy at baseline and Week 4. The primary endpoint was clinical remission, defined as Clinical Activity Index [CAI] <=4, at Week 12. Secondary endpoints included mucosal healing and symptomatic remission of key patient-reported outcomes [absence of blood in stool and weekly stool frequency <35].There was no statistical significant difference between the groups in the induction of clinical remission at Week 12, with 44.4% in the DIMS0150 group vs. 46.5% in the placebo group. However, the proportion of patients who achieved symptomatic remission was 32.1% in the DIMS0150 group vs. 14.0% in the placebo group at Week 4 [p = 0.020], and 44.4% vs. 27.9% at Week 8 [p = 0.061]. More patients on DIMS0150 compared with those on placebo had mucosal healing [34.6% vs. 18.6%; p = 0.09] and histological improvement regarding the Geboes score [30.9% vs. 9.3%; p = 0.0073] at Week 4. Significantly more patients on DIMS0150 were in clinical remission with mucosal healing at Week 4: 21% vs. 4.7% in the placebo group [p = 0.02]. DIMS0150 was well tolerated, and no safety signals compared with placebo were evident.Therapy with the topically applied TLR-9 agonist DIMS0150 is a promising and well-tolerated novel therapeutic option for treatment-refractory, chronic active UC patients, warranting further clinical trials.
EVALuna2:2191

Clinical efficacy of the Toll-like receptor 9 agonist cobitolimod using patient-reported-outcomes defined clinical endpoints in patients with ulcerative colitis - Atreya, Raja; Reinisch, Walter; Peyrin-Biroulet, Laurent; Scaldaferri, Franco; Admyre, Charlotte; Knittel, Thomas; Kowalski, Jan; Neurath, Markus; Hawkey, Christopher (Digestive and Liver Disease, 2018)
BACKGROUND: The Toll-like-receptor 9 (TLR-9) agonist cobitolimod (DIMS0150, Kappaproct®) is a promising therapeutic option for ulcerative colitis (UC) patients. AIMS: The objectives of this post-hoc analysis using the COLLECT study data was to investigate the clinical effects of cobitolimod using patient-reported-outcomes (PRO) defined endpoints. METHODS: Dual topical administration of cobitolimod was studied in a randomised, multicentre clinical trial named COLLECT in moderate-to-severe UC patients. Symptomatic remission (SR) was studied in 104 patients based on their e-diary records and was defined as absence of blood in stool and a mean daily stool frequency (SF) < 4. RESULTS: SR was achieved at week 4 in 17.1% of cobitolimod vs. 5.9% of placebo treated patients (p = 0.13), at week 8 in 35.7% vs. 17.6% (p = 0.07), and at week 12 in 38.6% vs. 17.6% (p = 0.04) of the patients, respectively. SR rates with cobitolimod and placebo in anti-TNFα experienced patients were smaller but with a broadly similar relative effect-size to anti-TNFα naïve patients. Clinical efficacy was higher in patients with moderate compared to severe disease. CONCLUSIONS: Application of the Toll-like-receptor 9 (TLR-9) agonist cobitolimod is able to induce remission as assessed by PRO measures in UC patients with moderate-to-severe activity as well as in anti-TNFα experienced and naïve patients supporting the overall efficacy of the substance.
EVALuna2:35138

Clinical experiences and predictors of success of treatment with vedolizumab in IBD patients: a cohort study - Mühl, Laura; Becker, Elisabeth; Müller, Tanja; Atreya, Raja; Atreya, Imke; Neurath, Markus; Zundler, Sebastian (BMC Gastroenterology, 2021)
Background: Vedolizumab has become a standard treatment for the inflammatory bowel diseases ulcerative colitis (UC) and Crohn’s disease (CD). However, there is an ongoing debate on the ideal individual treatment algorithms and means to predict treatment response are not routinely established. Aims: We aimed to describe our experiences with vedolizumab at a large German tertiary referral center and to identify clinical predictors of success of vedolizumab treatment. Methods: We performed a retrospective single-center cohort study employing univariable and multivariable analyses as well as Kaplan–Meier analyses of persistence on treatment. Results: 36% and 35% of the patients with UC and CD, respectively, reached clinical remission after 17 weeks. Patients with lower clinical disease activity were more likely to achieve remission. The median persistence on treatment was 33 months for UC and 29 months for CD. Conclusion: Our study confirms that vedolizumab is an efficient option for the treatment of UC and CD. Clinical parameters of disease activity may help to predict the success of treatment.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Inflammatory bowel diseases; Real-world data; Vedolizumab

Clinical Images: Voriconazole-induced synovitis, enthesitis, and periostitis - Valor-Méndez, Larissa; Wacker, Jochen; Schett, Georg; Manger, Bernhard; Fürst, Julia; Strauss, Richard; Kleyer, Arnd (Arthritis and Rheumatology, 2022)
CRIS-Team Scopus Importer:2022-07-08

Clinical Impact of the Current WHO Classification of Pituitary Adenomas - Saeger, W.; Honegger, J.; Theodoropoulou, M.; Knappe, U. J.; Schöfl, Christof; Petersenn, S.; Buslei, R. (Endocrine Pathology, 2016)
WHO classifications should be used for comparing the results from different groups of pathologist and clinicians by standardized histopathological methods. Our present report describes the important parameters of pituitary adenoma pathology as demand of the WHO classification for correlation to endocrine data and prognosis. The combination of HE stain based structures with immunostainings for pituitary hormones allows subclassification of adenomas as the best method not only for correlations to clinical hyperfunctions but also for statements to the sensitivity of drug therapies (somatostatin analogs, dopamine agonists). GH-, PRL- and ACTH-secreting pituitary adenomas are further classified based on the size and number of their secretory granules by electron microscopy, or as is mostly the case nowadays by cytokeratin staining pattern, into densely and sparsely granulated. Granulation pattern may be considered for the prediction of treatment response in patients with GH-secreting adenomas, since the sparsely granulated subtype was shown to be less responsive to somatostatin analog treatment. For prognosis, it is important to identify aggressive adenomas by measurements of the Ki-67 index, of the number of mitoses, and of nuclear expression of p53. Among the criteria for atypical adenomas, high Ki-67 labeling index and invasive character are the most important adverse prognostic factors. Promising molecular markers have been identified that might supplement the currently used proliferation parameters. For defining atypical adenomas in a future histopathological classification system, we propose to provide the proliferative potential and the invasive character separately.
EVALuna2:7318

Clinical management of pruritus - Staender, Sonja; Zeidler, Claudia; Magnolo, Nina; Raap, Ulrike; Mettang, Thomas; Kremer, Andreas; Weisshaar, Elke; Augustin, Matthias (Journal der Deutschen Dermatologischen Gesellschaft, 2015)
The care of patients with chronic pruritus as a symptom of a wide variety of underlying diseases continues to confront dermatologists with diagnostic and therapeutic challenges. However, a structured history and a physical examination may already substantially help in narrowing down the number of potential differential diagnoses. Apart form reducing the intensity of pruritus, identification and appropriate treatment of the underlying disease are important needs of patients. If these goals doesn't lead to improvement of itch, current guidelines provide a number of topical and systemic therapies for symptomatic treatment. Various skin lesions (for example, xerosis caused by irritant substances, secondary scratch lesions) prompt patients to consult a dermatologist, but most cases require an interdisciplinary therapeutic approach to identify potential internal medicine, neurologic, or psychosomatic aspects. Although great strides have been made in basic research, specific therapies are still rare, and a precise knowledge of the legal framework for the implementation of guidelines (for example, off-label use) is essential. This CME article gives an overview of the causes of and treatment options for chronic pruritus and discusses both advances in basic research as well as progress in clinical knowledge.
EVALuna2:1994

Clinical outcome of personalised treatment guided by genome and transcriptome sequencing in patients with neuroendocrine neoplasms: Updated results from the German NCT/DKTK MASTER trial - Kreutzfeldt, S.; Apostolidis, L.; Oles, M.; Horak, P.; Heilig, C. E.; Heining, C.; Hutter, B.; Klink, B.; Lamping, M.; Uhrig, S.; Stenzinger, A.; Winkler, E. C.; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-29

Clinical outcomes and immunogenicity analysis over 6 months following a switch from originator infliximab (Remicade (R)) to the biosimilar SB2 (Flixabi (R)) in inflammatory bowel disease patients - Fischer, Sven Moritz; Klenske, E.; Schmitt, H.; Vitali, Francesco; Hirschmann, S.; Koch, F.; Ramming, A.; Zundler, Sebastian; Nagore, D.; Uter, Wolfgang; Neurath, Markus; Atreya, Raja (2018)
EVALuna2:34075

Clinical presentation, disease course, and outcome of COVID-19 in hospitalized patients with and without pre-existing cardiac disease: a cohort study across 18 countries - Linschoten, M.; Uijl, A.; Schut, A.; Jakob, C. E. M.; Romao, L. R.; Bell, R. M.; Mcfarlane, E.; Stecher, M.; Zondag, A. G. M.; Van Iperen, E. P. A.; Hermans-Van Ast, J. F.; Lea, N. C.; et al. (European Heart Journal, 2022)
Aims Patients with cardiac disease are considered high risk for poor outcomes following hospitalization with COVID-19. The primary aim of this study was to evaluate heterogeneity in associations between various heart disease subtypes and in-hospital mortality.
CRIS-Team WoS Importer:2022-04-08

Clinical relevance of comprehensive genomic analysis in patients with advanced-stage neuroendocrine neoplasms: Results from the MASTER trial of the German Cancer Consortium - Kreutzfeldt, Simon; Apostolidis, Leonidas; Oles, Malgorzata; Horak, Peter; Heilig, Christoph E.; Heining, Christoph; Hutter, Barbara; Gieldon, Laura; Klink, Barbara; Lamping, Mario; Rieke, Damian T.; Uhrig, Sebastian; et al. (CANCER RESEARCH, 2019)
CRIS-Team WoS Importer:2019-10-15

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

Cobitolimod for moderate-to-severe, left-sided ulcerative colitis (CONDUCT): a phase 2b randomised, double-blind, placebo-controlled, dose-ranging induction trial - Atreya, Raja; Peyrin-Biroulet, Laurent; Klymenko, Andrii; Augustyn, Monica; Bakulin, Igor; Slankamenac, Dusan; Miheller, Pal; Gasbarrini, Antonio; Hébuterne, Xavier; Arnesson, Karin; Knittel, Thomas; Kowalski, Jan; et al. (Lancet Gastroenterology and Hepatology, 2020)
Background: Cobitolimod is a topically administered, DNA-based oligonucleotide that activates Toll-like receptor 9 (TLR9), and previous research has shown clinical efficacy in patients with moderate-to-severe ulcerative colitis. Here we assessed the efficacy and safety of different dose regimens of cobitolimod for induction therapy in patients with moderate-to-severe, left-sided ulcerative colitis. Methods: CONDUCT was a randomised, double-blind, five-arm, placebo-controlled, dose-ranging phase 2b study that recruited patients with moderate-to-severe, left-sided ulcerative colitis, with inadequate response to conventional or biological therapies, from 91 hospitals or outpatient clinics in 12 European countries. Eligible patients had a Mayo score of 6–12 with a centrally read endoscopic subscore (modified to exclude friability from grade 1) of 2 or higher and no individual subscore of less than 1, and confirmation of left-sided disease. Patients were randomised (1:1:1:1:1; block size of ten) via a computer-generated schedule and centralised interactive voice and web response system to receive rectal enemas of cobitolimod at 31 mg, 125 mg, or 250 mg at weeks 0 and 3 (2 × 31 mg, 2 × 125 mg, and 2 × 250 mg groups), cobitolimod at 125 mg at weeks 0, 1, 2, and 3 (4 × 125 mg group), or placebo. Randomisation was stratified by current glucocorticosteroid and previous tumour necrosis factor inhibitor treatment. Patients and all study personnel were masked to treatment allocation. The primary endpoint was the proportion of patients achieving clinical remission (Mayo subscores for rectal bleeding of 0, for stool frequency of 0 or 1 [with ≥1-point decrease from baseline], and for endoscopy of 0 or 1 [excluding friability]) at week 6. The primary analysis (based on intention to treat) and safety analysis were done in all randomly assigned patients who received at least one dose of active study drug or placebo. In this exploratory study, statistical tests were one-sided; p values of less than 0·10 were regarded as statistically significant, with no adjustment for multiplicity. This study is registered with ClinicalTrials.gov, NCT03178669, and is completed; the results here represent the final analysis. Findings: 213 patients were randomly assigned between June 30, 2017, and June 26, 2019. Of these, 211 patients received study treatment: 40 in the cobitolimod 2 × 31 mg group, 43 in the 2 × 125 mg group, 42 in the 4 × 125 mg group, 42 in the 2 × 250 mg group, and 44 in the placebo group. A greater proportion of patients were in clinical remission at week 6 in the cobitolimod 2 × 250 mg group than in the placebo group (nine [21%] of 42 patients vs three [7%] of 44; odds ratio [OR] 3·8 [80% CI 1·5–9·5]; one-sided p=0·025). We identified no significant difference in the proportion of patients with clinical remission in the cobitolimod 2 × 31 mg group (five [13%] of 40 patients; OR 2·0 [80% CI 0·7–5·5], p=0·18), 2 × 125 mg group (two [5%] of 43; 0·7 [0·2–2·2], p=0·66), or 4 × 125 mg (four [10%] of 42; 1·4 [0·5–3·9], p=0·33) compared with the placebo group. Treatment-emergent adverse events occurred in 21 (48%) patients in the placebo group, ten (25%) patients in the cobitolimod 2 × 31 mg group, 17 (40%) patients in the 2 × 125 mg group, 15 (36%) patients in the 4 × 125 mg group, and 18 (43%) patients in the 2 × 250 mg group. Severe adverse events occurred in eight (4%) of 211 patients (worsening of ulcerative colitis [seven patients] and abdominal hernia and wound dehiscence [one patient]). Ten patients (two [5%] in the placebo group, two [5%] in the cobitolimod 2 × 31 mg group, two [5%] in the 4 × 125 mg, and four [10%] in the 2 × 250 mg group) had a total of 13 serious adverse events; these were worsening of ulcerative colitis (eight events) and pruritus, rash, abdominal hernia, fascia dehiscence, and deep vein thrombosis (one event each). One patient in the placebo group died from total organ failure after receiving a colectomy for a serious adverse event of disease worsening. Interpretation: Two topical administrations of cobitolimod 250 mg were well tolerated and more effective than placebo in inducing clinical remission 6 weeks after the start of treatment. TLR9 activation is a promising novel therapeutic target in ulcerative colitis and warrants further testing, with phase 3 trials of cobitolimod planned. Funding: InDex Pharmaceuticals.
CRIS-Team Scopus Importer:2020-11-13

Cobitolimod for Moderate-to-Severe Left-Sided Ulcerative Colitis (CONDUCT): A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Trial - Atreya, Raja; Peyrin-Biroulet, Laurent; Klymenko, Andrii; Augustyn, Monica; Bakulin, Igor; Slankamenac, Dusan; Miheller, Pal; Gasbarrini, Antonio; Hebuterne, Xavier; Arnesson, Karin; Knittel, Thomas; Kowalski, Jan; et al. (AMERICAN JOURNAL OF GASTROENTEROLOGY, 2020)
CRIS-Team WoS Importer:2021-02-12

Cold or hot snare in endoscopy - that is the question - Vieth, Michael; Neurath, Markus (Endoscopy International Open, 2022)
In the current issue of Endoscopy International Open, Ikeda et al. [1] present a feasibility study on cold snare removal of colonic polyps. The aim was to elucidate whether the quality of the cold snare specimens can be increased by placing the tissues on filter pape
CRIS-Team WoS Importer:2022-05-27

Colitis-associated neoplasia: molecular basis and clinical translation - Försch, Sebastian; Neurath, Markus (Cellular and Molecular Life Sciences, 2014)
Crohn's disease and ulcerative colitis are both associated with an increased risk of inflammation-associated colorectal carcinoma. Colitis-associated cancer (CAC) is one of the most important causes for morbidity and mortality in patients with inflammatory bowel diseases (IBD). Colitis-associated neoplasia distinctly differs from sporadic colorectal cancer in its biology and the underlying mechanisms. This review discusses the molecular mechanisms of CAC and summarizes the most important genetic alterations and signaling pathways involved in inflammatory carcinogenesis. Then, clinical translation is evaluated by discussing new endoscopic techniques and their contribution to surveillance and early detection of CAC. Last, we briefly address different types of concepts for prevention (i.e., anti-inflammatory therapeutics) and treatment (i.e., surgical intervention) of CAC and give an outlook on this important aspect of IBD.
EVALuna2:1861

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

Colonoscopy, inflammatory bowel disease - Neumann, Helmut; Neurath, Markus (Endoscopy, 2014)
EVALuna2:1891

Combined de‐repression of chemoresistance associated mitogen‐activated protein kinase 14 and activating transcription factor 2 by loss of microrna‐622 in hepatocellular carcinoma - Fritz, Valerie; Malek, Lara; Gaza, Anne; Wormser, Laura; Appel, Majken; Kremer, Andreas; Thasler, Wolfgang E.; Neurath, Markus; Hellerbrand, Claus; Boßerhoff, Anja Katrin; Dietrich, Peter; Siebler, Jürgen (Cancers, 2021)
Chemoresistance is a major hallmark driving the progression and poor prognosis of hepatocellular carcinoma (HCC). Limited chemoresponse of HCC was demonstrated to be mediated by mitogen‐activated protein kinase 14 (MAPK14) and activating transcription factor 2 (ATF2). Recently, we have demonstrated loss of control of RAS‐RAF‐ERK‐signaling as a consequence of miR‐622 downregulation in HCC. However, the majority of target genes of this potent tumorsuppressive microRNA had remained elusive. The MAPK14‐ATF2‐axis represents a collateral pathway ensuring persisting ERK‐activation in the presence of sorafenib‐mediated RAF-inhibition. In contrast to the function of the MAPK14‐ATF2‐axis, both the expression and regulation of MAPK14 and ATF2 in human HCC remained to be clarified. We found combined overexpression of MAPK14 and ATF2 in human HCC cells, tissues and in sorafenib resistant cell lines. High expression of MAPK14 and ATF2 was associated with reduced overall survival in HCC patients. Deciphering the molecular mechanism promoting combined upregulation of MAPK14 and ATF2 in HCC, we revealed that miR‐622 directly targets both genes, resulting in combined de‐repression of the MAPK14‐ATF2‐axis. Together, miR‐622 represents a superior regulator of both RAS‐RAF‐ERK as well as MAPK14‐ATF2‐signaling pathways in liver cancer.
CRIS-Team Scopus Importer:2021-03-19
Keywords: HCC; Hepatocellular carcinoma; Liver cancer; MAPK14; MicroRNA; MiR‐622; RAS

Combined effects of PLK1 and RAS in hepatocellular carcinoma reveal rigosertib as promising novel therapeutic "dual-hit" option - Dietrich, Peter; Freese, Kim; Mahli, Abdo; Thasler, Wolfgang Erwin; Hellerbrand, Claus; Boßerhoff, Anja Katrin (Oncotarget, 2018)
Inhibition of RAS-RAF-ERK-signaling is a major mechanism mediated by the multi-kinase inhibitors sorafenib and regorafenib, the only effective therapeutic approaches for advanced hepatocellular carcinoma (HCC). This underlines the importance of RAS-RAF-ERK-signaling in HCC. Most RAS isoforms were not yet described to play crucial roles in HCC. However, several studies indicate that the HRAS isoform can function as potent oncogene in HCC, but pharmacologic RAS inhibition has not yet been investigated. Moreover, the cell cycle promoting polo-like kinase 1 (PLK1) is an increasingly recognized therapeutic target in HCC that can be activated by RAS-RAF-signaling. A recently developed small molecule inhibitor, ON-01910 ("rigosertib", RGS), was shown to interfere with both RAS- and PLK1-signaling. The aim of this study was to analyze the effects of RGS in HCC and to assess PLK1 and HRAS expression in HCC. RGS treatment reduced cell proliferation and induced cell cycle arrest in human HCC cell lines in vitro. Moreover, RGS strongly inhibited both ERK- and AKT-activation in HCC cells, indicating disruption of RAS-signaling. Analysis of HCC patient data showed that PLK1 and HRAS expression levels are upregulated during HCC development and in advanced HCC, respectively. High expression levels of PLK1 significantly correlated with poor patient survival. Moreover, high expression of both PLK1 and HRAS revealed combined effects on patient outcome. This underscores the importance of these genes and associated pathways in HCC. We newly demonstrate the therapeutic potential of RGS in HCC by inhibition of both PLK1 activation and major RAS-pathways, revealing a novel therapeutic "dual-hit" approach for HCC.
EVALuna2:34067

Combined lanreotide autogel and temozolomide in progressive neuroendocrine tumours: an interim safety analysis of the SONNET study - Hoersch, D.; Raderer, M.; Lahner, H.; Rinke, A.; Denecke, T.; Koch, A.; Raspel, A.; Naschold, B.; Houchard, A.; Pavel, Marianne Ellen (2017)
EVALuna2:34127

Comparative efficacy and safety of infliximab and vedolizumab therapy in patients with inflammatory bowel disease: a systematic review and meta-analysis - Peyrin-Biroulet, Laurent; Arkkila, Perttu; Armuzzi, Alessandro; Danese, Silvio; Guardiola, Jordi; Jahnsen, Jorgen; Lees, Charles; Louis, Edouard; Lukas, Milan; Reinisch, Walter; Roblin, Xavier; Jang, Minyoung; et al. (BMC Gastroenterology, 2022)
Background and aims There are limited comparative data for infliximab and vedolizumab in inflammatory bowel disease patients. Methods We conducted a systematic review and meta-analysis to compare the efficacy and safety of infliximab and vedolizumab in adult patients with moderate-to-severe Crohn's disease or ulcerative colitis. Results We identified six eligible Crohn's disease and seven eligible ulcerative colitis trials that randomised over 1900 participants per disease cohort to infliximab or vedolizumab. In the Crohn's disease and ulcerative colitis cohorts, infliximab yielded better efficacy than vedolizumab for all analysed outcomes (CDAI-70, CDAI-100 responses, and clinical remission for Crohn's disease and clinical response and clinical remission for ulcerative colitis) during the induction phase, with non-overlapping 95% confidence intervals. In the maintenance phase, similar proportions of infliximab- or vedolizumab-treated patients achieved clinical response, clinical remission, or mucosal healing in both Crohn's disease and ulcerative colitis. For the safety outcomes, rates of adverse events, serious adverse events, and discontinuations due to adverse events were similar in infliximab- and vedolizumab-treated patients in both diseases. The infection rate was higher in infliximab for Crohn's disease and higher in vedolizumab when treating patients with ulcerative colitis. There was no difference between the treatments in the proportions of patients who reported serious infections in both indications. Conclusions Indirect comparison of infliximab and vedolizumab trials in adult patients with moderate-to severe Crohn's disease or ulcerative colitis demonstrated that infliximab has better efficacy in the induction phase and comparable efficacy during the maintenance phase and overall safety profile compared to vedolizumab.
CRIS-Team WoS Importer:2022-06-24

Comparative real-world effectiveness and persistence of vedolizumab versus anti-TNF therapy in biologic-naive patients with Crohn's Disease with Propensity Score adjustment: Maintenance phase results at week-52 from the prospective VEDOIBD study - Di Giuseppe, R.; Plachta-Danielzik, S.; Bokemeyer, B.; Efken, P.; Mohl, W.; Hoffstadt, M.; Krause, T.; Schweitzer, A.; Schnoy, E.; Atreya, Raja; Teich, N.; Trentmann, L.; et al. (JOURNAL OF CROHNS & COLITIS, 2022)
CRIS-Team WoS Importer:2022-05-13

Comparative Transcriptomics of IBD Patients Indicates Induction of Type 2 Immunity Irrespective of the Disease Ideotype - Gonzalez Acera, Miguel; Patankar, Jay; Diemand, Leonard; Siegmund, Britta; Neurath, Markus; Wirtz, Stefan; Becker, Christoph (Frontiers in Medicine, 2021)
Inflammatory cytokines initiate and sustain the perpetuation of processes leading to chronic inflammatory conditions such as inflammatory bowel diseases (IBD). The nature of the trigger causing an inflammatory reaction decides whether type 1, type 17, or type 2 immune responses, typically characterized by the respective T- helper cell subsets, come into effect. In the intestine, Type 2 responses have been linked with mucosal healing and resolution upon an immune challenge involving parasitic infections. However, type 2 cytokines are frequently elevated in certain types of IBD in particular ulcerative colitis (UC) leading to the assumption that Th2 cells might critically support the pathogenesis of UC raising the question of whether such elevated type 2 responses in IBD are beneficial or detrimental. In line with this, previous studies showed that suppression of IL-13 and other type 2 related molecules in murine models could improve the outcomes of intestinal inflammation. However, therapeutic attempts of neutralizing IL-13 in ulcerative colitis patients have yielded no benefits. Thus, a better understanding of the role of type 2 cytokines in regulating intestinal inflammation is required. Here, we took a comparative transcriptomic approach to address how Th2 responses evolve in different mouse models of colitis and human IBD datasets. Our data show that type 2 immune-related transcripts are induced in the inflamed gut of IBD patients in both Crohn's disease and UC and across widely used mouse models of IBD. Collectively our data implicate that the presence of a type 2 signature rather defines a distinct state of intestinal inflammation than a disease-specific pathomechanism.
CRIS-Team Scopus Importer:2021-06-25
Keywords: chronic inflammation; IBD; intestine; type 2 immunity; ulcerative colitis

Comparing the effects of isocaloric oral and i.v. application of nutrient solutions on olfactory functioning - Bachlechner, Stephan; Denzer-Lippmann, M.; Wielopolski, Jan; Fische, Mr; Büttner, Andrea; Dörfler, Arnd; Schöfl, Christof; Münch, Georg; Kornhuber, Johannes; Thürauf, Norbert (2016)
EVALuna2:33154

Comparison of Acoustic Radiation Force Impulse (ARFI) Elastography Measurements with the 4C1 Transducer to the 6C1HD Transducer: A Phantom and Patient Study - Pfeifer, Lukas; Görtz, Rüdiger; Neurath, Markus; Strobel, Deike; Wildner, Dane (Ultraschall in der Medizin, 2016)
Purpose: The aim of this study was to evaluate whether acoustic radiation force impulse (ARFI) elastography done with the 4C1 probe yields comparable results to the recently introduced 6C1HD probe. Materials and Methods: Measurements with the 4C1 and 6C1HD probes (Acuson S2000) were performed and compared in four different inclusions of an elasticity phantom model (QA049 CIRS) as well as in the liver of healthy individuals and patients with liver cirrhosis. Results: Measurements with the 6C1HD probe were slightly higher in all phantom inclusions (8, 14, 45, 80kPA) with a mean of 1.48 m/s (95 %-CI; 1.47 - 1.49), 2.18 m/s (95 %-CI; 2.17 - 2.19), 3.61 m/s (95 %-CI; 3.57 - 3.64) and 4.34 m/s (95 %-CI; 4.29 - 4.39) compared to the 4C1 transducer with 1.46 m/s (95 %-CI; 1.45 - 1.47), 2.15 m/s (95 %-CI; 2.14 - 2.16), 3.39 m/s (95 %-CI; 3.37 - 3.41) and 3.98 m/s (95 %-CI; 3.75 - 4.21), respectively (p = 0.04, p < 0.01, p < 0.01, p < 0.01). Cirrhotic patients (n = 40) had a higher mean shear wave speed with 3.00 m/s (95 %-CI; 2.80 - 3.21) with the 6C1HD transducer compared to 2.81 m/s (95 %-CI; 2.64 - 2.99) with the 4C1 transducer (p = 0.03). Healthy individuals (n = 20) had a mean shear wave speed of 1.12 m/s (95 %-CI; 1.06 - 1.17) with the 6C1HD probe and 1.12 m/s (95 %-CI; 1.05 - 1.19) with the 4C1 probe (p = 0.96). Conclusion: ARFI values assessed with a 6C1HD transducer are slightly higher than measurements with a 4C1 transducer in an ARFI phantom and in patients with liver cirrhosis. As the difference is small, current cut-off values keep their usefulness but should be interpreted with caution if measurements are close to the cut-off.
EVALuna2:2195

Comparison of Choi, RECIST and Somatostatin Receptor PET/CT Based Criteria for the Evaluation of Response and Response Prediction to PRRT - Zwirtz, Kevin; Hardt, Juliane; Acker, Gueliz; Baur, Alexander D. J.; Pavel, Marianne Ellen; Huang, Kai; Brenner, Winfried; Prasad, Vikas (Pharmaceutics, 2022)
Aim: The most suitable method for assessment of response to peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NET) is still under debate. In this study we aimed to compare size (RECIST 1.1), density (Choi), Standardized Uptake Value (SUV) and a newly defined ZP combined parameter derived from Somatostatin Receptor (SSR) PET/CT for prediction of both response to PRRT and overall survival (OS). Material and Methods: Thirty-four NET patients with progressive disease (F:M 23:11; mean age 61.2 y; SD +/- 12) treated with PRRT using either Lu-177 DOTATOC or Lu-177 DOTATATE and imaged with Ga-68 SSR PET/CT approximately 10-12 weeks prior to and after each treatment cycle were retrospectively analyzed. Median duration of follow-up after the first cycle was 63.9 months (range 6.2-86.2). A total of 77 lesions (2-8 per patient) were analyzed. Response assessment was performed according to RECIST 1.1, Choi and modified EORTC (MORE) criteria. In addition, a new parameter named ZP, the product of Hounsfield unit (HU) and SUVmean (Standard Uptake Value) of a tumor lesion, was tested. Further, SUV values (max and mean) of the tumor were normalized to SUV of normal liver parenchyma. Tumor response was defined as CR, PR, or SD. Gold standard for comparison of baseline parameters for prediction of response of individual target lesions to PRRT was change in size of lesions according to RECIST 1.1. For prediction of overall survival, the response after the first and second PRRT were tested. Results: Based on RECIST 1.1, Choi, MORE, and ZP, 85.3%, 64.7%, 61.8%, and 70.6% achieved a response whereas 14.7%, 35.3%, 38.2%, and 29.4% demonstrated PD (progressive disease), respectively. Baseline ZP and ZPnormalized were found to be the only parameters predictive of lesion progression after three PRRT cycles (AUC ZP 0.753; 95% CI 0.6-0.9, p 0.037; AUC ZPnormalized 0.766; 95% CI 0.6-0.9; p 0.029). Based on a cut-off-value of 1201, ZP achieved a sensitivity of 86% and a specificity of 67%, while ZPnormalized reached a sensitivity of 86% and a specificity of 76% at a cut-off-value of 198. Median OS in the total cohort was not reached. In univariate analysis amongst all parameters, only patients having progressive disease according to MORE after the second cycle of PRRT were found to have significantly shorter overall survival (median OS in objective responders not reached, in PD 29.2 months; p 0.015). Patients progressive after two cycles of PRRT according to ZP had shorter OS compared to those responding (median OS for responders not reached, for PD 47.2 months, p 0.066). Conclusions: In this explorative study, we showed that Choi, RECIST 1.1, and SUVmax-based response evaluation varied significantly from each other. Only patients showing progressive disease after two PRRT cycles according to MORE criteria had a worse prognosis while baseline ZP and ZPnormalized performed best in predicting lesion progression after three cycles of PRRT.
CRIS-Team WoS Importer:2022-07-08

Comparison of Hemospray® and Endoclot™ for the treatment of gastrointestinal bleeding - Vitali, Francesco; Naegel, Andreas; Atreya, Raja; Zopf, Steffen; Neufert, Clemens; Neurath, Markus; Rath, Timo; Siebler, Jürgen (World Journal of Gastroenterology, 2019)
BACKGROUND Gastrointestinal (GI) bleeding is a common indication for endoscopy. For refractory cases, hemostatic powders (HP) represent “touch-free” agents. AIM To analyze short term (ST-within 72 h-) and long-term (LT-within 30 d-) success for achieving hemostasis with HP and to directly compare the two agents Hemospray (HS) and Endoclot (EC). METHODS HP was applied in 154 consecutive patients (mean age 67 years) with GI bleeding. Patients were followed up for 1 mo (mean follow-up: 3.2 mo). RESULTS Majority of applications were in upper GI tract (89%) with following bleeding sources: peptic ulcer disease (35%), esophageal varices (7%), tumor bleeding (11.7%), reflux esophagitis (8.7%), diffuse bleeding and erosions (15.3%). Overall ST success was achieved in 125 patients (81%) and LT success in 81 patients (67%). Re-bleeding occurred in 27% of all patients. In 72 patients (47%), HP was applied as a salvage hemostatic therapy, here ST and LT success were 81% and 64%, with re-bleeding in 32%. As a primary hemostatic therapy, ST and LT success were 82% and 69%, with re-bleeding occurring in 22%. HS was more frequently applied for upper GI bleeding (P = 0.04) CONCLUSION Both HP allow for effective hemostasis with no differences in ST, LT success and re-bleeding.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Endoclot; Gastrointestinal bleeding; Haemostasis; Hemospray; Hemostatic powder

Comparison of Hemospray (R) and Endoclot (TM) for the treatment of gastrointestinal bleeding - Vitali, Francesco; Naegel, Andreas; Atreya, Raja; Zopf, Steffen; Neufert, Clemens; Neurath, Markus; Rath, Timo; Siebler, Jürgen (World Journal of Gastroenterology, 2019)
BACKGROUND
CRIS-Team WoS Importer:2019-04-16

COMPARISON OF INFLAMMATION DURING METABOLIC CHANGES IN RHEUMATOID AND OSTEOARTHRITIS MOUSE MODELS - Sauermilch, H. M.; Hulser, M. L.; Schreiyaeck, C.; Luo, Y.; Bozec, Aline; Schett, Georg; Mueller-Ladner, U.; Neumann, E. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Comparison of PD-L1 mRNA Expression Measured with the CheckPoint Typer® Assay with PD-L1 Protein Expression Assessed with Immunohistochemistry in Non-small Cell Lung Cancer - Erber, Ramona; Stoehr, Robert; Herlein, Stefanie; Giedl, Claudia; Rieker, Ralf; Fuchs, Florian; Ficker, Joachim H.; Hartmann, Arndt; Veltrup, Elke; Wirtz, Ralph M.; Brueckl, Wolfgang M. (Anticancer Research, 2017)
Immunohistochemical (IHC) assessment of programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) has become important since the development of anti-PD-1/-PD-L1 directed drugs. Various PD-L1 antibodies and cut-offs have been used in different trials to predict response to these drugs, thus comparison of those studies is difficult. We compared PD-L1 mRNA expression measured by RT-qPCR with PD-L1 protein expression evaluated by IHC. Moreover, we investigated the impact of different tumour tissue acquisition methods on the reliability of PD-L1 measurement techniques.NSCLC cases (N=22), including n=9 mediastinal lymph node biopsies acquired by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and n=5 metastases, were evaluated prospectively for PD-L1 protein on tumor cells (TC) and immune cells (IC) using E1L3N and 28-8 antibodies and PD-L1 mRNA using the CheckPoint TYPER® assay.In primary NSCLC tissues, agreement between PD-L1 mRNA and TC staining using the 28-8 antibody was excellent (?=0.85, p=0.0002). Comparing both PD-L1 antibodies against each other showed a kappa value of 0.58 (p=0.0106). In EBUS-TBNA, PD-L1 mRNA correlated perfectly with the 28-8 antibody (?=1.0, p=0.0023). PD-L1 mRNA levels significantly differed when comparing 28-8 TC staining of tumours >49% with 1-49% and 0% (p=0.0040; p=0.0081, respectively). In metastatic lesions, differences between PD-L1 mRNA and IHC became apparent (?=0.2, p=0.2525).Testing of PD-L1 mRNA and 28-8 IHC showed an excellent agreement in NSCLC samples including mediastinal lymph node biopsies. Since PD-L1 expression in >50% TC detected by 28-8 IHC can be reliably detected by RT-qPCR, quantitative PD-L1 mRNA determination should be considered as an alternative to IHC as there is no interobserver variability in RNA results.
EVALuna2:6916

COMPETE trial: Peptide receptor radionuclide therapy (PRRT) with 177Lu-edotreotide vs. everolimus in progressive GEP-NET - Pavel, Marianne Ellen; Rinke, A.; Baum, R. P. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling - Kühn, Helen; Kappes, Leonie; Wolf, Katharina; Gebhardt, Lisa; Neurath, Markus; Reeh, Peter; Fischer, Michael J.M.; Kremer, Andreas (Scientific Reports, 2020)
Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (NaV) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, NaV1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing NaV-specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, β-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in NaV channel-mediated itch signalling. NaV1.7−/− showed substantial scratch reduction mainly towards strong pruritogens. NaV1.8−/− impaired histamine and 5-HT-induced scratching while NaV1.9 was involved in itch signalling towards 5-HT, C48/80 and SLIGRL. Furthermore, similar microfluorimetric calcium responses of sensory neurons and expression of itch-related TRP channels suggest no change in sensory transduction but in action potential transformation and conduction. The cumulative sum of scratching over all pruritogens confirmed a leading role of NaV1.7 and indicated an overall contribution of NaV1.9. Beside the proposed general role of NaV1.7 and 1.9 in itch signalling, scrutiny of time courses suggested NaV1.8 to sustain prolonged itching. Therefore, NaV1.7 and 1.9 may represent targets in pruritus therapy.
CRIS-Team Scopus Importer:2020-02-21

Complications in gastrointestinal endoscopy - Neumann, Helmut; Meier, Peter N. (Digestive Endoscopy, 2016)
EVALuna2:2158

Computational tissue staining of non-linear multimodal imaging using supervised and unsupervised deep learning - Pradhan, Pranita; Meyer, Tobias; Stallmach, Andreas; Waldner, Maximilian; Schmitt, Michael; Popp, Jürgen; Bocklitz, Thomas; Vieth, Michael (Biomedical Optics Express, 2021)
Hematoxylin and Eosin (H&E) staining is the 'gold-standard' method in histopathology. However, standard H&E staining of high-quality tissue sections requires long sample preparation times including sample embedding, which restricts its application for 'real-time' disease diagnosis. Due to this reason, a label-free alternative technique like non-linear multimodal (NLM) imaging, which is the combination of three non-linear optical modalities including coherent anti-Stokes Raman scattering, two-photon excitation fluorescence and second-harmonic generation, is proposed in this work. To correlate the information of the NLM images with H&E images, this work proposes computational staining of NLM images using deep learning models in a supervised and an unsupervised approach. In the supervised and the unsupervised approach, conditional generative adversarial networks (CGANs) and cycle conditional generative adversarial networks (cycle CGANs) are used, respectively. Both CGAN and cycle CGAN models generate pseudo H&E images, which are quantitatively analyzed based on mean squared error, structure similarity index and color shading similarity index. The mean of the three metrics calculated for the computationally generated H&E images indicate significant performance. Thus, utilizing CGAN and cycle CGAN models for computational staining is beneficial for diagnostic applications without performing a laboratory-based staining procedure. To the author's best knowledge, it is the first time that NLM images are computationally stained to H&E images using GANs in an unsupervised manner. Journal
CRIS-Team Scopus Importer:2021-04-30

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

Computer-aided detection of colorectal polyps using a newly generated deep convolutional neural network: from development to first clinical experience - Pfeifer, Lukas; Neufert, Clemens; Leppkes, Moritz; Waldner, Maximilian; Hafner, Michael; Beyer, Albert; Hoffman, Arthur; Siersema, Peter D.; Neurath, Markus; Rath, Timo (European Journal of Gastroenterology & Hepatology, 2021)
Aim The use of artificial intelligence represents an objective approach to increase endoscopist's adenoma detection rate (ADR) and limit interoperator variability. In this study, we evaluated a newly developed deep convolutional neural network (DCNN) for automated detection of colorectal polyps ex vivo as well as in a first in-human trial.
CRIS-Team WoS Importer:2022-03-18

Concept to gain trust for a German personal health record system using public cloud and FHIR - Ploner, Nico; Neurath, Markus; Schoenthaler, Martin; Zielke, Andreas; Prokosch, Hans-Ulrich (Journal of Biomedical Informatics, 2019)
Objective: Although a national Personal Health Record (PHR) infrastructure was supposed to have been introduced in Germany by law in 2006 and different providers are entering the market, no system has yet been widely adopted in Germany. There is also little information available on how current technical advancements affect German patients' and physicians' trust in PHR systems. Methods: Supporting scenarios obtained from clinicians, this study proposes a concept for a German PHR system using a public cloud infrastructure, smartphone access and focusing on trust, privacy, and interoperability. In advance to an eventual implementation, a multi-center questionnaire study has been conducted to predict patients' and physicians' intention to use that system and evaluate their trust in different providers of such a system. Results: Our results show that both patients and physicians are highly likely to use the PHR based on the present concept. Trust in healthcare providers exceeds trust in other institutions like private companies, health insurance companies, or even governmental institutions when offering such a PHR system. Conclusions: We recommend the implementation of this PHR system. To maximize patients' and physicians' trust in the system, it should be offered to patients by their healthcare provider. Further evaluation regarding its actual adoption and expected improvement in patient outcome based on the scenarios is advisable.
CRIS-Team Scopus Importer:2019-07-26
Keywords: Electronic medical records; FHIR; Health information exchange; Personal health records

Confocal endomicroscopy identifies loss of local barrier function in the duodenum of patients with Crohn's disease and ulcerative colitis - Lim, Lee G.; Neumann, Janina; Hansen, Torsten; Goetz, Martin; Hoffman, Arthur; Neurath, Markus; Galle, Peter R.; Chan, Yiong H.; Kiesslich, Ralf; Watson, Alastair J. (Inflammatory Bowel Diseases, 2014)
Increased cell shedding with gap formation and local barrier dysfunction can be identified endomicroscopically in the terminal ileum of patients with inflammatory bowel disease. We aim to evaluate whether these changes are also present in the duodenum of patients with inflammatory bowel disease.Fifteen patients with Crohn's disease (CD), 10 patients with ulcerative colitis (UC), and 10 controls underwent fluorescein-aided confocal laser endomicroscopy (CLE). CLE was performed on macroscopically normal antral and duodenal (D1, D2, D3, D4) mucosa. Representative CLE images were prospectively analyzed. Images were scored for the number of epithelial gaps, cell shedding, and the degree of fluorescein leakage into the intestinal lumen.Both CD and UC patients had significantly more epithelial gaps, epithelial cell shedding, and leakage of fluorescein into the duodenal lumen than controls. The degree of cell shedding and epithelial gap formation was similar in CD and UC patients. In all cases, macroscopic endoscopic appearances of the duodenum were normal, and conventional histological analysis showed a mild nonspecific duodenitis in 7 of 15 patients with CD. Patients with UC had a histologically normal duodenum. Gap formation, cell shedding, and fluorescein leakage was similar in CD with active compared with inactive disease, except for D2 shedding.CLE can detect epithelial damage and barrier loss in the duodenum of CD and UC patients that is not apparent on conventional endoscopy or histology.
EVALuna2:1900

Confocal Laser Endomicroscopy Can Identify Microscopic Signs of Inflammation in Patients With Food Allergy - Rath, Timo; Atreya, Raja; Neurath, Markus; Zopf, Yurdagül; Siebler, Jürgen (2017)
EVALuna2:33903

CONFOCAL LASER ENDOMICROSCOPY CAN PREDICT MAJOR CLINICAL EVENTS WITH VERY HIGH SENSITIVITY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES - Klenske, Entcho; Atreya, Raja; Zundler, Sebastian; Fischer, Sven Moritz; Neurath, Markus; Rath, Timo (GASTROINTESTINAL ENDOSCOPY, 2019)
CRIS-Team WoS Importer:2019-06-21

Confocal laser endomicroscopy carried out after oral intake of fluorescein sodium-containing bath additive - Nonaka, Kouichi; Neumann, Helmut; Ban, Shinichi (Digestive Endoscopy, 2016)
EVALuna2:2093

Confocal Laser Endomicroscopy for Diagnosing Malignant Pleural Effusions - Zirlik, Sabine; Hildner, Kai; Rieker, Ralf; Neurath, Markus; Fuchs, Florian; Vieth, Michael (Medical Science Monitor, 2018)
BACKGROUND Confocal laser endomicroscopy (CLE) enables "in vivo" microscopic tissue diagnosis based on tissue reflectance or tissue fluorescence upon application of fluorescence agents. The aim of the present study was to evaluate CLE as a new diagnostic approach for differentiation between malignant versus non-malignant pleural effusions. MATERIAL AND METHODS In 100 patients with pleural effusions, thoracentesis was performed. Cresyl violet and acriflavine were used as contrast agents for probe-based CLE of effusions. CLE video sequences were assessed by 4 independent investigators (2 experienced in this technique, 2 with only basic knowledge). In addition, all CLE samples were evaluated by an expert pathologist (p). Results were compared with conventional cytology of effusions and histology of cell blocks. RESULTS CLE reliably permitted identification of malignant cells in pleural effusions. Sensitivity for detection of malignant effusions was 87% (p: 87%) and 81% (p: 72%) for acriflavine and cresyl violet, respectively. With regard to specificity, acriflavine and cresyl violet yielded a mean value of 99% (p: 100%) and 92% (p: 100%). CONCLUSIONS In this pilot study, CLE permitted simple and rapid detection of malignant pleural effusions. Larger prospective studies are warranted to corroborate our findings.
EVALuna2:35147

Confocal laser endomicroscopy for functional barrier imaging in Crohn's disease - Neurath, Markus (Endoscopy, 2016)
EVALuna2:2099

Confocal laser endomicroscopy for in vivo diagnosis of Clostridium difficile associated colitis - a pilot study. - Günther, Claudia; Neumann, Helmut; Vieth, Michael; Mudter, Jonas; Becker, Christoph; Schoerner, Christoph; Atreya, Raja; et al. (PLoS ONE, 2013)
Clostridium difficile infection (CDI) is one of the most dreaded causes of hospital-acquired diarrhea. Main objective was to investigate whether confocal laser endomicroscopy (CLE) has the capability for in vivo diagnosis of C. difficile associated histological changes. Second objective was to prove the presence of intramucosal bacteria using CLE. 80 patients were prospectively included, 10 patients were diagnosed with CDI based on toxigenic culture. To validate the presence of intramucosal bacteria ex vivo, CLE was performed in pure C. difficile culture; additionally fluorescence in situ hybridization (FISH) was performed. Finally, CLE with fluorescence labelled oligonucleotide probe specific for C. difficile was performed ex vivo in order to prove the presence of bacteria. CLE identified CDI-associated histological changes in vivo (sensitivity and accuracy of 88.9% and 96.3%). In addition, intramucosal bacteria were visualized. The presence of these bacteria could be proven by CLE with labeled, specific molecular C. difficile probe and FISH-technique. Based on comparison between CLE and FISH analyses, sensitivity and specificity for the presence of intramucosal bacteria were 100%. CLE has the potential for in vivo diagnosis of CDI associated colitis. In addition, CLE allowed the detection of intramucosal bacteria in vivo. BACKGROUND METHODS RESULTS CONCLUSION

Confocal laser endomicroscopy for prediction of disease relapse in ulcerative colitis: a pilot study - Buda, Andrea; Hatem, Giorgia; Neumann, Helmut; D' Inca, Renata; Mescoli, Claudia; Piselli, Pierluca; Jackson, John; Bruno, Marco; Sturniolo, Giacomo Carlo (Journal of Crohns & Colitis, 2014)
Neoangiogenesis and increased endothelial permeability are observed as results of chronic intestinal inflammation. However, limited data on microvascular and crypt architecture during remission phases is available. The aim of this prospective investigator blinded cohort study was to assess crypt and microvascular architecture and function in ulcerative colitis by probe based confocal laser endomicroscopy; we also evaluated whether these findings may have the potential to predict disease relapse.19 ulcerative colitis patients in clinical and endoscopic remission and 19 controls were studied. A computer based image processing technique was applied to construct 20 mosaicing image sets from each subject. Remitting patients were sub-grouped into either inactive or quiescent disease according to histology.Pericrypt fluorescence (p<0.01), crypt diameter (p<0.05) but not intercrypt distance (p=0.07) were significantly increased in ulcerative colitis patients compared to controls. Patients with inactive disease showed a significant increase in fluorescence leakage (median fluorescence (IQR), 3888 (3560-4240) vs. 2696 (2502-3390), p<0.01), crypt diameter (median diameter (IQR), 92.5 (85.5-101) vs. 73 (70-77), p<0.05) and intercrypt distance (median distance (IQR), 82.5 (70.5-91.2) vs. 66 (59.5-73.5), p<0.05) compared to those with quiescent disease. A composite outcome score combining fluorescence leakage and crypt diameter was able to predict a disease flare during a 12 month follow-up period (p<0.01).In vivo intramucosal changes detected by confocal endomicroscopy in ulcerative colitis remittent patients can predict disease relapse. This observation may have further implications for disease management and medical treatment.
EVALuna2:1908

Confocal laser endomicroscopy for the differential diagnosis of ulcerative colitis and Crohn's disease: a pilot study - Tontini, Gian Eugenio; Mudter, Jonas; Atreya, Raja; Günther, Claudia; Zopf, Yurdagül; Wildner, Dane; Kiesslich, Ralf; Vecchi, Maurizio; Neurath, Markus; Neumann, Helmut; Vieth, Michael (Endoscopy, 2015)
The differential diagnosis of ulcerative colitis from Crohn's disease is of pivotal importance for the management of inflammatory bowel diseases, as both entities involve specific therapeutic management strategies. Confocal laser endomicroscopy (CLE) allows on-demand, in vivo characterization of architectural and cellular details during endoscopy. The aim of this study was to assess the efficacy of CLE to differentiate between ulcerative colitis and Crohn's disease.This was a prospective study involving consecutive patients with a well-established diagnosis of ulcerative colitis or Crohn's disease who underwent colonoscopy with fluorescein-aided confocal imaging.Overall, 79 patients were included (40 Crohn's disease, 39 ulcerative colitis). CLE findings in patients with Crohn's disease, showed significantly more discontinuous inflammation (87.5 % vs. 5.1 %), focal cryptitis (75.0 % vs. 12.8 %), and discontinuous crypt architectural abnormality (87.5 % vs. 10.3 %) than in ulcerative colitis (P < 0.0001). Conversely, ulcerative colitis was associated with severe, widespread crypt distortion (87.2 % vs. 17.5 % in Crohn's disease), decreased crypt density (79.5 % vs. 22.5 %), and frankly irregular surface (89.7 % vs. 17.5 %; P < 0.0001 for all comparisons). Statistically significant differences were not seen for heavy, diffuse lamina propria cell increase or mucin preservation. No granulomas were visible. Based on these findings, a CLE scoring system was developed that revealed excellent accuracy (93.7 %) when compared with the historical clinical diagnosis and the histopathological gold standard.CLE could visualize several disease-specific microscopic features, which are conventionally used in standard histopathology to differentiate between ulcerative colitis and Crohn's disease. However, because of the limited penetration depth of CLE, submucosal details or granulomas were not visible. The new scoring system may allow in vivo diagnosis of ulcerative colitis or Crohn's disease. Trial registered at ClinicalTrials.gov: NCT 02238665.
EVALuna2:2020

Confocal laser endomicroscopy guided endoscopic myotomy - Neumann, Helmut; Dallemagne, Bernard; Marescaux, Jacques; Inoue, Haru; Perretta, Silvana; Vieth, Michael (Gastroenterology, 2014)
EVALuna2:1895

Consensus on molecular imaging and theranostics in neuroendocrine neoplasms - Ambrosini, Valentina; Kunikowska, Jolanta; Baudin, Eric; Bodei, Lisa; Bouvier, Catherine; Capdevila, Jaume; Cremonesi, Marta; de Herder, Wouter W.; Dromain, Clarisse; Falconi, Massimo; Fani, Melpomeni; Fanti, Stefano; et al. (European Journal of Cancer, 2021)
Nuclear medicine plays an increasingly important role in the management neuroendocrine neoplasms (NEN). Somatostatin analogue (SSA)-based positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT) have been used in clinical trials and approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs). NETs form in cells that interact with the nervous system or in glands that produce hormones. These cells, called neuroendocrine cells, can be found throughout the body, but NETs are most often found in the abdomen, especially in the gastrointestinal tract. These tumours may also be found in the lungs, pancreas and adrenal glands. In addition to being rare, NETs are also complex and may be difficult to diagnose. Most NETs are non-functioning; however, a minority present with symptoms related to hypersecretion of bioactive compounds. NETs often do not cause symptoms early in the disease process. When diagnosed, substantial number of patients are already found to have metastatic disease. Several societies' guidelines address Neuroendocrine neoplasms (NENs) management; however, many issues are still debated, due to both the difficulty in acquiring strong clinical evidence in a rare and heterogeneous disease and the different availability of diagnostic and therapeutic options across countries. EANM Focus 3 reached consensus on employing 68gallium-labelled somatostatin analogue ([68Ga]Ga-DOTA-SSA)-based PET/CT with diagnostic CT or magnetic resonance imaging (MRI) for unknown primary NET detection, metastatic NET, NET staging/restaging, suspected extra-adrenal pheochromocytoma/paraganglioma and suspected paraganglioma. Consensus was reached on employing 18fluorine-fluoro-2-deoxyglucose ([18F]FDG) PET/CT in neuroendocrine carcinoma, G3 NET and in G1-2 NET with mismatched lesions (CT-positive/[68Ga]Ga-DOTA-SSA-negative). Peptide receptor radionuclide therapy (PRRT) was recommended for second line treatment for gastrointestinal NET with [68Ga]Ga-DOTA-SSA uptake in all lesions, in G1/G2 NET at disease progression, and in a subset of G3 NET provided all lesions are positive at [18F]FDG and [68Ga]Ga-DOTA-SSA. PRRT rechallenge may be used for in patients with stable disease for at least 1 year after therapy completion. An international consensus is not only a prelude to a more standardised management across countries but also serves as a guide for the direction to follow when designing new research studies.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Consensus; Molecular imaging; Neuroendocrine neoplasms; PRRT

Constrained multiple instance learning for ulcerative colitis prediction using histological images - Del Amor, Rocio; Meseguer, Pablo; Parigi, Tommaso Lorenzo; Villanacci, Vincenzo; Colomer, Adrian; Launet, Laetitia; Bazarova, Alina; Tontini, Gian Eugenio; Bisschops, Raf; De Hertogh, Gert; Ferraz, Jose G.; Goetz, Martin; et al. (Computer Methods and Programs in Biomedicine, 2022)
Background and Objective: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) affecting the colon and the rectum characterized by a remitting-relapsing course. To detect mucosal inflammation as-sociated with UC, histology is considered the most stringent criteria. In turn, histologic remission (HR) correlates with improved clinical outcomes and has been recently recognized as a desirable treatment target. The leading biomarker for assessing histologic remission is the presence or absence of neutrophils. Therefore, the finding of this cell in specific colon structures indicates that the patient has UC activity. However, no previous studies based on deep learning have been developed to identify UC based on neu-trophils detection using whole-slide images (WSI). Methods: The methodological core of this work is a novel multiple instance learning (MIL) framework with location constraints able to determine the presence of UC activity using WSI. In particular, we put forward an effective way to introduce constraints about positive instances to effectively explore additional weakly supervised information that is easy to obtain and enjoy a significant boost to the learning process. In addition, we propose a new weighted embedding to enlarge the relevance of the positive instances. Results: Extensive experiments on a multi-center dataset of colon and rectum WSIs, PICASSO-MIL, demon-strate that using the location information we can improve considerably the results at WSI-level. In com-parison with prior MIL settings, our method allows for 10% improvements in bag-level accuracy. Conclusion : Our model, which introduces a new form of constraints, surpass the results achieved from current state-of-the-art methods that focus on the MIL paradigm. Our method can be applied to other histological concerns where the morphological features determining a positive WSI are tiny and similar to others in the image. (c) 2022 Elsevier B.V. All rights reserved.
CRIS-Team WoS Importer:2022-09-02

Contact-free endoscopic photoacoustic sensing using speckle-analysis - Lengenfelder, Benjamin; Mehari, Fanuel; Hohmann, Martin; Löhr, Cita; Waldner, Maximilian; Schmidt, Michael; Zalevsky, Zeev; Klämpfl, Florian (Journal of Biophotonics, 2019)
Photoacoustic endoscopy (PAE) is an emerging imaging modality which offers a high imaging penetration and a high optical contrast in soft tissue. Most of the developed endoscopic photoacoustic sensing systems use miniaturized contact ultrasound transducers or complex optical approaches. In this work, a new fiber based detection technique using speckle-analysis for contact-free signal detection is presented. Phantom and ex-vivo experiments are performed in transmission and reflection-mode for proof of concept. In summary, the potential of the technique for endoscopic photoacoustic signal detection is demonstrated. The new technique might help in future to broaden the applications of PAE in imaging or guiding minimally invasive laser procedures.
Keywords: Photoacoustic endoscopy; speckle; remote sensing; laser surgery

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

Contrast-Enhanced Ultrasound Algorithms (CEUS-LIRADS/ESCULAP) for the Noninvasive Diagnosis of Hepatocellular Carcinoma – A Prospective Multicenter DEGUM Study - Schellhaas, Barbara; Bernatik, Thomas; Bohle, Wolfram; Borowitzka, Fanny; Chang, Johannes; Dietrich, Christoph F.; Dirks, Klaus; Donoval, Robert; Drube, Kristine; Friedrich-Rust, Mireen; Gall, Christine; Gittinger, Fleur; et al. (Ultraschall in der Medizin, 2020)
Background This prospective multicenter study funded by the DEGUM assesses the diagnostic accuracy of standardized contrast-enhanced ultrasound (CEUS) for the noninvasive diagnosis of hepatocellular carcinoma (HCC) in high-risk patients. Methods Patients at high risk for HCC with a histologically proven focal liver lesion on B-mode ultrasound were recruited prospectively in a multicenter approach. Clinical and imaging data were entered via online entry forms. The diagnostic accuracies for the noninvasive diagnosis of HCC were compared for the conventional interpretation of standardized CEUS at the time of the examination (= CEUS on-site) and the two CEUS algorithms ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk) and CEUS LI-RADS (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System). Results 321 patients were recruited in 43 centers; 299 (93.1 %) had liver cirrhosis. The diagnosis according to histology was HCC in 256 cases, and intrahepatic cholangiocarcinoma (iCCA) in 23 cases. In the subgroup of cirrhotic patients (n = 299), the highest sensitivity for the diagnosis of HCC was achieved with the CEUS algorithm ESCULAP (94.2 %) and CEUS on-site (90.9 %). The lowest sensitivity was reached with the CEUS LI-RADS algorithm (64 %; p < 0.001). However, the specificity of CEUS LI-RADS (78.9 %) was superior to that of ESCULAP (50.9 %) and CEUS on-site (64.9 %; p < 0.001). At the same time, the negative predictive value (NPV) of CEUS LI-RADS was significantly inferior to that of ESCULAP (34.1 % vs. 67.4 %; p < 0.001) and CEUS on-site (62.7 %; p < 0.001). The positive predictive values of all modalities were high (around 90 %), with the best results seen for CEUS LI-RADS and CEUS on-site. Conclusion This is the first multicenter, prospective comparison of standardized CEUS and the recently developed CEUS-based algorithms in histologically proven liver lesions in cirrhotic patients. Our results reaffirm the excellent diagnostic accuracy of CEUS for the noninvasive diagnosis of HCC in high-risk patients. However, on-site diagnosis by an experienced examiner achieves an almost equal diagnostic accuracy compared to CEUS-based diagnostic algorithms.
CRIS-Team Scopus Importer:2020-10-16
Keywords: CEUS algorithms; CEUS LI-RADS (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System); Contrast-enhanced ultrasound (CEUS); ESCULAP; Hepatocellular carcinoma

Contrast-enhanced ultrasound pattern of hepatocellular carcinoma in noncirrhotic liver - Results from the prospective multicentre DEGUM CEUS HCC study - Schellhaas, Barbara; Jesper, Daniel; Strobel, Deike (European Journal of Gastroenterology & Hepatology, 2023)
Objectives Contrast-enhanced ultrasound (CEUS) has a high diagnostic accuracy for the noninvasive diagnosis of hepatocellular carcinoma (HCC) in cirrhosis. However, as HCC in noncirrhosis becomes an emerging clinical concern, our study aimed to assess the diagnostic value of CEUS and the CEUS algorithms CEUS LI-RADS and ESCULAP in noncirrhotic liver in a prospective multicentre real-life setting. Methods High-risk patients for HCC with focal liver lesions upon B-mode ultrasound were recruited prospectively in a multicentre real-life approach to undergo standardized CEUS. Diagnostic accuracies of CEUS and the CEUS algorithms were assessed for the sub-collective of noncirrhotic patients. Histology, MRI and CT served as the reference standard. Results In total 47/517 patients were noncirrhotic. The reference standard of the lesions showed 30 HCCs (63.8%), four intrahepatic cholangiocellular carcinomas (iCCAs), two other malignancies and 11 benign lesions. HCCs in noncirrhosis showed a tendency towards larger tumor size and better differentiation. A typical CEUS pattern of arterial phase hyperenhancement and late-onset (>60 s), mild washout occurred in 22/30 HCCs (73.3%). Very late onset of washout > 4-6 min was not seen in noncirrhotic liver. The CEUS algorithm ESCULAP showed a perfect sensitivity (100 vs. 68% with CEUS LI-RADS), whereas CEUS LI-RADS had a superior specificity (83 vs. 53%). The positive predictive value was high with both algorithms. Conclusion The CEUS patterns of HCCs in noncirrhotic liver resembled those in cirrhosis. Our findings suggest that although designed for the application in cirrhosis only, the diagnostic accuracies of the CEUS algorithms in noncirrhotic liver seem comparable to the findings in cirrhosis.
CRIS-Team Scopus Importer:2023-02-10
Keywords: CEUS algorithm; cirrhosis; contrast-enhanced ultrasound; Contrast-Enhanced UltraSound Liver Reporting and Imaging Data System; DEGUM CEUS HCC Study; Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk; hepatocellular carcinoma; liver; noninvasive diagnosis; prospective multicentre real-life study

Contrast-Enhanced Ultrasound Patterns for the Non-invasive Diagnosis of Hepatocellular Carcinoma: A Prospective Multicenter Study in Histologically Proven Liver Lesions in a Real-Life Setting Demonstrating the Benefit of Extended Late Phase Observation - Schellhaas, Barbara; Bernatik, Thomas; Dirks, Klaus; Jesper, Daniel; Mauch, Martin; Potthoff, Andrej; Zimmermann, Patrick; Strobel, Deike (Ultrasound in Medicine and Biology, 2021)
The hallmark for the non-invasive diagnosis of hepatocellular carcinoma (HCC) with contrast-enhanced ultrasound (CEUS) in cirrhosis is arterial phase hyperenhancement (APHE), followed by late-onset (>60 s), mild washout. Large retrospective studies report this pattern of washout to occur in the vast majority of HCCs. However, a prospective multicenter validation of these findings is still missing. Thus, we initiated a prospective multicenter validation study assessing CEUS enhancement patterns in focal liver lesions of patients at risk for HCC. We analyzed lesions that were eventually histology proven in a real-life setting. CEUS patterns were assessed for subgroups of HCC, intrahepatic cholangiocellular carcinoma (iCCA) and non-HCC, non-iCCA lesions. The diagnosis was HCC in 316 lesions (median size: 40 mm), iCCA in 26 lesions (median size: 47.5 mm) and non-HCC, non-iCCA in 53 lesions (median size: 27 mm). Overall, 85.8% of HCCs exhibited APHE. APHE followed by washout occurred in 72.8% of HCCs and 50% of iCCAs and non-HCC, non-iCCA malignancies (p < 0.05). Early and marked washout was associated more commonly with iCCA; HCCs exhibited mostly late and mild washout (onset >4–6 min in 10% of cases). Our prospective data confirm that the typical pattern of APHE followed by late-onset, mild washout occurs in the majority of HCCs.
CRIS-Team Scopus Importer:2021-08-27
Keywords: Cirrhosis; Contrast enhancement pattern; Contrast-enhanced ultrasound; Examination standard; Guidelines; Hepatocellular carcinoma; Imaging; Intrahepatic cholangiocellular carcinoma; Non-invasive diagnosis; Ultrasound

Contrast-Enhanced µCT for Visualizing and Evaluating Murine Intestinal Inflammation - Jung, Dennis; Heiß, Rafael; Kramer, Viktoria; Thoma, Oana-Maria; Regensburger, Adrian; Rascher, Wolfgang; Uder, Michael; Neurath, Markus; Knieling, Ferdinand; Waldner, Maximilian (Theranostics, 2018)
Rationale: To develop a simple and fast protocol for the assessment of acute and chronic experimental intestinal inflammation using contrast-enhanced µCT. Methods: For the imaging studies, an acute 2% and 3% dextran sodium sulfate (n = 15, female, 8-12 weeks) and a chronic adoptive transfer colitis model (n = 10, female, 8-9 weeks) were established over 9 days or 6 weeks, respectively. Throughout the experiments, longitudinal measurement of murine intestinal wall thickness and time dependent perfusion was performed on a small animal µCT system (90 kV, 160 μA, FOV: 60 mm, scan time: 17 s, image size: 512x512, layer thickness: 118 µm) between 0.5 and 30 min after intravenous bolus injection of an iodine contrast agent. Weight development, small animal endoscopy, and histological ex vivo analysis were compared to contrast-enhanced µCT imaging findings. Results: Murine intestinal wall thickness was significantly increased in inflamed colons of acute colitis at day 9 in comparison to pre-inflamed state. Perfusion analysis revealed a late contrast enhancement in acute inflamed colons and the renal medulla at day 9 compared to control mice. An increasing intestinal wall thickness was monitored 3, 5 and 6 weeks after on-set of chronic colitis in comparison to controls. A good correlation with endoscopic (r = 0.75, p < 0.0001) and histologic degree of inflammation (r = 0.83, p = 0.04) was found. Conclusion: Contrast-enhanced µCT is a simple and fast method to assess acute intestinal inflammation and to monitor disease progression in experimental models of chronic colitis. According to our findings, one single contrast-enhanced µCT-scan is a valid non-invasive modality to quantify the degree of inflammation in the entire digestive tract in murine inflammatory models.
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Controlling in and out - the future of interfering with immune cell trafficking in inflammatory bowel disease - Zundler, Sebastian; Schulze, Lisa; Neurath, Markus (Expert Review of Clinical Immunology, 2022)
IntroductionImmune cell trafficking is a key requirement in the pathogenesis of inflammatory bowel diseases. Consistently, therapeutic strategies to target immune cell trafficking have been established and continue to be developed for the treatment of ulcerative colitis and Crohn's disease.Areas coveredIn this review, we briefly summarize the most important checkpoints of intestinal immune cell trafficking and their importance during IBD. Moreover, we provide an overview of associated therapeutic targets and previous as well as current efforts on treatment strategies related to these targets.Expert opinionFinally, we comment on potential future developments that might shape the field of immune cell trafficking in the context of IBD.
CRIS-Team WoS Importer:2023-01-06

Convalescent plasma treatment for SARS-CoV-2 infected high-risk patients: a matched pair analysis to the LEOSS cohort - Freise, Noemi F.; Gliga, Smaranda; Fischer, Johannes; Lübke, Nadine; Lutterbeck, Matthias; Schöler, Miriam; Bölke, Edwin; Orth, Hans Martin; Feldt, Torsten; Roemmele, Christoph; Wilke, Dominik; Schneider, Jochen; et al. (Scientific Reports, 2022)
Establishing the optimal treatment for COVID-19 patients remains challenging. Specifically, immunocompromised and pre-diseased patients are at high risk for severe disease course and face limited therapeutic options. Convalescent plasma (CP) has been considered as therapeutic approach, but reliable data are lacking, especially for high-risk patients. We performed a retrospective analysis of 55 hospitalized COVID-19 patients from University Hospital Duesseldorf (UKD) at high risk for disease progression, in a substantial proportion due to immunosuppression from cancer, solid organ transplantation, autoimmune disease, dialysis. A matched-pairs analysis (1:4) was performed with 220 patients from the Lean European Open Survey on SARS-CoV-2-infected Patients (LEOSS) who were treated or not treated with CP. Both cohorts had high mortality (UKD 41.8%, LEOSS 34.1%). A matched-pairs analysis showed no significant effect on mortality. CP administration before the formation of pulmonary infiltrates showed the lowest mortality in both cohorts (10%), whereas mortality in the complicated phase was 27.8%. CP administration during the critical phase revealed the highest mortality: UKD 60.9%, LEOSS 48.3%. In our cohort of COVID-19 patients with severe comorbidities CP did not significantly reduce mortality in a retrospective matched-pairs analysis. However, our data supports the concept that a reduction in mortality is achievable by early CP administration.
CRIS-Team Scopus Importer:2022-11-25

CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease - Ma, Christopher; Hanzel, Jurij; Panaccione, Remo; Sandborn, William J.; D'Haens, Geert R.; Ahuja, Vineet; Atreya, Raja; Bernstein, Charles N.; Bossuyt, Peter; Bressler, Brian; Bryant, Robert V.; Cohen, Benjamin; et al. (Gastroenterology, 2022)
Background & Aims: End points to determine the efficacy and safety of medical therapies for Crohn's disease (CD) and ulcerative colitis (UC) are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in inflammatory bowel disease. Methods: Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists. Results: A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for UC. In CD, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In UC, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities. Conclusions: This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of CD and UC.
CRIS-Team Scopus Importer:2022-09-02
Keywords: Crohn's Disease; End Point; Outcomes; Ulcerative Colitis

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: Influence of cancer and acute inflammatory disease on taste perception: a clinical pilot study - Schalk, Priska; Kohl, M.; Herrmann, H. J.; Schwappacher, R.; Rimmele, M. E.; Büttner, Andrea; Neurath, Markus; Zopf, Yurdagül; Siebler, Jürgen (Supportive Care in Cancer, 2019)
The "Acknowledgment Statement" of the published paper is incorrect. The correct statement should be the below: Acknowledgements We thank Sarah Vogel for her support in taste test realization and Yvonne Sauermann for preparation of the tastant solutions. The present work was carried out by Ms. Schalk in order to meet the requirements for the awarding of the title of Dr. med. at the FAU.
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Correction to: Influence of cancer and acute inflammatory disease on taste perception: a clinical pilot study (Supportive Care in Cancer, (2019), 27, 4, (1579), 10.1007/s00520-019-4642-6) - Schalk, Priska; Kohl, M.; Herrmann, H. J.; Schwappacher, R.; Rimmele, Martina; Büttner, Andrea; Neurath, Markus; Zopf, Yurdagül; Siebler, Jürgen (Supportive Care in Cancer, 2020)
The Acknowledgement Statement was incorrect in the original publication of this article [1] and the previous correction note [2]. The correct statement is as follows:
CRIS-Team Scopus Importer:2020-02-28

Correlation of skin rash and overall survival in patients with pancreatic cancer treated with gemcitabine and erlotinib-results from a non-interventional multi-center study - Westphalen, C. Benedikt; Kukiolka, Tobias; Garlipp, Benjamin; Hahn, Lars; Fuchs, Martin; Malfertheiner, Peter; Reiser, Marcel; Kütting, Fabian; Heinemann, Volker; Beringer, Andreas; Waldschmidt, Dirk T. (BMC Cancer, 2020)
Background: Gemcitabine/erlotinib treatment offers limited benefit in unselected patients with pancreatic ductal adenocarcinoma (PDAC). Development of skin rash has been associated with favorable outcomes in patients treated with gemcitabine/erlotinib. This study aimed to extend knowledge on the effectiveness of gemcitabine/erlotinib in metastatic PDAC in the context of clinical practice and with focus on skin rash. Methods: This multicenter, non-interventional study enrolled 376 patients with metastatic PDAC receiving gemcitabine/erlotinib. The primary endpoint was overall survival (OS) in patients with skin rash versus no skin rash. Secondary endpoints included progression-free survival (PFS), treatment satisfaction and safety. All data were analyzed using descriptive statistics. Survival time and time to disease progression were estimated using the Kaplan-Meier method. Effectiveness endpoints were analyzed for subgroups by skin rash grade (no rash, rash grade 1, rash grade ≥ 2), duration of erlotinib treatment (≤8 weeks, > 8 weeks), Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0-1, 2) and age (≤65 years, > 65 years). Results: Within the full analysis set (FAS; N = 270), 48 patients (17.8%) developed grade 1 rash, 51 patients (18.9%) grade ≥ 2 rash, while 171 patients (63.3%) did not develop a rash. Median OS of all patients was 9.11 months with an OS of 9.93 months in rash-positive and 8.68 months in rash-negative patients. Median PFS was 5.06 months for rash-positive and 4.11 months for rash-negative patients. PFS was longer in patients with rash grade ≥ 2 and in older patients (> 65 years). Examination using a multivariate Cox proportional model revealed that an age > 65 years was associated with longer OS (hazard ratio 0.640; p = 0.0327) and PFS (hazard ratio 0.642; p = 0.0026). Out of the 338 patients in the SAF, 310 patients (91.7%) experienced at least one AE, and 176 patients (52.1%) experienced skin-related side effects, all of which were CTC grade 1 to 3. Conclusions: Comparing rash-positive with rash-negative patients showed no significant difference in survival. While patients with rash grade ≥ 2 and older patients (independent of skin reactions) showed longer PFS, this did not translate into prolonged OS. The study did not reveal new safety signals. Trial registration: ClinicalTrials.gov Identifier: NCT01782690, retrospectively registered on 4 February 2013.
CRIS-Team Scopus Importer:2020-03-17
Keywords: Erlotinib; Gemcitabine; Non-interventional study; Overall survival; Pancreatic ductal adenocarcinoma; Progression-free survival; Skin rash

Corrigendum to "Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up": [Annals of Oncology 32 (2021) 439-451 - Baudin, E.; Caplin, M.; Garcia-Carbonero, R.; Fazio, Nicola; Ferolla, P.; Filosso, P. L.; Frilling, A.; De Herder, W. W.; Hoersch, D.; Knigge, U.; Korse, C. M.; Lim, E.; et al. (Annals of Oncology, 2021)
CRIS-Team Scopus Importer:2021-12-17

Cost-effectiveness Analysis of Subcutaneous Infliximab for Inflammatory Bowel Diseases in Sequential Biologic Treatment - Bouhnik, Yoram; Atreya, Raja; Casey, Daniel; Gorecki, Michat; Baik, Deborah; Yoon, Sang Wook; Kwon, Taek Sang; Jang, Minyoung (Inflammatory Bowel Diseases, 2022)
Background Inflammatory bowel disease (IBD) guidelines recommend tumor necrosis factor-alpha inhibitors (TNFis) for patients who have not responded to conventional therapy, and vedolizumab in case of inadequate response to conventional therapy and/or TNFis. Recent studies have shown that vedolizumab may also be effective in the earlier treatment lines. Therefore, we conducted cost-effectiveness analyses to determine the optimal treatment sequence in patients with IBD. Methods A Markov model with a 10-year time horizon compared the cost-effectiveness of different biologic treatment sequences in patients with moderate to severe ulcerative colitis (UC) and Crohn's disease (CD) from the UK and French perspectives. Subcutaneous formulations of infliximab, vedolizumab, and adalimumab were evaluated. Comparative effectiveness was based on a network meta-analysis of clinical trials and real-world evidence. Costs included pharmacotherapy, surgery, adverse events, and disease management. Results The results indicated that treatment sequences starting with infliximab were less costly and more effective than those starting with vedolizumab for patients with UC in the United Kingdom and France, and patients with just CD in France. For patients with CD in the United Kingdom, treatment sequences starting with infliximab resulted in better health outcomes with incremental cost-effectiveness ratios (ICERs) near the threshold. Conclusions Based on the ICERs, treatment sequences starting with infliximab are the dominant option for patients with UC in the United Kingdom, and patients with UC and CD in France. In UK patients with CD, ICERs were near the assumed "willingness to pay" threshold. These results reinforce the UK's National Institute for Health and Care Excellence recommendations for using infliximab prior to using vedolizumab in biologics-naive patients.
CRIS-Team WoS Importer:2022-08-19

Cost-effectiveness analysis of the Geriatric Fracture Center (GFC) concept: a prospective multicentre cohort study - Joeris, Alexander; Sprague, Sheila; Blauth, Michael; Gosch, Markus; Wattanapanom, Pannida; Jarayabhand, Rahat; Poeze, Martijn; Wong, Merng K.; Kwek, Ernest B.K.; Hegeman, Johannes H.; Perez-Uribarri, Carlos; Guerado, Enrique; et al. (BMJ Open, 2023)
INTRODUCTION: Geriatric Fracture Centers (GFCs) are dedicated treatment units where care is tailored towards elderly patients who have suffered fragility fractures. The primary objective of this economic analysis was to determine the cost-utility of GFCs compared with usual care centres. METHODS: The primary analysis was a cost-utility analysis that measured the cost per incremental quality-adjusted life-year gained from treatment of hip fracture in GFCs compared with treatment in usual care centres from the societal perspective over a 1-year time horizon. The secondary analysis was a cost-utility analysis from a societal perspective over a lifetime time horizon. We evaluated these outcomes using a cost-utility analysis using data from a large multicentre prospective cohort study comparing GFCs versus usual care centres that took place in Austria, Spain, the USA, the Netherlands, Thailand and Singapore. RESULTS: GFCs may be cost-effective in the long term, while providing a more comprehensive care plan. Patients in usual care centre group were slightly older and had fewer comorbidities. For the 1-year analysis, the costs per patient were slightly lower in the GFC group (-646.42), while the quality-adjusted life-years were higher in the usual care centre group (+0.034). The incremental cost-effectiveness ratio was 18 863.34 (US/quality-adjusted life-year). The lifetime horizon analysis found that the costs per patient were lower in the GFC group (-7210.35), while the quality-adjusted life-years were higher in the usual care centre group (+0.02). The incremental cost-effectiveness ratio was 320 678.77 (US/quality-adjusted life-year). CONCLUSIONS: This analysis found that GFCs were associated with lower costs compared with usual care centres. The cost-savings were greater when the lifetime time horizon was considered. This comprehensive cost-effectiveness analysis, using data from an international prospective cohort study, found that GFC may be cost-effective in the long term, while providing a more comprehensive care plan. A greater number of major adverse events were reported at GFC, nevertheless a lower mortality rate associated with these adverse events at GFC. Due to the minor utility benefits, which may be a result of greater adverse event detection within the GFC group and much greater costs of usual care centres, the GFC may be cost-effective due to the large cost-savings it demonstrated over the lifetime time horizon, while potentially identifying and treating adverse events more effectively. These findings suggest that the GFC may be a cost-effective option over the lifetime of a geriatric patient with hip fracture, although future research is needed to further validate these findings. LEVEL OF EVIDENCE: Economic, level 2. TRIAL REGISTRATION NUMBER: NCT02297581.
CRIS-Team Scopus Importer:2023-11-17
Keywords: health economics; orthopaedic & trauma surgery

COVID-19 and immune-mediated inflammatory diseases: effect of disease and treatment on COVID-19 outcomes and vaccine responses - Fagni, Filippo; Simon, David; Tascilar, Koray; Schoenau, Verena; Sticherling, Michael; Neurath, Markus; Schett, Georg (The Lancet Rheumatology, 2021)
At the beginning of the COVID-19 pandemic, patients with immune-mediated inflammatory diseases were considered to be at high risk for SARS-CoV-2 infection and the development of severe COVID-19. Data collected over the past year, however, suggest that a diagnosis of inflammatory arthritis, psoriasis, or inflammatory bowel diseases does not increase risk for SARS-CoV-2 infection or severe COVID-19 compared with people without these diseases. Furthermore, substantial data suggest that certain medications frequently used in patients with immune-mediated inflammatory diseases, in particular cytokine inhibitors, might even lower the risk for severe COVID-19. Conversely, glucocorticoids and potentially B-cell-depleting treatments seem to worsen COVID-19 outcomes. Additionally, the first data on SARS-CoV-2 vaccination in patients with these diseases suggest that tolerability of vaccination in patients with immune-mediated inflammatory diseases is good, although the immune response to vaccination can be somewhat reduced in this patient group, particularly those taking methotrexate or CD20-targeted treatment.
CRIS-Team Scopus Importer:2021-10-01

Covid-19 and immunomodulation in IBD - Neurath, Markus (Gut, 2020)
The current coronavirus pandemic is an ongoing global health crisis due to covid-19, caused by severe acute respiratory syndrome coronavirus 2. Although covid-19 leads to little or mild flu-like symptoms in the majority of affected patients, the disease may cause severe, frequently lethal complications such as progressive pneumonia, acute respiratory distress syndrome and organ failure driven by hyperinflammation and a cytokine storm syndrome. This situation causes various major challenges for gastroenterology. In the context of IBD, several key questions arise. For instance, it is an important question to understand whether patients with IBD (eg, due to intestinal ACE2 expression) might be particularly susceptible to covid-19 and the cytokine release syndrome associated with lung injury and fatal outcomes. Another highly relevant question is how to deal with immunosuppression and immunomodulation during the current pandemic in patients with IBD and whether immunosuppression affects the progress of covid-19. Here, the current understanding of the pathophysiology of covid-19 is reviewed with special reference to immune cell activation. Moreover, the potential implications of these new insights for immunomodulation and biological therapy in IBD are discussed.
CRIS-Team Scopus Importer:2020-05-08
Keywords: cytokines; inflammation; inflammatory bowel disease

COVID-19: biologic and immunosuppressive therapy in gastroenterology and hepatology - Neurath, Markus (Nature Reviews Gastroenterology & Hepatology, 2021)
The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health crisis causing major challenges for clinical care in patients with gastrointestinal diseases. Although triggering of anti-viral immune responses is essential for clearance of infection, some patients have severe lung inflammation and multiorgan failure due to marked immune cell dysregulation and cytokine storm syndrome. Importantly, the activation of cytotoxic follicular helper T cells and a reduction of regulatory T cells have a crucial, negative prognostic role. These findings lead to the question of whether immunosuppressive and biologic therapies for gastrointestinal diseases affect the incidence or prognosis of COVID-19 and, thus, whether they should be adjusted to prevent or affect the course of the disease. In this Review, data on the use of such therapies are discussed with a primary focus on inflammatory bowel disease, autoimmune hepatitis and liver transplantation. In particular, the roles of corticosteroids, classic immunosuppressive agents (such as thiopurines and mycophenolate mofetil), small molecules (such as Janus kinase (JAK) inhibitors), and biologic agents (such as tumour necrosis factor (TNF) blockers, vedolizumab and ustekinumab) are reviewed. Finally, the use of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines for the prevention of infection in patients with gastrointestinal diseases and concomitant immunosuppressive or biologic therapy will be discussed.
CRIS-Team Scopus Importer:2021-07-16

COVID-19 in cancer patients: clinical characteristics and outcome—an analysis of the LEOSS registry - Rüthrich, Maria Madeleine; Giessen-Jung, C.; Borgmann, S.; Classen, A. Y.; Dolff, S.; Grüner, B.; Hanses, F.; Isberner, N.; Köhler, P.; Lanznaster, J.; Merle, U.; Nadalin, S.; et al. (Annals of Hematology, 2020)
Introduction: Since the early SARS-CoV-2 pandemic, cancer patients have been assumed to be at higher risk for severe COVID-19. Here, we present an analysis of cancer patients from the LEOSS (Lean European Open Survey on SARS-CoV-2 Infected Patients) registry to determine whether cancer patients are at higher risk. Patients and methods: We retrospectively analyzed a cohort of 435 cancer patients and 2636 non-cancer patients with confirmed SARS-CoV-2 infection, enrolled between March 16 and August 31, 2020. Data on socio-demographics, comorbidities, cancer-related features and infection course were collected. Age-, sex- and comorbidity-adjusted analysis was performed. Primary endpoint was COVID-19-related mortality. Results: In total, 435 cancer patients were included in our analysis. Commonest age category was 76–85 years (36.5%), and 40.5% were female. Solid tumors were seen in 59% and lymphoma and leukemia in 17.5% and 11% of patients. Of these, 54% had an active malignancy, and 22% had recently received anti-cancer treatments. At detection of SARS-CoV-2, the majority (62.5%) presented with mild symptoms. Progression to severe COVID-19 was seen in 55% and ICU admission in 27.5%. COVID-19-related mortality rate was 22.5%. Male sex, advanced age, and active malignancy were associated with higher death rates. Comparing cancer and non-cancer patients, age distribution and comorbidity differed significantly, as did mortality (14% vs 22.5%, p value < 0.001). After adjustments for other risk factors, mortality was comparable. Conclusion: Comparing cancer and non-cancer patients, outcome of COVID-19 was comparable after adjusting for age, sex, and comorbidity. However, our results emphasize that cancer patients as a group are at higher risk due to advanced age and pre-existing conditions.
CRIS-Team Scopus Importer:2020-11-13
Keywords: Adjusted analysis; Cancer patients; Cohort study; COVID-19; LEOSS; Pandemic; SARS-CoV-2

COVID-19 - more than respiratory disease: a gastroenterologist's perspective. - Konturek, P. C.; Harsch, I. A.; Neurath, Markus; Zopf, Yurdagül (Journal of Physiology and Pharmacology, 2020)
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV2) outbreak is the most dramatic event since World War II. Originating as a cluster of unexplained cases of pneumonia, it turned out that this viral disease termed COVID-19 is not only a respiratory infection, but a systemic disease associated with a number of extrapulmonary complications. One of the medical disciplines that is strongly affected by this viral infection is gastroenterology. COVID-19 causes in some patients typical symptoms of enteritis such as diarrhea or abdominal pain. There is also evidence that this infection may lead to liver and pancreatic injury. Since the SARS-CoV2 virus was detected in stool, a fecal-oral route of transmission is possible. Moreover, viral receptor angiotensin converting enzyme 2 (ACE2) is highly expressed in the gastrointestinal tract and enables the invasion of the gastrointestinal epithelium as demonstrated in vitro and in vivo. COVID-19 pandemic has an impact on the daily practice and the workflows in endoscopy leading to a dramatic decrease of screening and surveillance procedures. COVID-19 impacts the therapy of patients with inflammatory bowel disease (IBD), particularly those using high doses of corticosteroids, immunosuppressive agents and biologics. Patients with preexisting liver disease, especially metabolic associated liver fatty disease (MALFD) with fibrosis or liver cirrhosis, are at high risk for severe COVID-19. As long as no active vaccine against SARS-CoV2 is available, gastroenterologists have to be aware of these problems that affect their daily routine practice.
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Keywords: SARS-CoV2; pandemic; COVID-19; gastrointestinal manifestations; anti-inflammatory therapy; gut microbiota; endoscopy; inflammatory bowel disease; liver disease

COVID-19 pandemic impact on healthcare professionals treating patients with neuroendocrine tumors (NET): An international NET CONNECT survey - Hernando, J.; Lamarca, A.; Cives, M.; Caplin, M. E.; Pavel, Marianne Ellen (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-10-15

COVID-19: risk for cytokine targeting in chronic inflammatory diseases? - Schett, Georg; Sticherling, Michael; Neurath, Markus (Nature Reviews Immunology, 2020)
CRIS-Team Scopus Importer:2020-04-28

CRISPR/Cas9 in Gastrointestinal Malignancies - Jefremow, André; Neurath, Markus; Waldner, Maximilian (Frontiers in Cell and Developmental Biology, 2021)
Gastrointestinal (GI) cancers such as colorectal cancer (CRC), gastric cancer (GC), esophageal cancer (EG), pancreatic duct adenocarcinoma (PDAC) or hepatocellular cancer (HCC) belong to the most commonly diagnosed types of cancer and are among the most frequent causes of cancer related death worldwide. Most types of GI cancer develop in a stepwise fashion with the occurrence of various driver mutations during tumor progression. Understanding the precise function of mutations driving GI cancer development has been regarded as a prerequisite for an improved clinical management of GI malignancies. During recent years, CRISPR/Cas9 has developed into a powerful tool for genome editing in cancer research by knocking in and knocking out even multiple genes at the same time. Within this review, we discuss recent applications for CRISPR/Cas9-based genome editing in GI cancer research including CRC, GC, EG, PDAC and HCC. These applications include functional studies of candidate genes in cancer cell lines or organoids in vitro as well as in murine cancer models in vivo, library screening for the identification of previously unknown driver mutations and even gene therapy of GI cancers.
CRIS-Team Scopus Importer:2021-12-31
Keywords: cancer of the biliary tract; colorectal cancer; CRISPR/cas9; esophageal cancer; gastrointestinal cancer; hepatocellular cancer; pancreatic cancer

Crohn's Disease: Improved Treatment by Treat-to-Target-Concept Comment - Atreya, Raja (Deutsche Medizinische Wochenschrift, 2018)
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Crohn's Disease: Risankizumab as Induction- and Maintenance Therapy Comment - Atreya, Raja (Deutsche Medizinische Wochenschrift, 2022)
CRIS-Team WoS Importer:2022-09-16

Crohn's disease - use of biomarkers in general practice - Vetter, Marcel; Neurath, M. F.; Atreya, Raja (MMW Fortschritte der Medizin, 2017)
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Cross-sectional imaging of intestinal barrier dysfunction by confocal laser endomicroscopy can identify patients with food allergy in vivo with high sensitivity - Rath, Timo; Dieterich, Walburga; Kätscher-Murad, Christiane; Neurath, Markus; Zopf, Yurdagül (Scientific Reports, 2021)
Food allergy (FA) affects approximately 3 to 4% of the adult population in westernized countries. Suspected FA is even more prevalent and requires extensive diagnostic work-up. Within this study, we evaluated whether assessment of the integrity of the epithelial barrier by confocal laser endomicroscopy (CLE) during colonoscopy can be used as a screening tool to identify patients with FA. 60 patients with suspected FA were prospectively included. Serology with total and food-specific IgE, anti-tissue transglutaminase, skin prick testing, food intolerance tests, food intake registration and assessment of clinical complaints were performed. During colonocopy, standardized CLE was performed in the terminal ileum and at two colorectal sites. Analysis of CLE images included functional (i.e. presence of epithelial barrier dysfunction) and quantitative parameters of intestinal architecture. 27 of 60 patients (45%) were diagnosed with FA. Barrier dysfunction was analyzed on 65.837 ileal and on 93.251 colonic images. 96% of patients with FA exhibited functional and structural barrier defects while barrier dysfunction was found in only 33% of patients without FA (p < 0.0001). Visualizing barrier dysfunction with CLE for in vivo diagnosis of FA had a sensitivity and specificity of 96% and 67%, respectively, with a positive and negative prediction of 70% and 96%, respectively. Parameters intrinsic to the crypt architecture including crypt diameter, intercrypt distance, crypt lumen diameter and colonic vasculature were not different between patients with and without FA. CLE-based imaging of the intestinal barrier during colonoscopy might help in stratifying patients with suspected FA for further diagnostic work-up.
CRIS-Team Scopus Importer:2021-06-25

Crosstalk between microbiota, pathogens and the innate immune responses - Günther, Claudia; Josenhans, Christine; Wehkamp, Jan (International Journal of Medical Microbiology, 2016)
Research in the last decade has convincingly demonstrated that the microbiota is crucial in order to prime and orchestrate innate and adaptive immune responses of their host and influence barrier function as well as multiple developmental and metabolic parameters of the host. Reciprocally, host reactions and immune responses instruct the composition of the microbiota. This review summarizes recent evidence from experimental and human studies which supports these arms of mutual relationship and crosstalk between host and resident microbiota, with a focus on innate immune responses in the gut, the role of cell death pathways and antimicrobial peptides. We also provide some recent examples on how dysbiosis and pathogens can act in concert to promote intestinal infection, inflammatory pathologies and cancer. The future perspectives of these combined research efforts include the discovery of protective species within the microbiota and specific traits and factors of microbes that weaken or enforce host intestinal homeostasis.
EVALuna2:2213

Current and Emerging Targeted Therapies for Ulcerative Colitis. - Pietschner, Robert; Rath, Timo; Neurath, Markus; Atreya, Raja (Visceral Medicine, 2023)
BACKGROUND: Ulcerative colitis is one of the main entities of inflammatory bowel diseases. The clinical course of this immune-mediated disorder is marked by unpredictable exacerbations and asymptomatic remission, causing lifelong morbidity. Optimized anti-inflammatory treatment is a prerequisite to not only restore the quality of life of the affected patients but also halt progressive bowel damage and reduce the risk for colitis-associated neoplasia. Advances in understanding the underlying immunopathogenesis of ulcerative colitis have led to the advent of targeted therapies that selectively inhibit crucial molecular structures or signaling pathways that perpetuate the inflammatory reaction. SUMMARY: We will delineate the mode of action and summarize efficacy and safety data of current and emerging targeted therapies in ulcerative colitis, which encompasses representatives of the drug classes of antibodies, small molecules, and oligonucleotides. These substances have already been approved for induction and maintenance treatment or are being tested in late-stage clinical trials in moderately-to-severely active ulcerative colitis patients. These advanced therapies have enabled us to define and achieve novel therapeutic outcomes, such as clinical and endoscopic remission, histological remission, mucosal healing, and recently, also barrier healing as an emerging outcome measure. KEY MESSAGES: Established and emerging targeted therapies and monitoring modalities broaden our therapeutic armamentarium and have enabled us to define novel therapeutic outcomes that have the potential to modify the individual disease course of patients with ulcerative colitis.
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Current and emerging therapeutic targets for IBD - Neurath, Markus (Nature Reviews Gastroenterology & Hepatology, 2017)
Various therapeutic advances have led to a paradigm shift in the clinical management of patients with IBD. The introduction of immunosuppressive (such as azathioprine) and biologic agents (such as TNF blockers) has markedly reduced the need to use corticosteroids for therapy. Furthermore, the α4β7 integrin blocker vedolizumab has been introduced for clinical IBD therapy. Moreover, various new inhibitors of cytokines (for example, IL-6-IL-6R and IL-12-IL-23 blockers or apremilast), modulators of cytokine signalling events (for example, JAK inhibitors or SMAD7 blocker), inhibitors of transcription factors (for example, GATA3 or RORγt) and new anti-adhesion and anti-T-cell-activation and migration strategies (for example, β7 integrin, sphingosine 1-phosphate receptors and MAdCAM1 inhibitors, regulatory T-cell therapy and stem cells) are currently being evaluated in controlled clinical trials. This Review aims to provide a comprehensive overview about current and future therapeutic approaches for IBD therapy. Furthermore, potential mechanisms of action of these therapeutic approaches and their implications for clinical therapy in IBD are discussed.
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Current and Future Targets for Mucosal Healing in Inflammatory Bowel Disease - Atreya, Raja; Neurath, Markus (Visceral Medicine, 2017)
The induction and subsequent maintenance of mucosal healing has emerged as one of the central therapeutic goals in the management of patients with inflammatory bowel disease (IBD) (Crohn's disease and ulcerative colitis). Current and novel treatment options are assessed regarding their therapeutic efficacy on the basis of their ability to induce mucosal healing. However, there is still substantial debate about the precise definition of mucosal healing. Here, we will give an overview regarding the definitions of mucosal healing as well as its probable effects on long-term disease behavior and finally focus on current and potential therapeutic targets to achieve this therapeutic goal in IBD patients.
EVALuna2:35478

Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation - Garn, Holger; Bahn, Sabine; Baune, Bernhard T.; Binder, Elisabeth B.; Bisgaard, Hans; Chatila, Talal A.; Chavakis, Triantafyllos; Culmsee, Carsten; Dannlowski, Udo; Gay, Steffen; Gern, James; Haahtela, Tari; et al. (Journal of Allergy and Clinical Immunology, 2016)
Recent research indicates that chronic inflammatory diseases, including allergies and autoimmune and neuropsychiatric diseases, share common pathways of cellular and molecular dysregulation. It was the aim of the International von-Behring-Röntgen Symposium (October 16-18, 2014, in Marburg, Germany) to discuss recent developments in this field. These include a concept of biodiversity; the contribution of urbanization, lifestyle factors, and nutrition (eg, vitamin D); and new mechanisms of metabolic and immune dysregulation, such as extracellular and intracellular RNAs and cellular and mitochondrial stress. Epigenetic mechanisms contribute further to altered gene expression and therefore to the development of chronic inflammation. These novel findings provide the foundation for further development of preventive and therapeutic strategies.
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Current Endoscopic Resection Techniques for Gastrointestinal Lesions: Endoscopic Mucosal Resection, Submucosal Dissection, and Full-Thickness Resection - Hoffman, Arthur; Atreya, Raja; Rath, Timo; Neurath, Markus (Visceral Medicine, 2021)
Background: Endoscopic resection of dysplastic lesions in early stages of cancer reduces mortality rates and is recommended by many national guidelines throughout the world. Snare polypectomy and endoscopic mucosal resection (EMR) are established techniques of polyp removal. The advantages of these methods are their relatively short procedure times and acceptable complication rates. The latter include delayed bleeding in 0.9% and a perforation risk of 0.4-1.3%, depending on the size and location of the resected lesion. EMR is a recent modification of endoscopic resection. A limited number of studies suggest that larger lesions can be removed en bloc with low complication rates and short procedure times. Novel techniques such as endoscopic submucosal dissection (ESD) are used to enhance en bloc resection rates for larger, flat, or sessile lesions. Endoscopic full-thickness resection (EFTR) is employed for non-lifting lesions or those not easily amenable to resection. Procedures such as ESD or EFTR are emerging standards for lesions inaccessible to EMR techniques. Summary: Endoscopic treatment is now regarded as first-line therapy for benign lesions. Key Message: Endoscopic resection of dysplastic lesions or early stages of cancer is recommended. A plethora of different techniques can be used dependent on the lesions.
CRIS-Team Scopus Importer:2021-04-19
Keywords: Complication rates; Early cancer; Endoscopic resection; Resection techniques

Current issues in inflammatory bowel disease neoplasia - Neumann, Helmut; Vieth, Michael (Histopathology, 2015)
Recent histological criteria and developments in the field of endoscopic imaging have led to higher detection rates of neoplasms in ulcerative colitis. Once a lesion is detected, endoscopic resection is recommended to guide subsequent surveillance or therapy and to gain adequate material for histological diagnosis. Further management is based on the grade of neoplasia and on whether the neoplasia is categorized as sporadic or colitis-associated. Nevertheless it may sometimes be difficult to distinguish colitis-associated neoplasms from sporadic neoplasms. A better way to report this may be ultimately classified. Here, we review endoscopic and histological parameters to help to differentiate colitis-associated neoplasia from sporadic lesions and discuss pathogenesis and therapeutic options.
EVALuna2:2101

Cyclic derivative of morphiceptin Dmt-cyclo-(D-Lys-Phe-D-Pro-Asp)-NH2(P-317), a mixed agonist of MOP and KOP opioid receptors, exerts anti-inflammatory and anti-tumor activity in colitis and colitis-associated colorectal cancer in mice - Zielińska, Marta; Szymaszkiewicz, Agata; Jacenik, Damian; Schodel, Lena; Sałaga, Maciej; Zatorski, Hubert; Kordek, Radzisław; Becker, Christoph; Krajewska, Wanda M.; Fichna, Jakub (European Journal of Pharmacology, 2020)
Endogenous opioid system is involved in the maintenance of the intestinal homeostasis. Recently, we proved that stimulation of opioid receptors using P-317, a cyclic morphiceptin analog, resulted in the alleviation of acute colitis in mice. The aim of the current study was to assess the effect of P-317 during colitis and colitis-associated colorectal cancer in mice. Colitis was induced by addition of dextran sodium sulfate (DSS) into drinking water. Colitis-associated colorectal cancer was induced by a single intraperitoneal injection of azoxymethane (AOM) and subsequent addition of DSS into drinking water (week 2, 5, 8). During macroscopic damage evaluation the samples were collected and used for biochemical (MPO activity assay), molecular (qPCR and western blot) and histological studies. In experimental colitis, P-317 induced an anti-inflammatory response as indicated by macroscopic and microscopic scores. In the colitis-associated colorectal cancer model, a significant difference in colorectal tumor development was observed between vehicle- and P-317-treated mice. P-317 decreased the total number of colonic tumors and inhibited MPO activity. Hematoxylin and eosin staining confirmed anti-tumor activity of P-317. The expression of TNF-α was decreased in P-317-treated mice as compared to the vehicle-treated group. P-317 decreased proliferation as well as β-catenin expression in tumors. P-317, a mixed MOP and KOP receptor agonist, induced an anti-inflammatory response in experimental colitis and decreased tumor development in colitis-associated colorectal cancer in mice.
CRIS-Team Scopus Importer:2020-09-18
Keywords: Colitis; Colitis-associated colorectal cancer; Morphiceptin; Opioid; Opioid receptor

Cyclin-Dependent Kinase Inhibitors and Their Therapeutic Potential in Colorectal Cancer Treatment - Thoma, Oana-Maria; Neurath, Markus; Waldner, Maximilian (Frontiers in Pharmacology, 2021)
Cyclin-dependent kinases (CDKs) are key players in cell cycle regulation. So far, more than ten CDKs have been described. Their direct interaction with cyclins allow progression through G1 phase, transitions to S and G2 phase and finally through mitosis (M). While CDK activation is important in cell renewal, its aberrant expression can lead to the development of malignant tumor cells. Dysregulations in CDK pathways are often encountered in various types of cancer, including all gastrointestinal (GI) tract tumors. This prompted the development of CDK inhibitors as novel therapies for cancer. Currently, CDK inhibitors such as CDK4/6 inhibitors are used in pre-clinical studies for cancer treatment. In this review, we will focus on the therapeutic role of various CDK inhibitors in colorectal cancer, with a special focus on the CDK4/6 inhibitors.
CRIS-Team WoS Importer:2022-02-04

Cyclosporine A regulates pro-inflammatory cytokine production in ulcerative colitis - Steiner, Stefanie; Daniel, Carolin; Fischer, Anika; Atreya, Imke; Hirschmann, Simon; Waldner, Maximilian; Neumann, Helmut; Neurath, Markus; Atreya, Raja; Weigmann, Benno (Archivum Immunologiae Et Therapiae Experimentalis, 2015)
Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel diseases (IBD), which are defined as relapsing inflammations of the gastrointestinal tract. Cyclosporine A (CsA) is a potential rescue treatment to avoid colectomy in severe steroid-refractory UC patients. The molecular mechanism of action of CsA in UC is nevertheless still not well understood. The aim of this study was to investigate the effect of CsA on a possible modulation of cytokine production by peripheral blood mononuclear cells (PBMCs) of controls and patients with UC or CD. Upon CsA treatment, analyses of cytokine levels revealed a significant reduction of IL-13 expression in PBMCs from patients with UC, whereas other cytokine expression levels remained unaffected. To address the question whether CsA treatment impinges on the induction of cell death, apoptosis assays were performed using CD4(+) T cells from peripheral blood of patients suffering from either UC or CD. It became clear that CsA treatment resulted in a specific induction of apoptosis in samples from controls and patients with UC but not with CD. Apoptosis induction was not mediated via the mitochondrial apoptosis pathway. The present data support the concept that CsA treatment modulates pro-inflammatory cytokine production and T cell survival in UC via the induction of apoptosis and might therefore help to explain the clinical efficacy of CsA in patients with UC.
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Cytokine and immune cell profiling in the cerebrospinal fluid of patients with neuro-inflammatory diseases - Lepennetier, Gildas; Hracsko, Zsuzsanna; Unger, Marina; Van Griensven, Martijn; Grummel, Verena; Krumbholz, Markus; Berthele, Achim; Hemmer, Bernhard; Kowarik, Markus C. (Journal of Neuroinflammation, 2019)
Background: Cytokines play multiple roles during neuro-inflammatory processes and several cytokines have been studied in the context of specific diseases. This study provides a comprehensive picture of cerebrospinal fluid (CSF) changes during neuro-inflammation by analyzing multiple cytokines in combination with immune cell subsets and standard CSF parameters. Methods: Using multiplex assays, we simultaneously measured 36 cytokines (CCL1-3, CCL7, CCL8, CCL11, CCL13, CCL19, CCL20, CCL22-27, CXCL1, CXCL2, CXCL5, CXCL6, CXCL8, CXCL9, CXCL11-13, CXCL16, CX3CL1, IL2, IL4, IL6, IL10, IL16, GM-CSF, IFNγ, MIF, TNFα, and MIB1β) in the CSF and serum of 75 subjects. Diagnoses included clinically isolated syndrome and relapsing-remitting multiple sclerosis (MS, n = 18), secondary progressive MS (n = 8), neuro-syphilis (n = 6), Lyme neuro-borreliosis (n = 13), bacterial and viral meningitis (n = 20), and patients with non-inflammatory neurological diseases (NIND, n = 10). Cytokine concentrations were correlated with CSF standard parameters and CSF immune cell subsets (CD4 and CD8 T cells, B cells, plasmablasts, monocytes, and NK cells) quantified by flow cytometry. Results: We observed increased levels of multiple cytokines (26/36) in patients with neuro-inflammatory diseases when compared to NIND that consistently correlated with CSF cell count and QAlbumin. Most CSF cytokine concentrations correlated with each other, but correlations between CSF and serum values were scarce (3/36). Within the CSF compartment, CXCL13 showed a strong association with B cells when analyzing all patients, as well as patients with an intact blood-brain barrier (BBB). NK cells positively correlated with CSF concentrations of multiple cytokines (22/36) when analyzing all patients. These correlations were maintained when looking at patients with a disrupted BBB but not detectable in patients with an intact BBB. Conclusions: Under conditions of neuro-inflammation, multiple CSF cytokines are regulated in parallel and most likely produced locally. A combined increase of CSF CXCL13 levels and B cells occurs under conditions of an intact BBB. Under conditions of a disrupted BBB, CSF NK cells show significantly increased values and seem to have a major contribution to overall inflammatory processes, reflected by a strong correlation with multiple cytokines. Future studies are necessary to address the exact kinetics of these cytokines during neuro-inflammation and their relation to specific diseases phenotypes.
CRIS-Team Scopus Importer:2019-11-26
Keywords: B cells; Blood-brain barrier; CSF; CXCL13; Cytokines; Immune cell subsets; Neuro-inflammation; NK cells

Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut - Mahapatro, Mousumi; Erkert, Lena; Becker, Christoph (Cells, 2021)
Cytokines are small proteins that are secreted by a vast majority of cell types in the gut. They not only establish cell-to-cell interactions and facilitate cellular signaling, but also regulate both innate and adaptive immune responses, thereby playing a central role in genetic, inflammatory, and infectious diseases of the gut. Both, immune cells and gut epithelial cells, play important roles in intestinal disease development. The epithelium is located in between the mucosal immune system and the gut microbiome. It not only establishes an efficient barrier against gut microbes, but it also signals information from the gut lumen and its composition to the immune cell compartment. Communication across the epithelial cell layer also occurs in the other direction. Intestinal epithelial cells respond to immune cell cytokines and their response influences and shapes the microbial community within the gut lumen. Thus, the epithelium should be seen as a translator or a moderator between the microbiota and the mucosal immune system. Proper communication across the epithelium seems to be a key to gut homeostasis. Indeed, current genome-wide association studies for intestinal disorders have identified several disease susceptibility loci, which map cytokine signatures and their related signaling genes. A thorough understanding of this tightly regulated cytokine signaling network is crucial. The main objective of this review was to shed light on how cytokines can orchestrate epithelial functions such as proliferation, cell death, permeability, microbe interaction, and barrier maintenance, thereby safeguarding host health. In addition, cytokine-mediated therapy for inflammation and cancer are discussed.
CRIS-Team Scopus Importer:2021-02-05
Keywords: cytokines; gut homeostasis; IBD; immunity; inflammation; signaling

Cytokines in inflammatory bowel disease - Neurath, Markus (Nature Reviews Immunology, 2014)
Cytokines have a crucial role in the pathogenesis of inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, where they control multiple aspects of the inflammatory response. In particular, the imbalance between pro-inflammatory and anti-inflammatory cytokines that occurs in IBD impedes the resolution of inflammation and instead leads to disease perpetuation and tissue destruction. Recent studies suggest the existence of a network of regulatory cytokines that has important implications for disease progression. In this Review, we discuss the role of cytokines produced by innate and adaptive immune cells, as well as their relevance to the future therapy of IBD.
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Cytokines in inflammatory bowel diseases – Update 2020 - Leppkes, Moritz; Neurath, Markus (Pharmacological research, 2020)
Inflammatory Bowel Diseases (IBD), namely Crohn's Disease and Ulcerative Colitis, cause a significant disease burden in modern civilization. Ever since the introduction of anti-TNF-directed therapies 20 years ago, cytokines have attracted a lot of research attention and several cytokine-directed therapies have been implemented in the clinical treatment of these diseases. The research progress in these past years has underlined the importance of both myeloid and lymphoid elements of the immune system in the pathogenesis of IBD and their cytokine-mediated interplay. The conceptual framework of the mucosal cytokine network has shifted during these years from a T helper (Th) dichotomy (Th1/Th2) to the effector/regulatory T cell balance, while nowadays, the importance of myeloid cell instruction of lymphocytes, namely by IL-12 and IL-23, is increasingly recognized. Anti-IL-12p40 agents, like ustekinumab, groundbreakingly changed patient care, and anti-IL23p19-directed approaches are on the verge of grand success. In this review we present a modular approach to understand the cytokine network and put it into the context of the pathogenesis of IBD with a special focus on publications since 2014.
CRIS-Team Scopus Importer:2020-06-09
Keywords: Biologicals; Crohn's disease; Cytokines; Gastroenterology; IBD; Ulcerative colitis

Daily adjustment of glucocorticoids by patients with adrenal insufficiency - Schöfl, Christof; Mayr, Bernhard; Maison, Nicole; Beuschlein, Felix; Meyer, Gesine; Badenhoop, Klaus; Kienitz, Tina; Quinkler, Marcus (Clinical Endocrinology, 2019)
Background: Patients with adrenal insufficiency (AI) require lifelong glucocorticoid (GC) replacement. AI patients need to adjust GC dosage in response to stressful events and illness in order to prevent life-threatening adrenal crisis (AC). Aim: To evaluate self-management of patients with AI. Methods: Four German centres, which are using patient's diary as part of their routine clinical practice, instructed AI patients to prospectively document any discomfort, intercurrent illness or stressful events as well as changes in GC therapy on a daily basis. Diaries of 80 patients (44 females, 52.9 ± 15.9 years, 34 primary AI) were collected and analysed. A symptom score sheet was used to evaluate severity of discomfort. Results: In total, 34 074 patient days (93.4 years) were recorded. 4622 days with discomfort were documented. On 35% of those days (n = 1621), patients increased their GC dose (4.8% of all days). Patients who recorded discomfort had a median of four episodes of discomfort, which lasted a median of 2 days. Women documented significantly more episodes of discomfort than men (P = 0.014). Low-to-median symptom scores resulted in GC increase by 50%-60%, whereas high symptom scores and/or fever resulted in doubling GC daily dose. However, dose increase was only 55% in situations indicating gastrointestinal (GI) infection. Conclusion: Severe discomfort did not always result in dose increase, especially in GI infection. However, low symptom scores resulted in an inappropriate GC increase in some patients. This underscores an urgent need for improved training methods. Keeping daily records might be a useful tool for continued and individualized patient education.
CRIS-Team Scopus Importer:2019-06-04
Keywords: Addison's disease; adrenal crisis; hydrocortisone; patient's diary

Das chronische Schmerzsyndrom - vom Darm ausgehend - Zopf, Yurdagül; Schink, Monic; Lukasch, U.; Dieterich, Walburga (International Journal of Learning, Teaching and Educational Research, 2019)
Summary: Besides urological and gynecological diseases, gastrointestinal disorders are a common cause for chronic abdominal pain in women. The spectrum ranges from rare disorders, e. g. celiac disease or inflammatory bowel disease (Crohn's disease and ulcerative colitis) to the more frequently occurring irritable bowel syndrome and to food intolerances. Other gastrointestinal disorders including diverticulitis, enteritis, malignant stenosis or obstructions caused by gastrointestinal tumors, may also cause chronic abdominal pain. Moreover, certain food components such as the so-called FODMAPs or gluten are responsible for intolerances leading to abdominal pain and bloating in a subgroup of patients. Especially in nutrition-associated disorders dietary changes or elimination diets can thus result in an improvement of clinical symptoms as well as in a reduction of chronic pain. Nutritional counselling should be conducted by a specialized nutritionist taking into account the individual thresholds for symptom-triggering food components. Furthermore, the influence of the human gut flora on gastrointestinal afflictions and pain perception is discussed, but further research is required to assess the therapeutic effects of e. g. probiotics.
CRIS-Team Scopus Importer:2019-11-05
Keywords: FODMAP; Food intolerances; Gluten; Irritable bowel syndrome; Pain syndrome; Pelvic pain

Death-associated protein kinase: A molecule with functional antagonistic duality and a potential role in inflammatory bowel disease (Review) - Steinmann, Sara; Scheibe, Kristina; Erlenbach-Wuensch, Katharina; Neufert, Clemens; Schneider-Stock, Regine (International Journal of Oncology, 2015)
The cytoskeleton-associated serine/threonine kinase death-associated protein kinase (DAPK) has been described as a cancer gene chameleon with functional antagonistic duality in a cell type and context specific manner. The broad range of interaction partners and substrates link DAPK to inflammatory processes especially in the gut. Herein we summarize our knowledge on the role of DAPK in different cell types that play a role under inflammatory conditions in the gut. Besides some promising experimental data suggesting DAPK as an interesting drug target in inflammatory bowel disease there are many open questions regarding direct evidence for a role of DAPK in intestinal inflammation.
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Deciphering Novel Mechanistic and Pharmacokinetic Effects of Tofacitinib in Intestinal Inflammation: Expect the Unexpected - Atreya, Raja; Neurath, Markus (Cellular and Molecular Gastroenterology and Hepatology, 2022)
CRIS-Team Scopus Importer:2022-02-04

Deciphering the role of HLA-DO in immune responses after allogeneic stem cell transplantation - Zeun, Julia; Flamann, Cindy; Neubeck, S.; Bausenwein, J.; Seyler, L.; Vogler, T.; Brey, Stefanie; Büttner-Herold, Maike; Hildner, Kai; Winkler, Thomas; Bruns, Heiko; Kretschmann, S.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2021)
CRIS-Team WoS Importer:2022-03-25

Deep enteroscopy with a conventional colonoscope: initial multicenter study by using a through-the-scope balloon catheter system - Ali, Rabia; Wild, Daniel; Shieh, Frederick; Diehl, David L.; Fischer, Monika; Tamura, Wataru; Rubin, David T.; Kumbhari, Vivek; Okolo, Patrick; Storm, Andrew; Halpern, Zamir; Neumann, Helmut; et al. (Gastrointestinal Endoscopy, 2015)
The advent of capsule endoscopy has revolutionized evaluation of the small bowel. Capsule endoscopy has become the criterion standard as the initial examination to diagnose small-bowel abnormalities, but does not allow for tissue sampling or therapeutic intervention. Deep enteroscopy can be performed by using a balloon-assisted device or a spiral overtube for both diagnostic and therapeutic interventions of the small bowel. Deep enteroscopy is time-consuming and requires special endoscopes and accessories to perform the examination. We studied a novel through-the-scope balloon catheter system used for deep enteroscopy that uses a conventional colonoscope and standard accessories.We performed a 9-center, retrospective study using a novel TTS balloon system for small-bowel evaluation. The new through-the-scope device is an on-demand balloon catheter that is inserted through the instrument channel of a standard colonoscope and enables deep advancement into the small bowel in either the anterograde or retrograde approach. It consists of a balloon inflation/deflation system and a single-use balloon catheter designed for anchoring in the small bowel. The balloon is inflated to an anchoring pressure in the small intestine, and a repetitive push-pull technique is performed, with the endoscope sliding over the guiding catheter to the inflated balloon. The catheter may be removed and reinserted to allow for therapeutic intervention while maintaining the endoscope position.A total of 98 patients were included; 52% were male, and the mean age was 55 years old (range 15-94 years). Indications included abdominal pain, iron-deficiency anemia, occult GI bleeding, diarrhea, abnormal capsule endoscopy, weight loss, protein losing enteropathy, retained foreign body, altered anatomy ERCP, and small-bowel strictures. Anterograde enteroscopy was performed in 65 patients. The average depth of insertion was 158 cm (range 50-350 cm) from the pylorus. Retrograde enteroscopy was performed in 33 cases. The average depth of insertion was 89 cm (range 20-150 cm) beyond the ileocecal valve. Overall, diagnostic yield was 44%. The average advancement time for the anterograde and retrograde enteroscopy cases was 15.5 minutes. There were no procedural adverse outcomes reported in the 98 cases.The TTS advancing balloon is a safe and effective way to perform deep enteroscopy by using a conventional colonoscope without the need for an overtube. Procedure time is shorter than that of other forms of deep enteroscopy. Diagnostic yield and depth of insertion are on par with other forms of deep enteroscopy. This is the largest reported study using this novel technology to diagnose and treat small-bowel disease.
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Deletion of the Casp8 gene in mice results in ileocolitis, gut barrier dysfunction, and malassimilation, which can be partially attenuated by inulin or sodium butyrate. - Günther, Claudia; Kaden-Volynets, Valentina; Zimmermann, Julia; Beisner, Julia; Becker, Christoph; Bischoff, Stephan C. (American Journal of Physiology-Gastrointestinal and Liver Physiology, 2019)
Genetic mouse models for ileocolitis are important to understand inflammatory bowel disease in humans. We examined dietetic factors that might aggravate or attenuate ileocolitis and related pathologies in such a model. Deletion of the caspase-8 gene results not only in ileocolitis but also in gut barrier dysfunction, liver steatosis, and malassimilation, which can be partially attenuated by oral inulin or sodium butyrate. Our data indicate that diet modifications can contribute to disease variability and therapy.
Keywords: caspase-8; fructose; intestinal barrier; inulin; sodium butyrate

Designer Thiopurine-analogues for Optimised Immunosuppression in Inflammatory Bowel Diseases - Atreya, Imke; Diall, Alexandra; Dvorsky, Radovan; Atreya, Raja; Henninger, Christian; Gruen, Mathias; Hofmann, Ute; Schaeffeler, Elke; Lopez Posadas, Rocío; Daehn, Ilse; Zenker, Stefanie; Doebroenti, Michael; et al. (Journal of Crohns & Colitis, 2016)
The clinical use of azathioprine and 6-mercaptopurine is limited by their delayed onset of action and potential side effects such as myelosuppression and hepatotoxicity. As these drugs specifically target the Vav1/Rac1 signalling pathway in T lamina propria lymphocytes via their metabolite 6-thio-GTP, we studied expression and optimised suppression of this pathway in inflammatory bowel diseases [IBD].Rac1 and Vav1 expressions were analysed in mucosal immune cells in IBD patients. Targeted molecular modelling of the 6-thio-GTP molecule was performed to optimise Rac1 blockade; 44 modified designer thiopurine-analogues were tested for apoptosis induction, potential toxicity, and immunosuppression. Activation of the Vav1/Rac1 pathway in lymphocytes was studied in IBD patients and in lamina propria immune cells in the presence or absence of thiopurine-analogues.Several thiopurine-analogues induced significantly higher T cell apoptosis than 6-mercaptopurine. We identified a compound, denoted B-0N, based on its capacity to mediate earlier and stronger induction of T cell apoptosis than 6-mercaptopurine. B-0N-treatment resulted in accelerated inhibition of Rac1 activity in primary peripheral blood T cells as well as in intestinal lamina propria immune cells. Compared with 6-thio-GTP and 6-mercaptopurine, B-0N-treatment was associated with decreased myelo- and hepatotoxicity.The Vav1/Rac1 pathway is activated in mucosal immune cells in IBD. The designer thiopurine-analogue B-0N induces immunosuppression more potently than 6-mercaptopurine.
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Detection by flow cytometry of anti-neutrophil cytoplasmic antibodies in a novel approach based on neutrophil extracellular traps - Roitsch, Stefan; Goesswein, Stefanie; Neurath, Markus; Leppkes, Moritz (Autoimmunity, 2018)
Background:Anti-neutrophil-cytoplasmic antibodies (ANCA) are auto-antibodies directed against components of neutrophil granulocytes and may be found in various inflammatory conditions, like small-vessel vasculitis or ulcerative colitis (UC). Routine ANCA screening is performed on ethanol-fixed neutrophils using indirect immunofluorescence technique. Yet, how neutrophil granule proteins become available to immunologic presentation is a matter of debate. In recent years, various studies have shown that neutrophils are able to extrude their chromatin decorated with granular proteins as neutrophil extracelullar traps (NETs).Aim: We hypothesized that (I) ANCA immunoreactivity may be found on NETs and (II) NETs may serve as a useful tool in a novel approach for ANCA detection.Methods: Sera from patients suffering from either ANCA-associated vasculitis (n=10), UC (n=30) or sera from patients without diagnosed ANCA-associated diseases (n=20), respectively, were subjected to indirect immunofluorescence and a newly developed method to detect ANCA by flow cytometry employing microbead technology.Results: ANCA-related immunofluorescence was readily detectable on ethanol-fixed NETs, establishing NETs as a structure carrying ANCA target antigens. Moreover, we observed that neutrophils form NETs in response to microbeads and stick to the surface of these beads. Using these NET-coated microbeads in flow cytometry, we were capable of reliably detecting p-ANCA, c-ANCA, and a-ANCA in tested patient sera. UC-related complex DNase-1-sensitive ANCA (NET-ANCA) antigens were also detected on NET-coated microbeads.Conclusion: NET-coated microbeads may be commercially developed as a novel tool for automated ANCA screening assays using flow cytometry.
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Detection of circulating extracelluar mRNAs by modified small-RNA-sequencing analysis - Akat, Kemal M.; Lee, Youngmin A.; Hurley, Arlene; Morozov, Pavel; Max, Klaas E. A.; Brown, Miguel; Bogardus, Kimberly; Sopeyin, Anuoluwapo; Hildner, Kai; Diacovo, Thomas G.; Neurath, Markus; Borggrefe, Martin; et al. (JCI Insight, 2019)
Extracellular mRNAs (ex-mRNAs) potentially supersede extracellular miRNAs (ex-miRNAs) and other RNA classes as biomarkers. We performed conventional small-RNA-sequencing (sRNA-seq) and sRNA-seq with T4 polynucleotide kinase (PNK) end treatment of total extracellular RNAs (exRNAs) isolated from serum and platelet-poor EDTA, acid citrate dextrose (ACD), and heparin plasma to study the effect on ex-mRNA capture. Compared with conventional sRNA-seq, PNK treatment increased the detection of informative ex-mRNAs reads up to 50-fold. The exRNA pool was dominated by RNA originating from hematopoietic cells and platelets, with additional contribution from the liver. About 60% of the 15- to 42-nt reads originated from the coding sequences, in a pattern reminiscent of ribosome profiling. Blood sample type had a considerable influence on the exRNA profile. On average approximately 350-1100 distinct ex-mRNA transcripts were detected depending on plasma type. In serum, additional transcripts from neutrophils and hematopoietic cells increased this number to near 2300. EDTA and ACD plasma showed a destabilizing effect on ex-mRNA and noncoding RNA ribonucleoprotein complexes compared with other plasma types. In a proof-of-concept study, we investigated differences between the exRNA profiles of patients with acute coronary syndrome and healthy controls. The improved tissue resolution of ex-mRNAs after PNK treatment enabled us to detect a neutrophil signature in ACS that escaped detection by ex-miRNA analysis.
CRIS-Team WoS Importer:2019-05-17

Detection of collagens by multispectral optoacoustic tomography as an imaging biomarker for Duchenne muscular dystrophy - Regensburger, Adrian; Fonteyne, Lina M.; Jüngert, Jörg; Wagner, Anna; Gerhalter, Teresa; Nagel, Armin Michael; Heiß, Rafael; Flenkenthaler, Florian; Qurashi, Matthias; Neurath, Markus; Klymiuk, Nikolai; Kemter, Elisabeth; et al. (Nature Medicine, 2019)
Biomarkers for monitoring of disease progression and response to therapy are lacking for muscle diseases such as Duchenne muscular dystrophy. Noninvasive in vivo molecular imaging with multispectral optoacoustic tomography (MSOT) uses pulsed laser light to induce acoustic pressure waves, enabling the visualization of endogenous chromophores. Here we describe an application of MSOT, in which illumination in the near- and extended near-infrared ranges from 680–1,100 nm enables the visualization and quantification of collagen content. We first demonstrated the feasibility of this approach to noninvasive quantification of tissue fibrosis in longitudinal studies in a large-animal Duchenne muscular dystrophy model in pigs, and then applied this approach to pediatric patients. MSOT-derived collagen content measurements in skeletal muscle were highly correlated to the functional status of the patients and provided additional information on molecular features as compared to magnetic resonance imaging. This study highlights the potential of MSOT imaging as a noninvasive, age-independent biomarker for the implementation and monitoring of newly developed therapies in muscular diseases.
CRIS-Team Scopus Importer:2019-12-17

Detection of Crohn's typical Anti-Yeast Glycan Antibodies by a novel Assay based on Flow Cytometry - Roth, Dominik; Lindemann, Aylin; Goesswein, S.; Neurath, Markus; Armbruster, F. P.; Leppkes, Moritz (Mycoses, 2021)
CRIS-Team WoS Importer:2021-10-08

Determinants Affecting the Clinical Implementation of a Molecularly Informed Molecular Tumor Board Recommendation: Experience from a Tertiary Cancer Center. - Tögel, Lars; Schubart, Christoph; Lettmaier, Sebastian; Neufert, Clemens; Hoyer, Juliane; Wolff, Kerstin; Moskalev, Evgeny; Stöhr, Robert; Agaimy, Abbas; Wiesmann da Silva Reis, André; Wullich, Bernd; Mackensen, Andreas; et al. (Cancers, 2023)
Molecular Tumor Boards (MTBs) converge state-of-the-art next-generation sequencing (NGS) methods with the expertise of an interdisciplinary team consisting of clinicians, pathologists, human geneticists, and molecular biologists to provide molecularly informed guidance in clinical decision making to the treating physician. In the present study, we particularly focused on elucidating the factors impacting on the clinical translation of MTB recommendations, utilizing data generated from gene panel mediated comprehensive genomic profiling (CGP) of 554 patients at the MTB of the Comprehensive Cancer Center Erlangen, Germany, during the years 2016 to 2020. A subgroup analysis of cases with available follow-up data (n = 332) revealed 139 cases with a molecularly informed MTB recommendation, which was successfully implemented in the clinic in 44 (31.7%) of these cases. Here, the molecularly matched treatment was applied in 45.4% (n = 20/44) of cases for ≥6 months and in 25% (n = 11/44) of cases for 12 months or longer (median time to treatment failure, TTF: 5 months, min: 1 month, max: 38 months, ongoing at data cut-off). In general, recommendations were preferentially implemented in the clinic when of high (i.e., tier 1) clinical evidence level. In particular, this was the case for MTB recommendations suggesting the application of PARP, PIK3CA, and IDH1/2 inhibitors. The main reason for non-compliance to the MTB recommendation was either the application of non-matched treatment modalities (n = 30)/stable disease (n = 7), or deteriorating patient condition (n = 22)/death of patient (n = 9). In summary, this study provides an insight into the factors affecting the clinical implementation of molecularly informed MTB recommendations, and careful considerations of these factors may guide future processes of clinical decision making.
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Keywords: Molecular Tumor Board; clinical decision making; precision medicine; molecular pathology; real-world data; cancer care

Determination and prospective validation of cut-off values for the diagnosis of liver cirrhosis for point shear-wave elastography/acoustic radiation force impulse imaging using the ACUSON Sequoia ultrasound system - Meitner-Schellhaas, Barbara; Schüler, Sophia; Vogl, T.; Jesper, Daniel; Vetter, Marcel; Waldner, Maximilian; Strobel, Deike (European Journal of Gastroenterology & Hepatology, 2024)
OBJECTIVES: Point shear-wave elastography (pSWE) alias acoustic radiation force impulse (ARFI) imaging is a well-established ultrasound-based technique for the non-invasive assessment of liver tissue stiffness. As cut-off values for liver cirrhosis cannot be transferred from one ultrasound system to another, this study aimed at determining cut-off values for the newly developed Siemens ACUSON Sequoia ultrasound system. METHODS: In a pilot study phase, two independent examiners conducted 10 pSWE measurements in an elasticity phantom and 32 healthy individuals for the determination of inter-examiner agreement. Afterwards, 22 cirrhotic patients and 57 patients with chronic liver disease undergoing liver biopsy underwent pSWE. Patient characteristics and stiffness values were compared for individuals with and without liver cirrhosis. Diagnostic accuracies of cut-off values for the diagnosis of liver cirrhosis were calculated using areas under the receiver operating characteristics analysis and Youden's index. In a subsequent validation study phase, these cut-off values were validated prospectively in 107 cirrhotic and 68 non-cirrhotic patients. RESULTS: Inter-examiner agreement was excellent for measurements in the elasticity phantom (intra-class correlation coefficient [ICC] = 0.998; P < 0.001), and good for measurements in patients (ICC = 0.844; P < 0.001). The best cut-off value for the diagnosis of liver cirrhosis was 1.405 m/s with an AUC of 0.872, a sensitivity of 88.2% and a specificity of 88.2% ( P < 0.001). CONCLUSION: ARFI elastography using the Siemens ACUSON Sequoia showed a good inter-examiner agreement. The optimal cut-off value was lower than the cut-off values described for former generations of ultrasound devices. These preliminary results should be confirmed in larger patient collectives with histology as the reference standard.
CRIS-Team Scopus Importer:2023-12-15

Development and Initial Validation of a New Endoscopic Training Model for Advanced Endoscopic Procedures - The HEAT International Endoscopy Study - Neumann, Helmut; Buder, Thomas; Loeffler, Silke; Rath, Timo; Naegel, Andreas; Neuhuber, Winfried (2016)
EVALuna2:184251

Development and validation of a classification and scoring system for the diagnosis of oral squamous cell carcinomas through confocal laser endomicroscopy - Oetter, Nicolai; Knipfer, Christian; Rohde, Maximilian; von Wilmowsky, Cornelius; Maier, Andreas; Brunner, Kathrin; Adler, Werner; Neukam, Friedrich Wilhelm; Neumann, Helmut; Stelzle, Florian (Journal of Translational Medicine, 2016)
Confocal laser endomicroscopy (CLE) is an optical biopsy method allowing in vivo microscopic imaging at 1000-fold magnification. It was the aim to evaluate CLE in the human oral cavity for the differentiation of physiological/carcinomatous mucosa and to establish and validate, for the first time, a scoring system to facilitate CLE assessment.The study consisted of 4 phases: (1) CLE-imaging (in vivo) was performed after the intravenous injection of fluorescein in patients with histologically confirmed carcinomatous oral mucosa; (2) CLE-experts (n = 3) verified the applicability of CLE in the oral cavity for the differentiation between physiological and cancerous tissue compared to the gold standard of histopathological assessment; (3) based on specific patterns of tissue changes, CLE-experts (n = 3) developed a classification and scoring system (DOC-Score) to simplify the diagnosis of oral squamous cell carcinomas; (4) validation of the newly developed DOC-Score by non-CLE-experts (n = 3); final statistical evaluation of their classification performance (comparison to the results of CLE-experts and the histopathological analyses).Experts acquired and edited 45 sequences (260 s) of physiological and 50 sequences (518 s) of carcinomatous mucosa (total: 95 sequences/778 s). All sequences were evaluated independently by experts and non-experts (based on the newly proposed classification system). Sensitivity (0.953) and specificity (0.889) of the diagnoses by experts as well as sensitivity (0.973) and specificity (0.881) of the non-expert ratings correlated well with the results of the present gold standard of tissue histopathology. Experts had a positive predictive value (PPV) of 0.905 and a negative predictive value (NPV) of 0.945. Non-experts reached a PPV of 0.901 and a NPV of 0.967 with the help of the DOC-Score. Inter-rater reliability (Fleiss` kappa) was 0.73 for experts and 0.814 for non-experts. The intra-rater reliability (Cronbach's alpha) of the experts was 0.989 and 0.884 for non-experts.CLE is a suitable and valid method for experts to diagnose oral cancer. Using the DOC-Score system, an accurate chair-side diagnosis of oral cancer is feasible with comparable results to the gold standard of histopathology-even in daily clinical practice for non-experienced raters.
EVALuna2:2055

Development and Validation of a Confocal Laser Endomicroscopy-Based Score for In Vivo Assessment of Mucosal Healing in Ulcerative Colitis Patients - Hundorfean, Gheorghe; Chiriac, Mircea T.; Mihai, Sidonia; Hartmann, Arndt; Mudter, Jonas; Neurath, Markus (Inflammatory Bowel Diseases, 2017)
Background: Endoscopic monitoring is fundamental for evaluating the therapeutic response in IBD, but a validated endomicroscopic mucosal healing (MH) score is not available to date. However, confocal laser endomicroscopy (CLE) might define MH more precisely than conventional endoscopy. The major aim was to establish and validate an MH score for ulcerative colitis (UC), based on CLE. Methods: In an initial pilot study (n = 10), various CLE changes were analyzed for identification of reproducible criteria for establishing a CLE score. Four reproducible CLE criteria were implemented in a following validation study. Subsequently, active UC patients (n = 23, Mayo score ≥6) were prospectively included and underwent colonoscopy with CLE before and after 3 anti-TNF applications. Patients were clinically followed over a period of 3 years. The endomicroscopic MH score (eMHs; range, 0-4) was compared with histopathology and endoscopy scores from the same colonic location. Results: The eMHs showed high sensitivity, specificity, and accuracy values (100% with 95% confidence interval [CI] of 15.81%-100%; 93.75% with 95% CI of 69.77%-99.84%, and 94.44%, respectively). The eMHs showed a good correlation with the histological Gupta score (rs = 0.82, P < 0.0001) and the endoscopic Mayo subscore (rs = 0.81%, P < 0.0001). Sixty percent of therapy responders presented an eMHs <1, which translated into long-lasting clinical remission and reduced hospitalization, steroid, and surgery need. Conclusions: CLE can accurately assess MH based on the newly developed and statistically validated eMHs in UC, and it is superior in predicting the long-lasting clinical outcome based on both descriptive and functional barrier imaging (NCT01417728).
EVALuna2:33794

Development and validation of the SIMPLE endoscopic classification of diminutive and small colorectal polyps - Iacucci, Marietta; Trovato, Cristina; Daperno, Marco; Akinola, Oluseyi; Greenwald, David; Gross, Seth A.; Hoffman, Arthur; Lee, Jeffrey; Lethebe, Brendan C.; Lowerison, Mark; Nayor, Jennifer; Neumann, Helmut; et al. (Endoscopy, 2018)
BACKGROUND: Prediction of histology of small polyps facilitates colonoscopic treatment. The aims of this study were: 1) to develop a simplified polyp classification, 2) to evaluate its performance in predicting polyp histology, and 3) to evaluate the reproducibility of the classification by trainees using multiplatform endoscopic systems. METHODS: In phase 1, a new simplified endoscopic classification for polyps - Simplified Identification Method for Polyp Labeling during Endoscopy (SIMPLE) - was created, using the new I-SCAN OE system (Pentax, Tokyo, Japan), by eight international experts. In phase 2, the accuracy, level of confidence, and interobserver agreement to predict polyp histology before and after training, and univariable/multivariable analysis of the endoscopic features, were performed. In phase 3, the reproducibility of SIMPLE by trainees using different endoscopy platforms was evaluated. RESULTS: Using the SIMPLE classification, the accuracy of experts in predicting polyps was 83 % (95 % confidence interval [CI] 77 % - 88 %) before and 94 % (95 %CI 89 % - 97 %) after training (P = 0.002). The sensitivity, specificity, positive predictive value, and negative predictive value after training were 97 %, 88 %, 95 %, and 91 %. The interobserver agreement of polyp diagnosis improved from 0.46 (95 %CI 0.30 - 0.64) before to 0.66 (95 %CI 0.48 - 0.82) after training. The trainees demonstrated that the SIMPLE classification is applicable across endoscopy platforms, with similar post-training accuracies for narrow-band imaging NBI classification (0.69; 95 %CI 0.64 - 0.73) and SIMPLE (0.71; 95 %CI 0.67 - 0.75). CONCLUSIONS: Using the I-SCAN OE system, the new SIMPLE classification demonstrated a high degree of accuracy for adenoma diagnosis, meeting the ASGE PIVI recommendations. We demonstrated that SIMPLE may be used with either I-SCAN OE or NBI.
EVALuna2:208001

Development of a new classification for in vivo diagnosis of duodenal epithelial tumors with confocal laser endomicroscopy: A pilot study - Nonaka, Kouichi; Ohata, Ken; Ichihara, Shin; Ban, Shinichi; Hiejima, Yoshimitsu; Minato, Yohei; Tashima, Tomoaki; Matsuyama, Yasushi; Takita, Maiko; Matsuhashi, Nobuyuki; Takasugi, Rumi; Neumann, Helmut (Digestive Endoscopy, 2016)
Confocal laser endomicroscopy (CLE) has been established for in vivo diagnosis of various gastrointestinal diseases. However, validated criteria for confocal diagnosis of duodenal tumors do not exist. Therefore, the aim of the present pilot study was to develop a novel classification for in vivo optical diagnosis of duodenal tumors using CLE.Consecutive patients with duodenal tumorous lesions were included. First, an initial classification system was developed which was then validated. Histopathology was used as a reference standard.A simple classification system for in vivo diagnosis of duodenal epithelial tumors using CLE was developed. Sensitivity, specificity, and accuracy were 90%, 100%, and 97%, respectively. Positive and negative predictive values were calculated as 100% and 96%. The kappa coefficient representing consistency was 1 between observers and within each observer.A new classification for in vivo diagnosis of duodenal epithelial tumors using confocal imaging has been developed. The new classification system allows adequate prediction of histology and could therefore be used to guide subsequent therapy of duodenal lesions.
EVALuna2:2094

Development of Reliable, Valid and Responsive Scoring Systems for Endoscopy and Histology in Animal Models for Inflammatory Bowel Disease - Koelink, Pim J.; Wildenberg, Manon E.; Stitt, Larry W.; Feagan, Brian G.; Koldijk, Martin; Van 'T Wout, Angelique B.; Atreya, Raja; Brandse, Johannan F.; Duijst, Suzanne; Te Velde, Anje A.; D'Haens, Geert R. A. M.; Levesque, Barrett G.; et al. (Journal of Crohns & Colitis, 2018)
Background and Aims: Although several endoscopic and histopathologic indices are available for evaluating the severity of inflammation in mouse models of colitis, the reliability of these scoring instruments is unknown. Our aim was to evaluate the reliability of the individual items in the existing indices and develop new scoring systems by selection of the most reliable index items. Methods: Two observers scored the histological slides [n = 224] and endoscopy videos [n = 201] from treated and untreated Interleukin[IL]-10 knock-out and T-cell transferred SCID mice. Intra-rater and inter-rater reliability for endoscopy and histology scores, and each individual item, were measured using intraclass correlation coefficients [ICCs]. The Mouse Colitis Histology Index [MCHI] and Mouse Colitis Endoscopy Index [MCEI] were developed using the most reliable items. Both were correlated to the colon density and to each other and were evaluated for their ability to detect changes in pathobiology. Results: The intraclass correlation coefficients (ICCs) for inter-rater agreement (95% CIs) for the total histology and endoscopy scores were 0.90 [0.87-0.92] and 0.80 [0.76-0.84], respectively. The MCHI and MCEI were highly correlated with colon density, with a Spearman Rho = 0.81[0.75-0.85] and 0.73 [0.66-0.79], respectively, and with each other, Spearman Rho = 0.71 [0.63-0.77]. The MCHI and MCEI were able to distinguish between the experimental groups within the models, with pairwise differences between the treated and untreated groups being statistically significant [p < 0.001]. Conclusions: These histological and endoscopic indices are valid and reliable measures of intestinal inflammation in mice, and they are responsive to treatment effects in pre-clinical studies.
EVALuna2:35155

Diagnosis and Surveillance of Barrett's Esophagus: Addressing the Transatlantic Divide - Ghaus, Saad; Neumann, Helmut; Muhammad, Humayun; Tontini, Gian Eugenio; Ishaq, Sauid (Digestive Diseases and Sciences, 2016)
Barrett's esophagus is a premalignant condition of the esophagus leading to esophageal adenocarcinoma. No consensus exists between the UK and USA concerning the diagnosis of Barrett's esophagus. Although the diagnostic procedure is common, the required findings and diagnostic criteria vary. Both guidelines require endoscopy showing columnar epithelia lining the esophagus, but the US guidelines require the additional finding of intestinal metaplasia on biopsy to confirm diagnosis. Achievement of a consensus is of particular importance due to the established progression from Barrett's esophagus to esophageal adenocarcinoma. Of further importance is the increasing incidence of esophageal adenocarcinoma, a condition with poor overall survival, leading to various opinions on the utility of surveillance in patients.A review of the vast array of literature revealed that substantial evidence exists in favor of both diagnostic criteria; hence, there is no easy way to identify the "correct" method of diagnosing Barrett's esophagus. USA recommends surveillance of Barrett's esophagus, whereas UK does not advocate it unless dysplasia is present. Surveillance was found to be effective, but this varied as did cost-effectiveness. Further research into diagnostic methods for Barrett's esophagus is needed to address areas of limited understanding, such that agreement can be reached and practice standardized. Surveillance was generally advocated, but with different criteria and time intervals, and new methods are being evaluated.
EVALuna2:2156

Diagnostic accuracy and interobserver variability of Dynamic Vascular Pattern (DVP) in primary liver malignancies - A simple semiquantitative tool for the analysis of contrast enhancement patterns - Schellhaas, B.; Waldner, Maximilian; Goertza, R. S.; Vitali, Francesco; Kielisch, Ch.; Pfeifer, Lukas; Strobel, Deike; Janka, Rolf Matthias; Neurath, Markus; Wildner, Dane (Clinical Hemorheology and Microcirculation, 2017)
Contrast-enhanced ultrasound (CEUS) is a valuable tool in the diagnostic approach of focal liver lesions, but occasionally subjective and observer-dependent. Semiquantitative evaluation of dynamic CEUS (DCEUS) with standardised software programmes such as Dynamic Vascular Pattern (DVP) could help to improve diagnostic accuracy and objectivity in liver tumour assessment.The present study aimed at evaluation of diagnostic accuracy of DVP in a clinical setting.DVP images of 52 focal liver lesions [30 hepatocellular carcinomas (HCCs), 15 intrahepatic cholangiocellular carcinomas (ICCs), 7 focal nodular hyperplasias (FNHs)] were analysed by four blinded observers with different levels of CEUS-experience. Diagnostic accuracies for the assessment of dignity and entity were evaluated.Mean sensitivity, specificity, positive and negative predictive value for detection of malignancy with DVP were 48.4% /67.8% /92.7% and 29.3%, respectively. Total diagnostic accuracies for dignity/entity were 63.9% /38.5% (HCC: 58.3% /25.8%; ICC: 73.3% /50%; FNH: 67.9% /67.9%). Interreader-agreement was moderate (?= 0.42-0.58). Differential diagnosis between ICC and HCC was most challenging.Although developed to improve diagnostic accuracy and objectivity in the assessment of focal liver lesions, DVP alone seems insufficient for differential diagnosis of HCC, ICC and FNH and cannot replace the skills of an experienced observer.
EVALuna2:14711

Diagnostic accuracy of contrast-enhanced ultrasound for the differential diagnosis of hepatocellular carcinoma: ESCULAP versus CEUS-LI-RADS - Schellhaas, Barbara; Görtz, Rüdiger; Pfeifer, Lukas; Kielisch, Christian; Neurath, Markus; Strobel, Deike (European Journal of Gastroenterology & Hepatology, 2017)
OBJECTIVE: A comparison is made of two contrast-enhanced ultrasound (CEUS) algorithms for the diagnosis of hepatocellular carcinoma (HCC) in high-risk patients: Erlanger Synopsis of Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at Risk (ESCULAP) and American College of Radiology Contrast-Enhanced Ultrasound-Liver Imaging Reporting and Data System (ACR-CEUS-LI-RADSv.2016). PATIENTS AND METHODS: Focal liver lesions in 100 high-risk patients were assessed using both CEUS algorithms (ESCULAP and CEUS-LI-RADSv.2016) for a direct comparison. Lesions were categorized according to size and contrast enhancement in the arterial, portal venous and late phases.For the definite diagnosis of HCC, categories ESCULAP-4, ESCULAP-Tr and ESCULAP-V and CEUS-LI-RADS-LR-5, LR-Tr and LR-5-V were compared. In addition, CEUS-LI-RADS-category LR-M (definitely/probably malignant, but not specific for HCC) and ESCULAP-category C [intrahepatic cholangiocellular carcinoma (ICC)] were compared.Histology, CE-computed tomography and CE-MRI served as reference standards. RESULTS: The reference standard among 100 lesions included 87 HCCs, six ICCs and seven non-HCC-non-ICC-lesions. For the diagnosis of HCC, the diagnostic accuracy of CEUS was significantly higher with ESCULAP versus CEUS-LI-RADS (94.3%/72.4%; p<0.01). Sensitivity, specificity and positive predictive value (PPV) and negative predictive value for ESCULAP/CEUS-LI-RADS were 94.3%/72.4%; 61.5%/69.2%; 94.3%/94%; and 61.5%/27.3%, respectively.The diagnostic accuracy for ICC (LR-M/ESCULAP-C) was identical with both algorithms (50%), with higher PPV for ESCULAP-C versus LR-M (75 vs. 50%). CONCLUSION: CEUS-based algorithms contribute toward standardized assessment and reporting of HCC-suspect lesions in high-risk patients. ESCULAP shows significantly higher diagnostic accuracy, sensitivity and negative predictive value with no loss of specificity compared with CEUS-LI-RADS. Both algorithms have an excellent PPV. Arterial hyperenhancement is the key feature for the diagnosis of HCC with CEUS. Washout should not be a necessary prerequisite for the diagnosis of definite HCC. CEUS-LI-RADS in its current version is inferior to ESCULAP for the noninvasive diagnosis of HCC. There are two ways to improve CEUS-LI-RADS: firstly, combination of the categories LR-4 and LR-5 for the diagnosis of definite HCC, and secondly, use of subtotal infiltration of a liver lobe as an additional feature.
EVALuna2:33804

Diagnostic Endoscopic Ultrasound in Pancreatology: Focus on Normal Variants and Pancreatic Masses - Vitali, Francesco; Zundler, Sebastian; Jesper, Daniel; Wildner, Dane; Strobel, Deike; Frulloni, Luca; Neurath, Markus (Visceral Medicine, 2023)
Background: Endoscopic ultrasound (EUS) is a main tool in gastroenterology for both diagnosis and exclusion of pancreatic pathology. It allows minimally invasive assessment of various diseases or anatomic variations affecting the pancreas also with the help of new Doppler technologies, elastography, contrast-enhanced imaging including post hoc image processing with quantification analyses, three-dimensional reconstruction, and artificial intelligence. EUS also allows interventional direct access to the pancreatic parenchyma and the retroperitoneal space, to the pancreatic duct, pancreatic masses, cysts, and vascular structures. Summary: This review aimed to summarize new developments of EUS in the field of pancreatology. We highlight the role of EUS in evaluating pancreatic pathology by describing normal anatomic variants like pancreas divisum, pancreatic lipomatosis, pancreatic fibrosis in the elderly and characterizing pancreatic masses, both in the context of chronic pancreatitis and within healthy pancreatic parenchyma. EUS is considered the optimal imaging modality for pancreatic masses of uncertain dignity and allows both cytological diagnosis and histology, which is essential not only for neoplastic conditions but also for tailoring therapy for benign inflammatory conditions. Key Messages: EUS plays an indispensable role in pancreatology and the development of new diagnostic and interventional approaches to the retroperitoneal space and the pancreas exponentially increased over the last years. The development of computer-aided diagnosis and artificial intelligence algorithms hold the potential to overcome the obstacles associated with interobserver variability and will most likely support decision-making in the management of pancreatic disease.
CRIS-Team Scopus Importer:2023-11-03
Keywords: Contrast-enhanced endoscopic ultrasound; Elastometry; Endoscopic ultrasound; Pancreatic cancer; Pancreatitis

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 - 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)
SARS-CoV-2 antibody assays are used for epidemiological studies and for the assessment of vaccine responses in highly vulnerable patients. So far, data on cross-reactivity of SARS-CoV-2 antibody assays is limited. Here, we compared four enzyme-linked immunosorbent assays (ELISAs; Vircell SARS-CoV-2 IgM/IgA and IgG, Euroimmun SARS-CoV-2 IgA and IgG) for detection of anti-SARS-CoV-2 antibodies in 207 patients with COVID-19, 178 patients with serological evidence of different bacterial infections, 107 patients with confirmed viral respiratory disease, and 80 controls from the pre-COVID-19 era. In COVID-19 patients, the assays showed highest sensitivity in week 3 (Vircell-IgM/A and Euroimmun-IgA: 78.9% each) and after week 7 (Vircell-IgG: 97.9%; Euroimmun-IgG: 92.1%). The antibody indices were higher in patients with fatal disease. In general, IgM/IgA assays had only limited or no benefit over IgG assays. In patients with non-SARS-CoV-2 respiratory infections, IgG assays were more specific than IgM/IgA assays, and bacterial infections were associated with more false-positive results than viral infections. The specificities in bacterial and viral infections were 68.0 and 81.3% (Vircell-IgM/IgA), 84.8 and 96.3% (Euroimmun-IgA), 97.8 and 86.0% (Vircell-IgG), and 97.8 and 99.1% (Euroimmun-IgG), respectively. Sera from patients positive for antibodies against Mycoplasma pneumoniae, Chlamydia psittaci, and Legionella pneumophila yielded particularly high rates of unspecific false-positive results in the IgM/IgA assays, which was revealed by applying a highly specific flow-cytometric assay using HEK 293 T cells expressing the SARS-CoV-2 spike protein. Positive results obtained with anti-SARS-CoV-2 IgM/IgA ELISAs require careful interpretation, especially if there is evidence for prior bacterial respiratory infections.
CRIS-Team Scopus Importer:2021-06-18
Keywords: Antibody; Bacterial infections; Coronavirus; COVID-19; Euroimmun; SARS-CoV-2; Vircell

Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease - Mayr, Lisa; Grabherr, Felix; Schwrzler, Julian; Reitmeier, Isabelle; Sommer, Felix; Gehmacher, Thomas; Niederreiter, Lukas; He, Gui-Wei; Ruder, Barbara; Kunz, Kai T. R.; Tymoszuk, Piotr; Hilbe, Richard; et al. (Nature Communications, 2020)
The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.
CRIS-Team WoS Importer:2020-05-12

Differences in the bacterial pattern of histamine intolerant patients - Schink, Monic; Tietz, Esther; Dieterich, Walburga; Pinzer, Theresa C.; Wirtz, Stefan; Neurath, Markus; Zopf, Yurdagül (2018)
EVALuna2:35188

Differences in the Bacterial Pattern of Patients with Histamine Intolerance Veränderte intestinale bakterielle Zusammensetzung bei Patienten mit Histaminintoleranz - Schink, Monic; Konturek, Peter C.; Tietz, Esther; Dieterich, Walburga; Neurath, Markus; Zopf, Yurdagül (Aktuelle Ernährungsmedizin, 2019)
Background Histamine intolerance (HIT) is a controversially discussed disorder. An impaired degradation of oral histamine intake due to diamine oxidase (DAO) deficiency is suggested as main cause, but other factors, including an altered gut flora, may also contribute to elevated histamine levels. We aimed to determine differences in the intestinal bacterial pattern of HIT-patients in comparison to healthy persons (HC). Material and methods All participants had a blood testing for total IgE, food-specific IgEs, TNF-α, plasma histamine and serum DAO activities. Stool samples were collected for analysis of stool histamine and zonulin levels. The bacterial composition of the stool samples was analysed by 16s rRNA sequencing using Illumina platform. Results A total of 18 participants (30.2±12.5yrs, 94,4% female) were included in the study, and categorized into HIT-patients (n=8, 28.9±11.2 yrs, 100% female) and healthy controls (n=10, 31.3±13.9yrs, 90% female). No significant differences in stool histamine levels were observed between groups, but HIT-patients showed tendentially increased levels of fecal zonulin. Microbiome analysis revealed a reduced bacterial diversity (p=0.05) and a higher abundance of Proteobacteria in the HIT-group. Additionally, HIT-patients showed a significantly decreased abundance of the butyrate-producing genera Faecalibacterium (p=0.045) and Butyricimonas (p=0.003) as well as lower proportions of Sutterella (p=0.043) and Hespellia (p=0.043). No increased numbers of known histamine-producing bacteria were detected in the study groups. Conclusion Our study results suggest an alteration of the microbial composition in HIT-patients. The higher abundance of Proteobacteria and lower abundance of butyrate-producing bacteria, as well as elevated stool zonulin levels indicate a dysbiosis and impaired intestinal barrier. However, an elevated histamine exposure due to gut bacteria may not be responsible for HIT pathogenesis.
CRIS-Team Scopus Importer:2019-11-05
Keywords: dysbiosis; histamine intolerance; intestinal barrier; microbiome

Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice - Müller-Tribbensee, Sonja; Karna, Manoj; Khalil, Mohammad; Neurath, Markus; Reeh, Peter; Engel, Matthias (PLoS ONE, 2015)
Various transient receptor potential (TRP) channels in sensory neurons contribute to the transduction of mechanical stimuli in the colon. Recently, even the cold-sensing menthol receptor TRPM(melastatin)8 was suggested to be involved in murine colonic mechano-nociception.To analyze the roles of TRPM8, TRPA1 and TRPV4 in distension-induced colonic nociception and pain, TRP-deficient mice and selective pharmacological blockers in wild-type mice (WT) were used. Visceromotor responses (VMR) to colorectal distension (CRD) in vivo were recorded and distension/pressure-induced CGRP release from the isolated murine colon ex vivo was measured by EIA.Distension-induced colonic CGRP release was markedly reduced in TRPA1-/- and TRPV4-/- mice at 90/150 mmHg compared to WT. In TRPM8-deficient mice the reduction was only distinct at 150 mmHg. Exposure to selective pharmacological antagonists (HC030031, 100 ?M; RN1734, 10 ?M; AMTB, 10 ?M) showed corresponding effects. The unselective TRP blocker ruthenium red (RR, 10 ?M) was as efficient in inhibiting distension-induced CGRP release as the unselective antagonists of mechanogated DEG/ENaC (amiloride, 100 ?M) and stretch-activated channels (gadolinium, 50 ?M). VMR to CRD revealed prominent deficits over the whole pressure range (up to 90 mmHg) in TRPA1-/- and TRPV4-/- but not TRPM8-/- mice; the drug effects of the TRP antagonists were again highly consistent with the results from mice lacking the respective TRP receptor gene.TRPA1 and TRPV4 mediate colonic distension pain and CGRP release and appear to govern a wide and congruent dynamic range of distensions. The role of TRPM8 seems to be confined to signaling extreme noxious distension, at least in the healthy colon.
EVALuna2:2004

Differential diagnosis in inflammatory bowel disease colitis: state of the art and future perspectives - Tontini, Gian Eugenio; Vecchi, Maurizio; Pastorelli, Luca; Neurath, Markus; Neumann, Helmut (World Journal of Gastroenterology, 2015)
Distinction between Crohn's disease of the colon-rectum and ulcerative colitis or inflammatory bowel disease (IBD) type unclassified can be of pivotal importance for a tailored clinical management, as each entity often involves specific therapeutic strategies and prognosis. Nonetheless, no gold standard is available and the uncertainty of diagnosis may frequently lead to misclassification or repeated examinations. Hence, we have performed a literature search to address the problem of differential diagnosis in IBD colitis, revised current and emerging diagnostic tools and refined disease classification strategies. Nowadays, the differential diagnosis is an untangled issue, and the proper diagnosis cannot be reached in up to 10% of patients presenting with IBD colitis. This topic is receiving emerging attention, as medical therapies, surgical approaches and leading prognostic outcomes require more and more disease-specific strategies in IBD patients. The optimization of standard diagnostic approaches based on clinical features, biomarkers, radiology, endoscopy and histopathology appears to provide only marginal benefits. Conversely, emerging diagnostic techniques in the field of gastrointestinal endoscopy, molecular pathology, genetics, epigenetics, metabolomics and proteomics have already shown promising results. Novel advanced endoscopic imaging techniques and biomarkers can shed new light for the differential diagnosis of IBD, better reflecting diverse disease behaviors based on specific pathogenic pathways.
EVALuna2:2010

Differential effects of ?4?7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo - Fischer, Anika; Zundler, Sebastian; Atreya, Raja; Rath, Timo; Voskens, Caroline; Hirschmann, Simon; Lopez Posadas, Rocío; Watson, Alastair; Becker, Christoph; Schuler, Gerold; Neufert, Clemens; Atreya, Imke; et al. (Gut, 2016)
Gut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in IBDs. We aimed to analyse the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via ?4?7 and G protein receptor GPR15.We assessed the expression of homing receptors on T cells in peripheral blood and inflamed mucosa. We studied the migration pattern and homing of Teff and Treg cells to the inflamed gut using intravital confocal microscopy and FACS in a humanised mouse model in dextran sodium sulfate-treated NSG (NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ) mice.Expression of GPR15 and ?4?7 was significantly increased on Treg rather than Teff cells in peripheral blood of patients with UC as compared with Crohn's disease and controls. In vivo analysis in a humanised mouse model showed augmented gut homing of UC Treg cells as compared with controls. Moreover, suppression of UC (but not control) Teff and Treg cell homing was noted upon treatment with the ?4?7 antibody vedolizumab. In contrast, siRNA blockade of GPR15 had only effects on homing of Teff cells but did not affect Treg homing in UC. Clinical vedolizumab treatment was associated with marked expansion of UC Treg cells in peripheral blood.?4?7 rather than GPR15 is crucial for increased colonic homing of UC Treg cells in vivo, while both receptors control UC Teff cell homing. Vedolizumab treatment impairs homing of UC Treg cells leading to their accumulation in peripheral blood with subsequent suppression of systemic Teff cell expansion.
EVALuna2:2173

Differential Effects of Ontamalimab Versus Vedolizumab on Immune Cell Trafficking in Intestinal Inflammation and Inflammatory Bowel Disease - Schulze, Lisa; Becker, Emily; Dedden, Mark; Liu, Lijuan; Van Passen, Chiara; Mohamed Abdou, Mariam; Müller, Tanja; Wiendl, Maximilian; Ullrich, Karen; Atreya, Imke; Leppkes, Moritz; Ekici, Arif Bülent; et al. (Journal of Crohns & Colitis, 2023)
Background and Aims: The anti-MAdCAM-1 antibody ontamalimab demonstrated efficacy in a phase II trial in ulcerative colitis and results of early terminated phase III trials are pending, but its precise mechanisms of action are still unclear. Thus, we explored the mechanisms of action of ontamalimab and compared it to the anti-α4β7 antibody vedolizumab. Methods: We studied MAdCAM-1 expression with RNA sequencing and immunohistochemistry. The mechanisms of action of ontamalimab were assessed with fluorescence microscopy, dynamic adhesion and rolling assays. We performed in vivo cell trafficking studies in mice and compared ontamalimab and vedolizumab surrogate [-s] antibodies in experimental models of colitis and wound healing. We analysed immune cell infiltration under anti-MAdCAM-1 and anti-α4β7 treatment by single-cell transcriptomics and studied compensatory trafficking pathways. Results: MAdCAM-1 expression was increased in active inflammatory bowel disease. Binding of ontamalimab to MAdCAM-1 induced the internalization of the complex. Functionally, ontamalimab blocked T cell adhesion similar to vedolizumab, but also inhibited L-selectin-dependent rolling of innate and adaptive immune cells. Despite conserved mechanisms in mice, the impact of ontamalimab-s and vedolizumab-s on experimental colitis and wound healing was similar. Single-cell RNA sequencing demonstrated enrichment of ontamalimab-s-treated lamina propria cells in specific clusters, and in vitro experiments indicated that redundant adhesion pathways are active in these cells. Conclusions: Ontamalimab has unique and broader mechanisms of action compared to vedolizumab. However, this seems to be compensated for by redundant cell trafficking circuits and leads to similar preclinical efficacy of anti-α4β7 and anti-MAdCAM-1 treatment. These results will be important for the interpretation of pending phase III data.
CRIS-Team Scopus Importer:2023-12-15

Differential Effects of Very-Low-Volume Exercise Modalities on Telomere Length, Inflammation, and Cardiometabolic Health in Obese Metabolic Syndrome Patients: A Subanalysis from Two Randomized Controlled Trials - Reljic, Dejan; Koller, Adriana; Herrmann, Hans J.; Ekici, Arif Bülent; Neurath, Markus; Zopf, Yurdagül (Antioxidants, 2023)
Oxidative stress (OS) and inflammation are features of metabolic syndrome (MetS) that can contribute to the shortening of telomere length (TL), a marker of cellular ageing. Research indicates that exercise can positively influence MetS-associated conditions and TL. However, the effects of low-volume exercise types on TL are still unknown. We investigated the impact of very-low-volume high-intensity interval training (LV-HIIT), one-set resistance training (1-RT), and whole-body electromyostimulation (WB-EMS) on TL, inflammation, and cardiometabolic indices in 167 MetS patients. Data were derived from two randomized controlled trials where patients were allocated to an exercise group (2 sessions/week, for 12 weeks) or a control group. All groups received standard-care nutritional weight loss counselling. TL was determined as the T/S ratio (telomere to single-copy gene amount). All groups significantly reduced body weight (p < 0.05), but the T/S-ratio (p < 0.001) only increased with LV-HIIT. OS-related inflammatory markers (C-reactive protein, interleukin-6, and lipopolysaccharide-binding protein) only decreased (p < 0.05) following LV-HIIT. The MetS severity z-score improved with LV-HIIT (p < 0.001) and 1-RT (p = 0.014) but not with WB-EMS. In conclusion, very-low-volume exercise modalities have differential effects on telomeres, inflammation, and cardiometabolic health. Only LV-HIIT but not strength-based low-volume exercise increased TL in MetS patients, presumably due to superior effects on OS-related inflammatory markers.
CRIS-Team Scopus Importer:2023-11-10
Keywords: anti-aging; cellular age; electromyostimulation; high-intensity interval training; inflammatory markers; metabolic diseases; oxidative stress; resistance training; telomeres

Differentiation of malignant liver tumors by software-based perfusion quantification with dynamic contrast-enhanced ultrasound (DCEUS) - Wildner, Dane; Schellhaas, Barbara; Strack, Daniel; Görtz, Rüdiger; Pfeifer, Lukas; Fießler, Cornelia; Neurath, Markus; Strobel, Deike (Clinical Hemorheology and Microcirculation, 2019)
BACKGROUND: Enhancement patterns on contrast-enhanced ultrasound (CEUS) help to distinguish different liver tumors.
CRIS-Team WoS Importer:2019-04-16

Different levels of healing in inflammatory bowel diseases: mucosal, histological, transmural, barrier and complete healing - Neurath, Markus; Vieth, Michael (Gut, 2023)
Mucosal healing on endoscopy has emerged as a key prognostic parameter in the management of patients with IBD (Crohn's disease, ulcerative colitis/UC) and can predict sustained clinical remission and resection-free survival. The structural basis for this type of mucosal healing is a progressive resolution of intestinal inflammation with associated healing of ulcers and improved epithelial barrier function. However, in some cases with mucosal healing on endoscopy, evidence of histological activity in mucosal biopsies has been observed. Subsequently, in UC, a second, deeper type of mucosal healing, denoted histological healing, was defined which requires the absence of active inflammation in mucosal biopsies. Both levels of mucosal healing should be considered as initial events in the resolution of gut inflammation in IBD rather than as indicators of complete transmural healing. In this review, the effects of anti-inflammatory, biological or immunosuppressive agents as well as small molecules on mucosal healing in clinical studies are highlighted. In addition, we focus on the implications of mucosal healing for clinical management of patients with IBD. Moreover, emerging techniques for the analysis of mucosal healing as well as potentially deeper levels of mucosal healing such as transmural healing and functional barrier healing of the mucosa are discussed. Although none of these new levels of healing indicate a definitive cure of the diseases, they make an important contribution to the assessment of patients' prognosis. The ultimate level of healing in IBD would be a resolution of all aspects of intestinal and extraintestinal inflammation (complete healing).
CRIS-Team Scopus Importer:2023-09-22
Keywords: Crohn's disease; endoscopy; mucosal barrier; ulcerative colitis

DIFFERENT NUTRIENT INTAKE AND PREVALENCE OF GASTROINTESTINAL COMORBIDITIES IN WOMEN WITH ENDOMETRIOSIS - Schink, Monic; Konturek, P. C.; Herbert, S. L.; Renner, S. P.; Burghaus, Stefanie; Blum, Simon; Fasching, Peter; Neurath, Markus; Zopf, Yurdagül (Journal of Physiology and Pharmacology, 2019)
Even though endometriosis presents one of the most common gynaecological diseases, the pathogenesis is insufficiently studied. Besides immunologic, inflammatory or oxidative processes, recent studies also suggest an influence of nutrition on disease onset and progression. Because data about the actual nutrient intake of endometriosis patients are scarce, we aimed to examine the actual nutrient intake and potential influencing factors in these women. A total of 156 women with endometriosis (EM) and 52 age-matched controls were included in this retrospective case-control study. All women filled in a validated food frequency questionnaire to acquire the nutrient intake of the past 12 months and a disease-related questionnaire for the determination of disease status, clinical symptoms and comorbidities. Patients with endometriosis suffered significantly more from diet-related comorbidities like food intolerances (25.6% versus 7.7%; P = 0.009) and allergies (57% versus 31%; P < 0.001) compared to controls. Also gastrointestinal symptoms, including constipation, flatulence, pyrosis, diarrhea or frequent defecation, were higher in the EM group (77% versus 29%; P < 0.001). The nutrient intake of patients with endometriosis differed significantly compared to controls with a significantly lower ingestion of organic acids (P = 0.006), maltose (P = 0.0.16), glycogen (P = 0.035), tetradecenoic acid (P = 0.041), methionine (P = 0.046), lysine (P = 0.048), threonine (P = 0.046) and histidine (P = 0.049). The total intake of animal proteins was significantly lower in the EM group compared to the controls (P = 0.047). EM patients showed a decreased intake of vitamin C (P = 0.031), vitamin B-12 (P = 0.008) and magnesium (P = 0.043) compared to controls. This study confirms a high association of endometriosis and gastrointestinal disorders accompanied by an altered nutrient intake. A dietary intervention by a professional nutritionist may help to reduce disease burden in the affected women.
CRIS-Team WoS Importer:2019-10-18

Digital Chromoendoscopy With i-Scan for In Vivo Prediction of Advanced Colorectal Neoplasia: A Multicenter Study - Albrecht, Heinz; Naegel, Andreas; Tasdelen, Hueseyin; Rath, Timo; Grauer, Martin; Neurath, Markus; Neumann, Helmut; Vieth, Michael (Journal of Clinical Gastroenterology, 2016)
Recent studies have analyzed the potential of advanced endoscopic imaging techniques for differentiating hyperplastic and adenomatous colorectal lesions. Latest endoscopic resection techniques now also allow for treatment of more advanced staged lesions including treatment of early cancerous lesions.To assess the potential of the i-scan technology to differentiate between adenomatous polyps and advanced staged neoplasia.Consecutive patients undergoing colonoscopy at a tertiary referral center were included. After a dedicated training, participating endoscopists underwent a review of 298 unknown images of colonic lesions to assess colorectal lesion histology.Overall accuracy for prediction of advanced staged neoplasia was 92.2% (sensitivity: 94.2%, specificity 90.9%). The positive and negative predictive values were calculated as 87.5% and 95.9%, respectively. The ?-value for differentiating adenomatous polyps and advanced staged neoplasia was 0.8193 (0.7894 to 0.8492). Intraobserver agreement was calculated with a ?-value of 0.9301 (0.8875 to 0.9727).Accurate interpretation of i-scan images for prediction of advanced colorectal neoplasia can successfully be performed even by nonexpert endoscopists with a high overall accuracy and excellent interobserver agreements.
EVALuna2:2189

Discovery and Differential Processing of HLA Class II-Restricted Minor Histocompatibility Antigen LB-PIP4K2A-1S and Its Allelic Variant by Asparagine Endopeptidase - Kremer, Anita; Bausenwein, Judith; Lurvink, Ellie; Kremer, Andreas; Rutten, Caroline E.; van Bergen, Cornelis A.M.; Kretschmann, Sascha; van der Meijden, Edith; Honders, Maria W.; Mazzeo, Daniela; Watts, Colin; Mackensen, Andreas; et al. (Frontiers in Immunology, 2020)
Minor histocompatibility antigens are the main targets of donor-derived T-cells after allogeneic stem cell transplantation. Identification of these antigens and understanding their biology are a key requisite for more insight into how graft vs. leukemia effect and graft vs. host disease could be separated. We here identified four new HLA class II-restricted minor histocompatibility antigens using whole genome association scanning. For one of the new antigens, i.e., LB-PIP4K2A-1S, we measured strong T-cell recognition of the donor variant PIP4K2A-1N when pulsed as exogenous peptide, while the endogenously expressed variant in donor EBV-B cells was not recognized. We showed that lack of T-cell recognition was caused by intracellular cleavage by a protease named asparagine endopeptidase (AEP). Furthermore, microarray gene expression analysis showed that PIP4K2A and AEP are both ubiquitously expressed in a wide variety of healthy tissues, but that expression levels of AEP were lower in primary acute myeloid leukemia (AML). In line with that, we confirmed low activity of AEP in AML cells and demonstrated that HLA-DRB1*03:01 positive primary AML expressing LB-PIP4K2A-1S or its donor variant PIP4K2A-1N were both recognized by specific T-cells. In conclusion, LB-PIP4K2A-1S not only represents a novel minor histocompatibility antigen but also provides evidence that donor T-cells after allogeneic stem cell transplantation can target the autologous allelic variant as leukemia-associated antigen. Furthermore, it demonstrates that endopeptidases can play a role in cell type-specific intracellular processing and presentation of HLA class II-restricted antigens, which may be explored in future immunotherapy of AML.
CRIS-Team Scopus Importer:2020-04-07
Keywords: allogeneic stem cell transplantation; CD4 T-cells; graft vs. leukemia effect; HLA class II; minor histocompatibility antigens

Disease Control in Progressive Pancreatic and Intestinal Neuroendocrine Tumors by Combined Treatment with Lanreotide Autogel and Temozolomide: The SONNET Study - Pavel, Marianne Ellen; Denecke, T.; Lahner, H.; Hoersch, D.; Rinke, A.; Koch, A.; Liyanage, N.; Raspel, A.; Pape, U. F.; Raderer, M. (2018)
EVALuna2:34120

Disease-modifying antirheumatic drugs in rheumatoid arthritis patients with a history of colorectal cancer - Kleinert, S.; Waldner, Maximilian; Wendler, J.; Kunzmann, V. (Zeitschrift für Rheumatologie, 2016)
Cells of the adaptive immune system are relevant for the anti-tumor immune response; therefore, the basal therapy with disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis patients with a history of gastrointestinal cancer must be carefully considered.This article presents the evidence regarding colorectal cancer (CRC) and rheumatoid arthritis.The article is based on a PubMed search as well as a search in congress abstracts of the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Current recommendations regarding screening and follow-up of CRC are summarized for clinically active rheumatologists. The current status of therapy and future therapeutic options are presented. The lower incidence of CRC in rheumatoid arthritis (RA) patients and the incidence under treatment with various DMARDs are described. The treatment options for RA patients in different tumor situations, e.g. during cytostatic therapy, palliative and curative situations are discussed, as well as the available evidence. In spite of the unsatisfactory level of evidence, conclusions and practical considerations for use by rheumatologists in clinical practice are discussed.
EVALuna2:2111

Disentangling tryptophan metabolism in inflammatory bowel diseases - Becker, Christoph; Adolph, Timon Erik (Gut, 2023)
CRIS-Team WoS Importer:2023-02-03

Dissociated response as a new biomarker of treatment response in neuroendocrine tumors: Results from phase 3 of the RAISE project - Dromain, C.; Pavel, Marianne Ellen; Ronot, M.; Schaefer, N.; Mandair, D.; Gueguen, D.; Cheng, C.; Cahane, D.; Jegou, S.; Balazard, F. (JOURNAL OF NEUROENDOCRINOLOGY, 2021)
CRIS-Team WoS Importer:2021-03-12

Distant metastases in colorectal carcinoma: A proposal for a new M1 subclassification - Merkel, Susanne; Weber, K.; Croner, R. S.; Golcher, H.; Göhl, Jonas; Agaimy, Abbas; Semrau, S.; Wein, Axel; Hohenberger, Werner; Wittekind, C.; Siebler, Jürgen (Ejso, 2016)
In 2010, the seventh Tumour-Node-Metastasis (TNM) cancer staging system of the International Union for Cancer Control (UICC) and the American Joint Committee of Cancer (AJCC) introduced a subdivision of M1 in the TNM classification of colorectal carcinomas. For the eighth TNM edition which will be released in the autumn of 2016 and will become effective in January 2017 new proposals are appreciated. The aim of our study was to define a new and better proposal for M1 subclassification.In a total of 814 patients with stage IV colorectal carcinoma treated between 1995 and 2013 prognostic factors were analysed in univariate and multivariate analyses.Advanced age, treatment in the earlier period 1995-2003, involvement of multiple metastatic sites, and non-curative resection were found to be independent prognostic factors. In patients with only one metastatic site, survival was good in patients with liver or lung metastasis, moderate in patients with metastasis of the peritoneum or non-regional lymph nodes and poor in patients with other rarely metastatic involved organs. The new proposal defines M1a, Metastasis confined to one organ: liver or lung (2-year survival 51.6%); M1b, Metastasis confined to one organ: peritoneum or non-regional lymph nodes, or Metastasis confined to liver plus lung (2-year survival 39.4%); and M1c, Metastasis confined to one organ: all other sites, or Metastasis in more than one organ, except liver plus lung (2-year survival 21.6%).The new proposal can identify three prognostic groups in stage IV colorectal carcinomas with significant differences in survival.
EVALuna2:2060

Distinct mircobiomes in right- and left-sided colon cancer - Langheinrich, Melanie C.; Wirtz, Stefan; Kneis, Barbara; Weber, Klaus; Brunner, Maximilian; Krautz, Christian; Trebicka, Jonel; Agaimy, Abbas; Grützmann, Robert; Kersting, Stephan (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Distribution and Cytokine Profile of Peripheral B Cell Subsets Is Perturbed in Pediatric IBD and Partially Restored during a Successful IFX Therapy - Schnell, Alexander; Schwarz, Benedikt; Wahlbuhl, Mandy; Allabauer, Ida; Hess, Merlin; Weber, Simone; Werner, Felix; Schmidt, Hannah; Rechenauer, Tobias; Siebenlist, Gregor; Kaspar, Sonja; Ehrsam, Christoph; et al. (Inflammatory Bowel Diseases, 2021)
Background: The role of B cells in inflammatory bowel disease (IBD) is ambiguous, as B cells may have both pathogenic and protective functions in IBD. We studied B cell subsets before and after initiation of an anti-tumor necrosis factor alpha (anti-TNFα) therapy in pediatric IBD. The aim of the study was to examine the behavior of B cells in pediatric IBD patients undergoing an anti-TNFα therapy and, more specifically, to clarify their association with a successful or an unsuccessful infliximab (IFX) treatment. Methods: A total of N = 42 pediatric IBD patients (Crohn disease, n = 30; ulcerative colitis, n = 12) for whom an anti-TNFα therapy with and without a concomitant azathioprine (AZA) medication was administered were recruited. Fourteen healthy age-matched children served as control patients. Blood samples were collected before initiation of the anti-TNFα therapy, before the fourth infusion at the end of the induction phase, and after 6 and 12 months under therapy maintenance. Flow cytometry (CD20, CD27, CD38, CD138) and intracellular staining (interleukin 10 [IL10], TNFα, granzyme B) were performed. Responders to successful IFX therapy were classified exhibiting a fecal calprotectin level of below 100 μg/g or achieving levels of <10% of the baseline value at initiation than at the end of the 12-month follow-up period. Results: Before initiation of anti-TNFα therapy, flow cytometry revealed increased percentages of naïve B cells whereas transitional B cells were reduced compared with those in the healthy control patients. The IL10-producing B cells of both ulcerative colitis and Crohn disease patients were reduced at the initiation of IFX therapy, whereas TNFα-producing transitional CD24hiCD38hi B cells in ulcerative colitis patients were increased compared with those in healthy control patients. After 12 months of therapy, we detected a significant increase of IL10-producing transitional B cells in responding patients. The IFX trough levels in the responding patients showed a significant increase until 6 months after IFX initiation, attaining mean values of 9.9 μg/mL, whereas the IFX dosage was significantly lower than that in the nonresponding patients. The IFX trough levels in AZA-treated patients reached earlier therapeutic levels than in patients without AZA comedication, whereas during the course of the IFX therapy, comedication with AZA had no significant effect on the outcome. Conclusions: Attaining a normalization of IL10 production among CD24hiCD38hi B cells after 12 months of therapy may represent additional information about the reconstitution of a patient's immune system in responding patients. The achievement of an IFX trough level of 10 μg/mL at 6 months of treatment is associated with a successful anti-TNFα therapy. In addition, AZA comedication supports an earlier achievement of therapeutic IFX trough levels.
CRIS-Team Scopus Importer:2021-02-26
Keywords: children; Crohn disease; TNFα inhibitor; transitional B cells; ulcerative colitis

DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms - Yao, James; Bergsland, Emily; Aggarwal, Rahul; Aparicio, Ana; Beltran, Himisha; Crabtree, Judy S.; Hann, Christine L.; Ibrahim, Toni; Byers, Lauren A.; Sasano, Hironobu; Umejiego, John; Pavel, Marianne Ellen (Oncologist, 2022)
This review describes neuroendocrine neoplasms (NEN) classification, incidence, pathogenesis, and current management, focusing on delta-like ligand 3 (DLL3) in NEN progression and prognosis. Therapeutic targeting of DLL3 is addressed, and ongoing studies of DLL3-targeting therapies are summarized.
CRIS-Team WoS Importer:2022-08-26

Doctoral Scholarships Results of previous Doctoral Scholarships - Dietz, Lisa (Zeitschrift für Gastroenterologie, 2019)
CRIS-Team WoS Importer:2019-04-02

Does Pyroptosis Play a Role in Inflammasome-Related Disorders? - Zhang, Jiajia; Wirtz, Stefan (International Journal of Molecular Sciences, 2022)
Inflammasomes are multiprotein complexes orchestrating intracellular recognition of endogenous and exogenous stimuli, cellular homeostasis, and cell death. Upon sensing of certain stimuli, inflammasomes typically activate inflammatory caspases that promote the production and release of the proinflammatory cytokines IL-1 beta, IL-1 alpha, and IL-18 and induce a type of inflammatory cell death known as "pyroptosis". Pyroptosis is an important form of regulated cell death executed by gasdermin proteins, which is largely different from apoptosis and necrosis. Recently, several signaling pathways driving pyroptotic cell death, including canonical and noncanonical inflammasome activation, as well as caspase-3-dependent pathways, have been reported. While much evidence exists that pyroptosis is involved in the development of several inflammatory diseases, its contribution to inflammasome-related disorders (IRDs) has not been fully clarified. This article reviews molecular mechanisms leading to pyroptosis, and attempts to provide evidence for its possible role in inflammasome-related disorders, including NLR pyrin domain containing 3 (NLRP3) inflammasome disease, NLR containing a caspase recruitment domain 4 (NLRC4) inflammasome disease, and pyrin inflammasome disease. Although the specific mechanism needs further investigations, these studies have uncovered the role of pyroptosis in inflammasome-related disorders and may open new avenues for future therapeutic interventions.
CRIS-Team WoS Importer:2022-09-30

Does the Beneficial Antipruritic Effect of Bezafibrate in Primary Biliary Cholangitis Depend on Autotaxin Activity? - Kremer, Andreas; Le Cleac'H, Aline; Wolf, Katharina; Chazouilleres, Olivier; Lemoinne, Sara; De Chaisemaitin, Luc; Chollet-Martin, Sylvie; Humbert, Lydie; Rainteauu, Dominique; Poupon, Raoul; Rousseau, Alexandra; Corpechot, Christophe (2018)
EVALuna2:35137

Does the "polyp paradox" really exist? - Neumann, Helmut; Rerknimitr, Rungsun (Digestive Diseases and Sciences, 2014)
EVALuna2:1883

Dose-dependent differential effects of vedolizumab therapy on adhesion of regulatory and effector T cells - Becker, Elisabeth; Wiendl, Maximilian; Schulz-Kuhnt, Anja; Atreya, I.; Atreya, Raja; Neurath, Markus; Zundler, Sebastian (JOURNAL OF CROHNS & COLITIS, 2020)
CRIS-Team WoS Importer:2020-04-10

Double-Balloon Enteroscopy-detected Lipid Islets in the Small Bowel are Strong Predictors of Cardiovascular Disease when associated with Angiectasia and Bleeding - Albrecht, Heinz; Hagel, Wolfgang H.; Hagel, Alexander; Neurath, Markus; Raithel, Martin (Journal of Gastrointestinal and Liver Diseases, 2016)
Double-balloon enteroscopy (DBE) is a sensitive and safe procedure for the detection and treatment of mid-gastrointestinal bleeding (MGIB). It combines the possibility of a panenteroscopy with the immediate chance for intervention. This study evaluates the yield of DBE for the detection and treatment of MGIB in an unselected patient cohort.In a five-year period a total of 119 DBEs were carried out on 62 patients due to MGIB. Inclusion criteria were hematochezia, melena, anemia, positive hemoccult-test and iron deficiency. All pre-existing diseases or comorbidities were evaluated. Two main statistical methodologies were used in data analysis: descriptive statistics to describe the basic features of our data and Fisher's exact test for comparisons of proportions.The diagnostic yield was 69% (pathological findings in 43/62 patients) and the main diagnoses in all DBE-procedures were angiodysplasia (22%, 26/119 DBE), followed by lipid islets (18%, 21/119 DBE). In all patients with lipid islets this diagnosis was significantly connected with cardiovascular diseases. The combination of lipid islets and a relevant bleeding source appeared in 79% of the 19 patients with these findings. Of these, 53% had to be treated due to the bleeding event. The overall therapeutic intervention rate was 58%. Serious complications such as perforation or pancreatitis did not occur.Double-balloon enteroscopy as the gold standard for small bowel investigation in MGIB confirmed its high diagnostic yield in an unselected cohort of patients. A new strong combination of lipid islets with cardiovascular disease was revealed, with a high incidence of angiectasia bleeding. This combination should be evaluated in more detail as a new risk factor for MGIB, and should be regarded in this population when therapeutic anticoagulation is needed.
EVALuna2:2076

Drug Levels in the Maternal Serum, Cord Blood and Breast Milk of a Ustekinumab-Treated Patient with Crohn's Disease - Klenske, Entcho; Osaba, Lourdes; Nagore, Daniel; Rath, Timo; Neurath, Markus; Atreya, Raja (Journal of Crohns & Colitis, 2019)
Ustekinumab [UST] therapy during pregnancy has not yet been extensively evaluated in patients with Crohn's disease. Here, we present the case of a 24-year-old woman with therapy-refractory Crohn's disease, who was treated with UST until Week 30 of pregnancy and successfully delivered a healthy baby boy, who had normal development in the follow-up period of one year. The cord blood UST level was markedly higher than the measured maternal serum drug level. The trough level in the breast milk after re-initiating postpartum UST therapy was initially in the same range as the corresponding serum trough level, and then decreased during maintenance therapy. This is one of the first reports describing the drug levels in the breast milk after re-initiating UST treatment in a Crohn's disease patient.
CRIS-Team WoS Importer:2019-03-06

Drug rediscovery in gastroenterology: From off-label to on-label use of thioguanine in inflammatory bowel disease - De Boer, Nanne K.H.; Simsek, Melek; Meijer, Berrie; Neurath, Markus; Van Bodegraven, Ad; Mulder, Chris J.J. (Gut, 2023)
Drug rediscovery refers to the principle of using € old' drugs outside the indications mentioned in the summary of product characteristics. In the past decades, several drugs were rediscovered in a wide variety of medical fields. One of the most recent examples is the unconditional registration of thioguanine (TG), a thiopurine derivative, in patients with inflammatory bowel disease in the Netherlands. In this paper, we aim to visualise potential hurdles that hamper drug rediscovery in general, emphasise the global need for optimal use and development of potentially useful drugs, and provide an overview of the registration process for TG in the Netherlands. With this summary, we aim to guide drug rediscovery trajectories in the near future.
CRIS-Team Scopus Importer:2023-07-21
Keywords: azathioprine; crohn's disease; drug development; drug metabolism; inflammatory bowel disease

Drug Therapy in Gastroenterology: Molecular Basis of IBD - Neurath, Markus (Drug Research, 2021)
CRIS-Team WoS Importer:2021-12-03

Dual opposing actions of STW 5 on TRP receptors mediate neuronal desensitisation in vitro - Khalil, Mohammad; Zhang, Zehua; Abdel-Aziz, H.; Rabini, S.; Ammar, R. M.; Reeh, Peter; Engel, Matthias (Life Sciences, 2020)
Aims: STW 5 is an herbal drug combination used for the treatment of functional gastrointestinal disorders (FGIDs) with visceral hypersensitivity as the therapy-resistant hallmark. STW 5 has been clinically proven to alleviate visceral hypersensitivity-related symptoms, including abdominal pain, bloating, nausea, and early satiety. However, the molecular and cellular mechanisms underlying the antinociceptive action of STW 5 remain unknown. Here, we investigate the role of STW 5 in the calcium mobilisation of dorsal root ganglion (DRG) sensory neurons. Main methods: Calcium imaging experiments were performed with freshly dissociated cultured murine DRG neurons isolated from mice by microfluorometry. TRPA1-deficient DRGs, TRPV1-deficient DRGs, TRPA1/V1 double-deficient DRGs, and wild-type DRGs have been used to investigate the role of TRPs ion channels in mediating STW 5 action. Key findings: STW 5 (1.74 and 5.8 mg/ml) induced calcium ion influx into DRG neurons in a concentration-dependent manner. Calcium transients were desensitised during repeated exposure to STW 5, an effect that was facilitated in TRPA1-deficient DRGs and less pronounced in TRPV1-deficient DRGs compared to wild-type (WT) DRGs. Significance: Repeated exposure to STW 5 induced desensitisation of sensory neurons and may ultimately contribute to its proven clinical efficacy against sensory-related symptoms in patients with FGID, including abdominal pain, bloating, nausea, and early satiety. This effect is modulated by the two prominent irritant sensors in nociceptors, TRPA1 and TRPV1.
CRIS-Team Scopus Importer:2020-07-31
Keywords: Abdominal pain; Dorsal root ganglion; Functional gastrointestinal disorders; STW 5; Visceral hypersensitivity

Dual role of the mycobacterial cord factor TDM in cross-regulation of macrophage responses to IFN gamma - Killy, Barbara; Huber, Angelika; Ekici, Arif Bülent; Wirtz, Stefan; Dalpke, A.; Lang, Roland (2017)
EVALuna2:33888

Duchenne muscular dystrophy and malignant hyperthermia: a genetic study of the ryanodine receptor in 47 patients - Rohde, Doris; Schmitt, Heike; Winterpacht, Andreas; Münster, Tino (European Journal of Anaesthesiology, 2014)
EVALuna2:9224

Dynamic Adhesion Assay for the Functional Analysis of Anti-adhesion Therapies in Inflammatory Bowel Disease - Becker, Elisabeth; Schramm, Simon; Binder, Marie-Theres; Allner, Clarissa; Wiendl, Maximilian; Neufert, Clemens; Atreya, Imke; Neurath, Markus; Zundler, Sebastian (Journal of Visualized Experiments, 2018)
Gut homing of immune cells is important for the pathogenesis of inflammatory bowel diseases (IBD). Integrin-dependent cell adhesion to addressins is a crucial step in this process and therapeutic strategies interfering with adhesion have been successfully established. The anti-α4β7 integrin antibody, vedolizumab, is used for the clinical treatment of Crohn's disease (CD) and ulcerative colitis (UC) and further compounds are likely to follow. The details of the adhesion procedure and the action mechanisms of anti-integrin antibodies are still unclear in many regards due to the limited available techniques for the functional research in this field. Here, we present a dynamic adhesion assay for the functional analysis of human cell adhesion under flow conditions and the impact of anti-integrin therapies in the context of IBD. It is based on the perfusion of primary human cells through addressin-coated ultrathin glass capillaries with real-time microscopic analysis. The assay offers a variety of opportunities for refinements and modifications and holds potentials for mechanistic discoveries and translational applications.
EVALuna2:207768

Dynamic Contrast-Enhanced Ultrasound (DCE-US) for the Characterization of Hepatocellular Carcinoma and Cholangiocellular Carcinoma - Wildner, D.; Pfeifer, Lukas; Görtz, Rüdiger; Bernatik, T.; Sturm, J.; Neurath, Markus; Strobel, Deike (Ultraschall in der Medizin, 2014)
Purpose: In a prospective study, we compared the different perfusion kinetics of HCC and ICC using dynamic contrast-enhanced ultrasound (DCE-US). Materials and Methods: Patients with proven HCC and ICC were included. Three-minute video clips of CEUS examinations (CPS - low MI mode) after a bolus injection of 1.2 ml SonoVue(®) were recorded and analyzed with quantification software (VueBox(®)). Parameters for the arterial contrast enhancement [rise time (RT), time-to-peak (TTP)] towards portal venous contrast enhancement [mean transit time (local) (mTTl) and fall time (FT)] were quantified. Furthermore, contrast wash-out after peak enhancement (PE) (40 s, 80 s, 100 s and 120 s after PE) was compared between HCC and ICC. Results: 43 patients with proven HCC (n = 23 HCC; cirrhosis n = 16) and ICC (n = 20 ICC; Cirrhosis n = 6) were examined. No statistical difference of the arterial DCEUS parameters was found between HCC and ICC. Contrast enhancement of the portal venous and late phases showed significantly lower values in the ICC group indicating early wash-out of the contrast agent: mTTl (p = 0.0209): HCC 118.4 s (SD± 88.4); ICC 64.8 s (SD± 49.7). FT (p = 0.0433): HCC 42.5 s (SD± 27.7); ICC 27.7 s (SD± 16.2). The percental loss of intensity at a definite time point after PE was significantly higher in ICC than in HCC lesions. Conclusion: DCE-US is able to detect and quantify differences in perfusion kinetics between HCC and ICC. Whereas arterial contrast enhancement patterns may overlap between HCC and ICC, a timed characterization of wash-out kinetics may offer an additional tool to characterize HCC and ICC. The presence of a rapid loss of signal intensity in the early portal venous phase is significantly higher in ICC than in HCC lesions.
EVALuna2:1876

Dynamic imaging of iel-iec co-cultures allows for quantification of cd103-dependent t cell migration - Enderle, Karin; Dinkel, Martin; Spath, Eva-Maria; Schmid, Benjamin; Zundler, Sebastian; Tripal, Philipp; Neurath, Markus; Hildner, Kai; Neufert, Clemens (International Journal of Molecular Sciences, 2021)
Intraepithelial lymphocytes (IEL) are widely distributed within the small intestinal epithelial cell (IEC) layer and represent one of the largest T cell pools of the body. While implicated in the pathogenesis of intestinal inflammation, detailed insight especially into the cellular cross-talk between IELs and IECs is largely missing in part due to lacking methodologies to monitor this interaction. To overcome this shortcoming, we employed and validated a murine IEL-IEC (organoids) ex vivo co-culture model system. Using livecell imaging we established a protocol to visualize and quantify the spatio-temporal migratory behavior of IELs within organoids over time. Applying this methodology, we found that IELs lacking CD103 (i.e., integrin alpha E, ITGAE) surface expression usually functioning as a retention receptor for IELs through binding to E-cadherin (CD324) expressing IECs displayed aberrant mobility and migration patterns. Specifically, CD103 deficiency affected the ability of IELs to migrate and reduced their speed during crawling within organoids. In summary, we report a new technology to monitor and quantitatively assess especially migratory characteristics of IELs communicating with IEC ex vivo. This approach is hence readily applicable to study the effects of targeted therapeutic interventions on IEL-IEC cross-talk.
CRIS-Team Scopus Importer:2021-05-21
Keywords: CD103; Intestinal organoids; Intraepithelial lymphocytes; Life cell imaging; Lympho-cyte migration

DYNAMICS OF CHOLESTEROL AND BLOOD PRESSURE IN 4,484 ADULTS WITH TYPE 1 OR TYPE 2 DIABETES AFTER INITIATION OF CGM - Lanzinger, S.; Best, F.; Bergmann, Tanja; Laimer, M.; Lipovsky, B.; Danne, T.; Zimny, S.; Bramlage, P.; Meyhofer, S.; Holl, R. (DIABETES TECHNOLOGY & THERAPEUTICS, 2022)
CRIS-Team WoS Importer:2022-05-20

Dynamics of Fukuoka Criteria and Patient Management in Pancreatic Intraductal Papillary Mucinous Neoplasms (IPMNs) During Follow-Up - Schellhaas, Barbara; Vitali, Francesco; Wildner, Dane; Görtz, Rüdiger; Pfeifer, Lukas; Konturek, Peter C.; Neurath, Markus; Strobel, Deike (Medical Science Monitor, 2017)
BACKGROUND Pancreatic intraductal papillary mucinous neoplasms (IPMNs) present a clinical challenge. Evidence-based guidelines are lacking. The so-called "Fukuoka criteria" were developed to assess the risk of malignancy in IPMNs upon imaging. However, little is known about their diagnostic value and the natural course of IPMNs. Thus, the aim of this study was the assessment of Fukuoka criteria and patient management in pancreatic IPMNs -during follow-up. MATERIAL AND METHODS IPMNs were identified via retrospective survey of endoscopic ultrasound (EUS) examinations. Fukuoka criteria were assessed on EUS findings and additional imaging (CT, MRI, ultrasound). Patients' symptoms and comorbidities were recorded. Dynamics of Fukuoka criteria and patient management were compared at first presentation and during follow-up. RESULTS We screened 1324 EUS examinations. Sixty-five patients (male/female, 14/37; mean age, 68.8 years; range, 48-85 years) with IPMNs were identified (57 branch duct (BD-)IPMNs, 3 main duct (MD-) IPMNs, 5 mixed-type (MT)-IPMNs). Seven patients received surgical resection (4 BD-IPMNs, 2 MD-IPMNs, 1 MT-IPMN). Nine BD-IPMNs had neither surgery nor follow-up. Fifty-one patients (44 BD-IPMNs, 2 MD-IPMNs, 5 MT-IPMNs) underwent follow-up (mean duration, 18.7 months; range, 3-139 months). There were 15/51 patients who were initially Fukuoka-positive. One MD-IPMN, 4/5 MT-IPMNs, and 13/44 BD-IPMNs showed progressive changes but were not resected due to patients' refusal or comorbidities. Four BD-IPMNs converted to Fukuoka-positive. CONCLUSIONS Evidence-based guidelines for non-invasive dignity assessment of IPMNs are lacking. In our study, MD-IPMNs displayed greater dynamics than BD-IPMNs and MT-IPMNs concerning Fukuoka criteria. Prospective long-term studies are needed to clarify prognostic significance of the single Fukuoka criteria and sensible duration of follow-up.
EVALuna2:33822

Dynamics of Hemoglobin A1c, Body Mass Index, and Rates of Severe Hypoglycemia in 4434 Adults with Type 1 or Type 2 Diabetes After Initiation of Continuous Glucose Monitoring - Lanzinger, Stefanie; Best, Frank; Bergmann, Tanja; Laimer, Markus; Lipovsky, Boris; Danne, Thomas; Zimny, Stefan; Bramlage, Peter; Meyhoefer, Svenja; Holl, Reinhard W. (Diabetes Technology & Therapeutics, 2022)
Background: Continuous glucose monitoring (CGM) might have beneficial effects on glycemic control and body mass index (BMI) in adults with type 1 (T1D) or type 2 diabetes (T2D).Methods: The diabetes prospective follow-up registry was used to identify individuals with T1D or T2D >= 18 years starting CGM management in 2015 or later and follow-up information available. Hemoglobin A1c (HbA1c), BMI, and event rates of severe hypoglycemia in the year before CGM start were compared with two follow-up periods: (1) CGM use for 3-6 months and (2) CGM use for >6 months. Repeated measurements linear and negative binomial regressions were used (adjustment for sex, age at diabetes onset, and baseline parameters) and stratified by diabetes type.Results: Mean follow-up time was 1.8 years in T1D (n = 2994) and 1.9 years in T2D (n = 1440). In T1D, adjusted mean HbA1c decreased significantly from 7.65% (95% confidence interval: 7.62-7.68) at baseline to 7.54% (7.51-7.57) during follow-up. BMI increased slightly (baseline: 25.4 kg/m(2) [25.3-25.5], follow-up >6 months: 25.8 kg/m(2) [25.7-25.9]), whereas event rates of severe hypoglycemia were significantly lower after >6 months with CGM (9.0 events/100 patient-years [PY; 8.0-10.1]) compared with baseline (11.3 events/100 PY [10.4-12.2]) in adults with T1D. In T2D, HbA1c decreased from 7.21% (7.17%-7.25%) to 7.00% (6.95%-7.04%) and BMI did not change after CGM initiation.Conclusion: Our results provide real-world evidence on CGM management in adult individuals with T1D or T2D. We suggest strengthening patients' and physicians' readiness toward diabetes technology in T2D and more openness of health insurance to cover cost based on proven benefits.
CRIS-Team WoS Importer:2022-07-22

Dynamic traction force measurements of migrating immune cells in 3D matrices - Böhringer, David; Cóndor, Mar; Bischof, Lars; Czerwinski, Tina; Gampl, Niklas; Ngo, Phuong; Bauer, Andreas; Bosch-Voskens, Caroline; Lopez Posadas, Rocío; Franze, Kristian; Budday, Silvia; Mark, Christoph; et al. (2025)
Immune cells such as natural killer (NK) cells migrate with high speeds of several µm/min through dense tissue, but the traction forces are unknown. We present a method to measure dynamic traction forces of fast migrating cells in non-linear biopolymer matrices. The method accounts for the mechanical non-linearity of the 3D tissue matrix and can be applied to time series of confocal or bright-field image stacks. The method is highly sensitive over a large range of forces and object sizes, from ∼1 nN for axon growth cones up to ∼10 µN for mouse intestinal organoids. We find that NK cells display bursts of large traction forces that increase with matrix stiffness and facilitate migration through tight constrictions.<br
https://cris.fau.de/converis/publicweb/Publication/321683487

Dynamic, transient, and robust increase in the innervation of the inflamed mucosa in inflammatory bowel diseases - Gonzalez Acera, Miguel; Bubeck, Marvin; Mascia, Fabrizio; Diemand, Leonard; Sturm, Gregor; Kuehl, Anja A.; Atreya, Raja; Lie, Dieter Chichung; Neurath, Markus; Schumann, Michael; Klose, Christoph S. N.; Trajanoski, Zlatko; et al. (Cells, 2021)
Inflammatory bowel diseases (IBD) are characterized by chronic dysregulation of immune homeostasis, epithelial demise, immune cell activation, and microbial translocation. Each of these processes leads to proinflammatory changes via the release of cytokines, damage-associated molecular patterns (DAMPs), and pathogen-associated molecular patterns (PAMPs), respectively. The impact of these noxious agents on the survival and function of the enteric nervous system (ENS) is poorly understood. Here, we show that in contrast to an expected decrease, experimental as well as clinical colitis causes an increase in the transcript levels of enteric neuronal and glial genes. Immunostaining revealed an elevated neuronal innervation of the inflamed regions of the gut mucosa. The increase was seen in models with overt damage to epithelial cells and models of T cell-induced colitis. Transcriptomic data from treatment naïve pediatric IBD patients also confirmed the increase in the neuroglial genes and were replicated on an independent adult IBD dataset. This induction in the neuroglial genes was transient as levels returned to normal upon the induction of remission in both mouse models as well as colitis patients. Our data highlight the dynamic and robust nature of the enteric nervous system in colitis and open novel questions on its regulation.
CRIS-Team Scopus Importer:2021-10-08
Keywords: Crohn’s disease; Enteric nervous system; Inflammatory bowel diseases; Neurogenesis; Ulcerative colitis

Early-onset coronary atherosclerosis in patients with low levels of omega-3 fatty acids - Bittner, D. O.; Göller, Markus; Zopf, Yurdagül; Achenbach, Stephan; Marwan, Mohamed (European Journal of Clinical Nutrition, 2020)
Objectives: Coronary artery calcification (CAC) can reliably predict cardiovascular events. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are thought to inhibit vascular calcification on a cellular level and in animal models, however, the correlation in humans is controversial. Methods: In symptomatic patients, CAC was quantified according to Agatstons’ method using non-contrast coronary CT. We assessed the association of EPA and DHA with early-onset coronary atherosclerosis, defined as presence of CAC above the 75th Agatston-Score (AS) percentile in sex adjusted age categories. Erythrocyte fatty acid composition was analyzed with a standardized methodology. The percentage of EPA and DHA in relation to all fatty acids present in the erythrocyte membrane is regarded the Omega-3 Index®. Results: Among 71 patients, 51 were below and 20 were above the 75th AS-percentile. No differences were seen in age, gender, cardiovascular risk factors, and relevant medication. In univariable analysis, significantly lower values for EPA (0.77%[0.63; 0.97] vs. 0.93%[0.72; 1.21]; p = 0.045), DHA (4.90%[4.12; 5.57] vs. 5.50%[4.58; 6.52]; p = 0.038) and the Omega-3 Index (5.73%[4.75; 6.35] vs. 6.22%[5.46; 7.71]; p = 0.034) were seen in patients above the 75th AS-percentile. All other fatty acids showed no significant differences. In multivariable analysis, the Omega-3 Index showed a significant inverse association with early onset of CAC (OR: 0.533 (95%CI: 0.303–0.938; p = 0.029)), independent of age, gender, statin use, and creatinine level (all p > 0.05). Conclusions: Low levels of EPA and DHA (Omega-3 Index) are associated with early-onset coronary atherosclerosis. This finding needs to be validated in larger cohorts and might help understand the beneficial cardiovascular effects of omega-3 fatty acids.
CRIS-Team Scopus Importer:2020-01-21

Early Symptom Improvement With Risankizumab Treatment in Patients With Moderately to Severely Active Crohn's Disease: Analysis From a Phase 2 Study - Feagan, Brian G.; Sandborn, William J.; D'Haens, Geert R.; Panes, Julian; Kaser, Arthur; Ferrante, Marc; Louis, Edouard; Dewit, Olivier; Seidler, Ursula; Kim, Kyung-Jo; Kligys, Kristina; Wallace, Kori; et al. (AMERICAN JOURNAL OF GASTROENTEROLOGY, 2019)
CRIS-Team WoS Importer:2020-02-28

ECCO Topical Review: Refractory Inflammatory Bowel Disease - Raine, Tim; Verstockt, Bram; Kopylov, Uri; Karmiris, Konstantinos; Goldberg, Rimma; Atreya, Raja; Burisch, Johan; Burke, John; Ellul, Pierre; Hedin, Charlotte; Holubar, Stefan D.; Katsanos, Konstantinos; et al. (Journal of Crohns & Colitis, 2021)
Inflammatory bowel disease is a chronic disease with variable degrees of extent, severity, and activity. A proportion of patients will have disease that is refractory to licensed therapies, resulting in significant impairment in quality of life. The treatment of these patients involves a systematic approach by the entire multidisciplinary team, with particular consideration given to medical options including unlicensed therapies, surgical interventions, and dietetic and psychological support. The purpose of this review is to guide clinicians through this process and provide an accurate summary of the available evidence for different strategies.
CRIS-Team WoS Importer:2021-11-12

Editorial: Loss of Epithelial Barrier Integrity in Inflammatory Diseases: Cellular Mediators and Therapeutic Targets - Weidinger, Carl; Krug, Susanne M.; Voskens, Caroline; Moschen, Alexander R.; Atreya, Imke (Frontiers in Medicine, 2021)
CRIS-Team WoS Importer:2022-01-14

Editorial: Modulating Cytokines as Treatment for Autoimmune Diseases and Cancer - Mortier, Erwan; Ma, Averil; Malynn, Barbara A.; Neurath, Markus (Frontiers in Immunology, 2020)
CRIS-Team Scopus Importer:2020-11-06
Keywords: cytokine; inflammation; inhibitor; oncology; therapy

Effectiveness of vedolizumab therapy in a real-world setting in Germany: First results of the VEDOibd study comparing vedolizumab to the use of other biologics - Bokemeyer, B.; Plachta-Danielzik, S.; Sobotzki, C.; Mohl, W.; Hoffstadt, M.; Krause, T.; Atreya, Raja; Von Der Ohe, M.; Graefe, U.; Trentmann, L.; Eisold, M.; Linde, A.; et al. (JOURNAL OF CROHNS & COLITIS, 2020)
CRIS-Team WoS Importer:2020-04-10

Effect of Lanreotide Depot/Autogel on Urinary 5-Hydroxyindoleacetic Acid and Plasma Chromogranin A Biomarkers in Nonfunctional Metastatic Enteropancreatic Neuroendocrine Tumors - Pavel, Marianne Ellen; Phan, Alexandria T.; Wolin, Edward M.; Mirakhur, Beloo; Liyanage, Nilani; Pitman Lowenthal, Susan; Fisher, George A.; Vinik, Aaron I. (Oncologist, 2019)
Background: Urinary 5-hydroxyindoleacetic acid (5-HIAA) is an established biomarker in neuroendocrine tumors and carcinoid syndrome; however, its role in nonfunctional neuroendocrine tumors is not defined. We present post hoc data on urinary 5-HIAA and plasma chromogranin A (CgA) from the CLARINET study. Methods: Patients with well- or moderately differentiated, nonfunctioning, locally advanced or metastatic enteropancreatic neuroendocrine tumors were randomized to deep subcutaneous lanreotide depot/autogel 120 mg or placebo once every 28 days for 96 weeks. Tumor response, evaluated centrally (RECIST 1.0), and progression-free survival (PFS) were assessed by treatment and biochemical response, defined as (a) baseline >upper limit of normal (ULN, 41.6 μmol per day 5-HIAA; 98.1 μg/L CgA) and (b) ≥50% decrease from baseline and to ≤ULN value on study. Results: Forty-eight percent (82 of 171; lanreotide, n = 45; placebo, n = 37) and 66% (129 of 195; lanreotide, n = 65; placebo, n = 64) of randomized patients had 5-HIAA and CgA > ULN at baseline. Among patients with >ULN baseline values who did not progress after 96 weeks of treatment, significantly greater reductions in 5-HIAA and CgA were observed in lanreotide-treated versus placebo-treated patients throughout the study (all p <.05). PFS was significantly prolonged among 5-HIAA responders versus nonresponders (median not reached vs. 16.2 months, p <.0001; hazard ratio [HR] = 0.21, 95% confidence interval [CI], 0.09–0.48) and CgA responders versus nonresponders (median not reached vs. 16.2 months, p =.0070; HR = 0.30, 95% CI, 0.12–0.76), regardless of treatment arm. PFS was also significantly prolonged among lanreotide-treated 5-HIAA responders versus nonresponders (p =.0071) but was not significantly different among placebo-treated 5-HIAA responders versus nonresponders. There were no significant differences in PFS between lanreotide-treated CgA responders versus nonresponders or between placebo-treated CgA responders versus nonresponders. Conclusions: The 5-HIAA findings are noteworthy because they occurred in patients with nonfunctioning enteropancreatic neuroendocrine tumors. Monitoring 5-HIAA and CgA may be useful when treating patients with nonfunctional neuroendocrine tumors. Implications for Practice: Current guidelines focus only on the monitoring of 5-hydroxyindoleacetic acid (5-HIAA) in the diagnosis and management of functional neuroendocrine tumors with carcinoid syndrome. The current post hoc analysis of patients with nonfunctional enteropancreatic neuroendocrine tumors in the CLARINET study demonstrated that measuring and following both 5-HIAA and chromogranin A as biomarkers of disease progression may be useful in the management of patients with nonfunctional neuroendocrine tumors.
CRIS-Team Scopus Importer:2019-05-02
Keywords: 5-Hydroxyindoleacetic acid; Lanreotide; Neuroendocrine tumor; Plasma chromogranin A

Effect of oral bolus versus sustained release application of nutrient solution on olfaction - Denzer-Lippmann, Melanie; Bachlechner, S.; Wielopolski, Jan; Fischer, M.; Büttner, Andrea; Dörfler, Arnd; Schöfl, Christof; Münch, Gerald; Kornhuber, Johannes; Thürauf, Norbert (2016)
EVALuna2:33155

Effect of Seladelpar on Pruritus in Primary Biliary Cholangitis: 26-Week Analysis of an Ongoing International, randomized, Dose Ranging Phase 2 Study - Kremer, Andreas; Bowlus, Christopher L.; Neff, Guy W.; Aspinall, Richard; Galambos, Michael R.; Goel, Aparna; Hirschfield, Gideon; Mayo, Marlyn J.; Swain, Mark Gordon; Borg, Brian; Doerffel, Yvonne; Gordon, Stuart C.; et al. (2018)
EVALuna2:35128

Effect of SGLT2 inhibition on ketone bodies in patients with stable chronic heart failure - Pietschner, Robert; Kolwelter, Julie; Bosch, Agnes; Kannenkeril, Dennis; Ott, C.; Schiffer, Mario; Achenbach, Stephan; Schmieder, Roland (DIABETOLOGIA, 2021)
CRIS-Team WoS Importer:2021-10-01

Effects of Anti-Integrin Treatment With Vedolizumab on Immune Pathways and Cytokines in Inflammatory Bowel Diseases - Rath, Timo; Billmeier, Ulrike; Ferrazzi, Fulvia; Ekici, Arif Bülent; Neurath, Markus; Atreya, Raja; Vieth, Michael (Frontiers in Immunology, 2018)
Background and aims: Despite proven clinical efficacy of vedolizumab (VDZ) for inducing and maintaining remission in patients with Crohn's disease (CD) and ulcerative colitis (UC), subgroups of patients have no therapeutic benefit from anti-α4β7 integrin therapy with VDZ. Within this study, we aimed to identify genetic, cellular, and immunological mechanisms that define response and failure to VDZ treatment. Methods: Intestinal RNA sequencing was performed in UC and CD patients before and at week 14 of VDZ therapy. α4β7 expression on peripheral and mucosal immune cells was assessed by flow cytometry and immunohistochemistry. Cellular modes of VDZ-mediated action were analyzed ex vivo and in VDZ-treated inflammatory bowel disease patients. Results: Transcriptome analysis showed an impairment of signaling cascades associated with adhesion, diapedesis, and migration of granulocytes and agranulocytes upon VDZ therapy. In non-remitters to VDZ therapy, a tissue destructive and leukocyte-mediated inflammatory activity with activation of TNF-dependent pathways was present, all of which were inhibited in remitters to VDZ. Clinical remission was associated with a significant reduction of α4β7 expression on Th2 and Th17 polarized mucosal CD4+ T cells at week 14 of VDZ therapy and with significantly higher numbers of α4β7-expressing mucosal cells prior to the initiation of VDZ therapy compared with non-remitters. Conclusion: Intestinal α4β7 expression prior to VDZ therapy might represent a biomarker that predicts therapeutic response to subsequent VDZ treatment. Due to high activation of TNF signaling in VDZ non-remitters, anti-TNF treatment might represent a promising therapeutic strategy in VDZ refractory patients.
EVALuna2:34622

Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients With Active Ulcerative Colitis - Danese, Silvio; Neurath, Markus; Kopoń, Adam; Zakko, Salam F.; Simmons, Timothy C.; Fogel, Ronald; Siegel, Corey A.; Panaccione, Remo; Zhan, Xiaojiang; Usiskin, Keith; Chitkara, Denesh (Clinical Gastroenterology and Hepatology, 2020)
Background & Aims: New oral therapeutic agents are needed for patients with ulcerative colitis (UC) who are unresponsive or intolerant to conventional therapy. Methods: We performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naïve to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies. The study was performed at 61 sites in 14 countries (screening from January 2015 through May 2017). Patients were randomly assigned to groups given apremilast 30 mg (n = 57), apremilast 40 mg (n = 55), or placebo (n = 58) twice daily for 12 weeks; patients were then randomly assigned to groups that received apremilast, 30 or 40 mg twice daily, for an additional 40 weeks. Endoscopies were performed and biopsies were collected during the screening phase, at week 12, and at week 52. Blood and fecal samples were also collected and analyzed throughout the study. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or less, with no individual subscore above 1. Results: Clinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P =.01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P =.27 compared with placebo). Differences in clinical remission between the 30 mg and 40 mg apremilast groups were associated with differences in endoscopic improvement. Both apremilast groups had similar improvements from baseline in Mayo score components (stool frequency score, rectal bleeding score, physician's global assessment). The 30 mg and 40 mg apremilast groups had greater median percent reductions in C-reactive protein (measured by a high-sensitivity blood test) and fecal calprotectin through week 12 than the placebo group. At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group. The most frequent apremilast-associated adverse events were headache and nausea. Conclusions: Although the primary endpoint of clinical remission was not met in this phase 2 trial, a greater proportion of patients with active UC who received apremilast (30 mg or 40 mg) had improvements in clinical and endoscopic features, and markers of inflammation, at 12 weeks. Clinical remission was maintained to week 52 in up to 40% of patients who continued apremilast until that time point. ClinicalTrials.gov no: NCT02289417
CRIS-Team Scopus Importer:2020-09-25
Keywords: Biologic-Naïve; CRP; IBD; TMS

Effects of different isocaloric oral nutrient solutions on olfactory functioning, hunger and food craving - Thürauf, Norbert; Denzer-Lippmann, Melanie; Bachlechner, Stephan; Wielopolski, Jan; Fischer, Marie; Büttner, Andrea; Dörfler, Arnd; Schöfl, Christof; Münch, Gerald; Kornhuber, Johannes (2017)
EVALuna2:33148

Effects of glucose concentration in the tumor microenvironment on Non Small Lung Cancer (NSCLC) Progression - Gähler, Alexander; Hohenberger, Katja; Tausche, Patrick; Chiriac, Mircea-Teodor; Rauh, Manfred; Trufa, Denis; Geppert, Carol-Immanuel; Rieker, Ralf; Sirbu, Horia; Neurath-Finotto, Susetta (JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2021-12-03

Effects of liver cirrhosis and patient condition on clinical outcomes in intrahepatic cholangiocarcinoma: a retrospective analysis of 156 cases in a single center - Jesper, Daniel; Heyn, Sabrina; Schellhaas, Barbara; Pfeifer, Lukas; Görtz, Rüdiger; Zopf, Steffen; Neurath, Markus; Strobel, Deike (European Journal of Gastroenterology & Hepatology, 2018)
OBJECTIVE: The incidence of intrahepatic cholangiocarcinoma (iCCA) has been increasing over the past few decades. Liver cirrhosis is an independent risk factor for the development of iCCA. This study aimed to examine the prognostic impact of liver cirrhosis and patient condition on the treatment of iCCA. PATIENTS AND METHODS: We retrospectively analyzed the cases of 156 patients diagnosed with iCCA between 1990 and 2014 in our center. Patients were divided into subgroups depending on the presence and severity of liver cirrhosis and the type of treatment. Clinical data, patient characteristics, and overall survival were compared between these groups. RESULTS: Forty-seven (30%) of 156 patients had liver cirrhosis, predominantly with Child-Pugh scores A (n=27) and B (n=12). The median survival differed between patients receiving tumor resection (34 months), chemotherapy (10 months), and best supportive care (2 months). An Eastern Cooperative Oncology Group Performance Status score more than 1 was a predictor of poor survival in all patients (P<0.001), independent of the presence of cirrhosis. Resection could be performed less frequently in cirrhotic patients (6 vs. 31 patients; P=0.04). If resection was performed, the presence of cirrhosis A/B did not influence survival. Cirrhosis A/B did not influence the outcome in patients receiving chemotherapy either. In cirrhotic patients receiving chemotherapy, cancer antigen 19-9 levels above 129 U/ml were associated with a significantly shorter survival (22.5 vs. 3 months, P=0.0003). CONCLUSION: The presence of liver cirrhosis in iCCA has been underestimated. There was no difference in survival between noncirrhotic patients and patients with compensated cirrhosis. Patients' general condition seems to be of more prognostic value in the treatment of iCCA than the presence of cirrhosis. Therefore, the presence of cirrhosis A/B should not prevent patients with a good Eastern Cooperative Oncology Group Performance Status score from receiving tumor resection or chemotherapy.
EVALuna2:34071

Effects of low-volume high-intensity interval training in a community setting: a pilot study - Reljic, Dejan; Wittmann, Felix; Fischer, Joachim E. (European Journal of Applied Physiology, 2018)
PURPOSE: High-intensity interval training (HIIT) is emerging as an effective and time-efficient exercise strategy for health promotion. However, most HIIT studies are conducted in laboratory settings and evidence regarding the efficacy of time-efficient "low-volume" HIIT is based mainly on demanding "all-out" protocols. Thus, the aim of this pilot study was to assess the feasibility and efficacy of two low-volume (≤ 30 min time-effort/week), non-all-out HIIT protocols, performed 2 ×/week over 8 weeks in a community-based fitness centre. METHODS: Thirty-four sedentary men and women were randomised to either 2 × 4-min HIIT (2 × 4-HIIT) or 5 × 1-min HIIT (5 × 1-HIIT) at 85-95% maximal heart rate (HRmax), or an active control group performing moderate-intensity continuous training (MICT, 76 min/week) at 65-75% HRmax. RESULTS: The exercise protocols were well tolerated and no adverse events occurred. 2 × 4-HIIT and 5 × 1-HIIT exhibited lower dropout rates (17 and 8 vs. 30%) than MICT. All training modes improved VO2max (2 × 4-HIIT: + 20%, P < 0.01; 5 × 1-HIIT: + 27%, P < 0.001; MICT: + 16%, P < 0.05), but the HIIT protocols required 60% less time commitment. Both HIIT protocols and MICT had positive impact on cholesterol profiles. Only 5 × 1-HIIT significantly improved waist circumference (P < 0.05) and subjective work ability (P < 0.05). CONCLUSIONS: The present study indicates that low-volume HIIT can be feasibly implemented in a community-based setting. Moreover, our data suggest that practical (non-all-out) HIIT that requires as little as 30 min/week, either performed as 2 × 4-HIIT or 5 × 1-HIIT, may induce significant improvements in VO2max and cardiometabolic risk markers.
EVALuna2:209173

Effects of time-efficient, high intensity Interval Endurance Training on cardiorespiratory Fitness and cardiometabolic Risk Markers in a Real-World-Setting: A randomized-controlled Pilot Study - Reljic, Dejan; Wittmann, Felix; Fischer, Joachim (2018)
EVALuna2:209174

Effects of ustekinumab versus tumor necrosis factor inhibition on enthesitis: Results from the enthesial clearance in psoriatic arthritis (ECLIPSA) study - Guilhon de Araujo, Elizabeth; Englbrecht, Matthias; Höpken, Sabrina; Finzel, Stephanie; Kampylafka, Eleni; Kleyer, Arnd; Bayat, Sara; Schoenau, Verena; Hueber, Axel; Rech, Jürgen; Schett, Georg (Seminars in Arthritis and Rheumatism, 2018)
OBJECTIVES: To date, all studies addressing on anti-inflammatory drugs in PsA have been carried out in psoriatic arthritis (PsA) patients with polyarticular disease. Specific studies on enthesitis are missing. IL-23 is considered to play a central role in the development of enthesitis. We therefore speculated that therapeutic inhibition of IL-12/IL-23 is particularly effective in enthesitis-driven PsA patients. METHODS: Enthesial CLearance In PSoriatic Arthritis (ECLIPSA) is a prospective randomized-controlled open-label study. Patients with PsA with active enthesitis were randomized 1:1 to receive either ustekinumab (UST; arm 1) or tumor necrosis factor inhibitors (TNFi; arm 2). Primary endpoint was complete clearance of enthesitis, defined by Spondyloarthritis Research Consortium of Canada (SPARCC) index equal to zero at 24weeks. RESULTS: 51 patients (UST = 25; TNFi = 26) were screened, 47 enrolled (UST = 23; TNFi = 24) and 46 completed the study. Mean ± SD SPARCC index at baseline was 4.8 ± 2.6 in the UST group and 3.5 ± 2.3 in the TNFi group with no significant difference. After 24 weeks, 73.9% of UST patients and 41.7% of TNFi patients reached the primary endpoint (SPARCC = 0) indicating clearance from enthesitis (p = 0.018). UST achieved superior responses as compared to TNFi with respect to enthesitis (p = 0.007) and psoriatic skin disease (p = 0.030) but not for arthritis (p = 0.95). CONCLUSION: These results indicate that p40-IL-12/IL-23 inhibition is superior to TNFi in the clearance of enthesitis. Future stratified therapeutic approaches in PsA patients may therefore consider the presence or absence of enthesitis as a discriminator of response between different cytokine blocking modalities.
EVALuna2:34482

Effects of Vedolizumab in Patients With Primary Sclerosing Cholangitis and Inflammatory Bowel Diseases - Lynch, Kate D.; Chapman, Roger W.; Keshav, Satish; Montano-Loza, Aldo J.; Mason, Andrew L.; Kremer, Andreas; Vetter, Marcel; De Krijger, Manon; Ponsioen, Cyriel Y.; Trivedi, Palak; Hirschfield, Gideon; Schramm, Christoph; et al. (Clinical Gastroenterology and Hepatology, 2020)
BACKGROUND & AIMS: Gut-homing lymphocytes that express the integrin alpha 4 beta 7 and CCR9 might contribute to development of primary sclerosing cholangitis (PSC). Vedolizumab, which blocks the integrin alpha 4 beta 7, is used to treat patients with inflammatory bowel diseases (IBD), but there are few data on its efficacy in patients with PSC. We investigated the effects of vedolizumab in a large international cohort of patients with PSC and IBD.
CRIS-Team WoS Importer:2020-01-03

Effects of very low volume high intensity versus moderate intensity interval training in obese metabolic syndrome patients: a randomized controlled study - Reljic, Dejan; Frenk, Fabienne; Herrmann, Hans J.; Neurath, Markus; Zopf, Yurdagül (Scientific Reports, 2021)
Physical activity is a cornerstone in the treatment of obesity and metabolic syndrome (MetS). Given the leading physical activity barrier of time commitment and safety concerns about vigorous exercise in high-risk groups, this study aimed to investigate the effects of two extremely time-efficient training protocols (< 30 min time effort per week), either performed as high- (HIIT) or moderate-intensity interval training (MIIT) over 12 weeks, in obese MetS patients. In total, 117 patients (49.8 ± 13.6 years, BMI: 38.2 ± 6.2 kg/m2) were randomized to HIIT (n = 40), MIIT (n = 37) or an inactive control group (n = 40). All groups received nutritional counseling to support weight loss. Maximal oxygen uptake (VO2max), MetS severity (MetS z-score), body composition and quality of life (QoL) were assessed pre-and post-intervention. All groups significantly reduced body weight ( 3%) but only the exercise groups improved VO2max, MetS z-score and QoL. VO2max (HIIT: + 3.1 mL/kg/min, p < 0.001; MIIT: + 1.2 mL/kg/min, p < 0.05) and MetS z-score (HIIT: − 1.8 units, p < 0.001; MIIT: − 1.2 units, p < 0.01) improved in an exercise intensity-dependent manner. In conclusion, extremely low-volume interval training, even when done at moderate intensity, is sufficiently effective to improve cardiometabolic health in obese MetS patients. These findings underpin the crucial role of exercise in the treatment of obesity and MetS.
CRIS-Team Scopus Importer:2021-02-12

Effects of whole-body electromyostimulation combined with individualized nutritional support on body composition in patients with advanced cancer: a controlled pilot trial - Schink, Kristin; Herrmann, Hans J.; Schwappacher, Raphaela; Meyer, Julia; Orlemann, Till; Waldmann, Elisabeth; Wullich, Bernd; Kahlmeyer, Andreas; Fietkau, Rainer; Lubgan, Dorota; Beckmann, Matthias; Hack, Carolin; et al. (BMC Cancer, 2018)
BACKGROUND: Physical exercise and nutritional treatment are promising measures to prevent muscle wasting that is frequently observed in advanced-stage cancer patients. However, conventional exercise is not always suitable for these patients due to physical weakness and therapeutic side effects. In this pilot study, we examined the effect of a combined approach of the novel training method whole-body electromyostimulation (WB-EMS) and individualized nutritional support on body composition with primary focus on skeletal muscle mass in advanced cancer patients under oncological treatment. METHODS: In a non-randomized controlled trial design patients (56.5% male; 59.9 ± 12.7 years) with advanced solid tumors (UICC III/IV, N = 131) undergoing anti-cancer therapy were allocated to a usual care control group (n = 35) receiving individualized nutritional support or to an intervention group (n = 96) that additionally performed a supervised physical exercise program in form of 20 min WB-EMS sessions (bipolar, 85 Hz) 2×/week for 12 weeks. The primary outcome of skeletal muscle mass and secondary outcomes of body composition, body weight and hand grip strength were measured at baseline, in weeks 4, 8 and 12 by bioelectrical impedance analysis and hand dynamometer. Effects of WB-EMS were estimated by linear mixed models. Secondary outcomes of physical function, hematological and blood chemistry parameters, quality of life and fatigue were assessed at baseline and week 12. Changes were analyzed by t-tests, Wilcoxon signed-rank or Mann-Whitney-U-tests. RESULTS: Twenty-four patients of the control and 58 of the WB-EMS group completed the 12-week trial. Patients of the WB-EMS group had a significantly higher skeletal muscle mass (0.53 kg [0.08, 0.98]; p = 0.022) and body weight (1.02 kg [0.05, 1.98]; p = 0.039) compared to controls at the end of intervention. WB-EMS also significantly improved physical function and performance status (p < 0.05). No significant differences of changes in quality of life, fatigue and blood parameters were detected between the study groups after 12 weeks. CONCLUSIONS: Supervised WB-EMS training is a safe strength training method and combined with nutritional support it shows promising effects against muscle wasting and on physical function in advanced-stage cancer patients undergoing treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02293239 (Date: November 18, 2014).
EVALuna2:35141

Effects of whole-body electromyostimulation exercise and caloric restriction on cardiometabolic risk profile and muscle strength in obese women with the metabolic syndrome: a pilot study - Reljic, Dejan; Konturek, Peter; Herrmann, H. J.; Neurath, Markus; Zopf, Yurdagül (Journal of Physiology and Pharmacology, 2020)
Obesity, particularly in conjunction with further cardiometabolic risk factors, is associated with an increased risk of cardiovascular disease and mortality. Increased physical activity and dietary modifications are cornerstones of therapeutic interventions to treat obesity and related risk factors. Whole-body electromyostimulation (WB-EMS) has emerged as an innovative, time-efficient type of exercise that can provide positive effects on body composition and muscle strength. However, the impact of WB-EMS on cardiometabolic health in obese individuals with metabolic syndrome (MetS) has yet to be determined. The aim of this pilot study was, therefore, to investigate the feasibility and effects of WB-EMS on cardiometabolic risk markers and muscle strength in obese women diagnosed with MetS. Twenty-nine obese women (56.0 ± 10.9 years, BMI: 36.7 ± 4.6 kg/m2) with the clinical diagnosis of MetS were randomized to either 12 weeks of WB-EMS (n = 15) or an inactive control group (CON, n = 14). Both groups received nutritional counseling (aim: -500 kcal energy deficit/day). WB-EMS was performed 2x/week (20 min/session). Body composition, maximum strength (Fmax) of major muscle groups, selected cardiometabolic risk indices and the metabolic syndrome Z-score (MetS-Z) were determined baseline and after the intervention. WB-EMS was well tolerated and no adverse events occurred. Body weight was significantly reduced in both groups by an average of 3 kg (P < 0.01). The body fat percentage was only decreased in the WB-EMS group (P = 0.018). Total cholesterol concentrations decreased in the WB-EMS group (P = 0.018) and in CON (P = 0.027). Only the WB-EMS group increased Fmax significantly in all major muscle groups (P < 0.05) and improved the overall cardiometabolic risk score (MetS-Z, P = 0.029). This pilot study indicates that WB-EMS can be considered as a feasible and time-efficient exercise option for improving body composition, muscle strength and cardiometabolic health in obese women with MetS. Moreover, these findings underpin the crucial role of exercise during weight loss interventions in improving health outcomes.
CRIS-Team Scopus Importer:2020-06-30

Efficacy and Safety of Angioplasty Balloon Interposition in CT-Guided Percutaneous Thermal Ablation of Hepatic Malignancies to Protect Adjacent Organs - Schlappa, Michael; Wuest, Wolfgang; Siebler, Jürgen; Grützmann, Robert; Uder, Michael; Schmid, Axel (Cardiovascular and Interventional Radiology, 2022)
Purpose To evaluate the feasibility and safety of placing angioplasty balloons between the liver surface and adjacent organs in CT-guided thermal ablation of subcapsular liver malignancies in case of inadequate success of conventional dissection techniques. Materials and Methods A retrospective, single-centre database query identified 327 hepatic malignancies in 153 patients treated in 215 sessions from 2016 to 2018 by thermal ablation. Demographic data, tumour size, distance to adjacent structures, complications and long-term outcomes were assessed when ancillary procedures were performed to protect adjacent organs. Results In 21 of 327 (6.4%) ablations, thermal protection was necessary. Balloon interposition was successfully performed in 9 cases in 8 patients after hydrodissection or gas insufflation failed to separate adherent organs. Median pre- and post-balloon insertion distance was 0 mm [0-2 mm] and 17 mm [8-20 mm]. No balloons were damaged, ruptured or slid away from their initial position. Technical success of MWA and protection of adherent structures were achieved in all procedures. In a median follow-up of 11.5 months [0-49 months], the local control rate was 88.9% as 1 patient was treated twice with an interval of 3 months for local recurrence. Three non-process-related major complications and 1 minor complication occurred. Conclusion Balloon interposition is a safe and feasible method to enable thermal ablation to a greater number of patients, even after established thermo-protective techniques fail to separate the colon or stomach from the liver surface.
CRIS-Team WoS Importer:2022-07-22

Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results - Pavel, Marianne Ellen; Ćwikła, Jaroslaw B.; Lombard-Bohas, Catherine; Borbath, Ivan; Shah, Tahir; Pape, Ulrich F.; Capdevila, Jaume; Panzuto, Francesco; Truong Thanh, Xuan Mai; Houchard, Aude; Ruszniewski, Philippe (European Journal of Cancer, 2021)
Introduction: This prospective, single-arm, phase 2 study assessed the efficacy and safety of lanreotide autogel (LAN) administered at a reduced dosing interval in patients with progressive neuroendocrine tumours (NETs) after LAN standard regimen. Methods: Patients had metastatic or locally advanced, grade 1 or 2 midgut NETs or pancreatic NETs (panNETs) and centrally assessed disease progression on LAN 120 mg every 28 days. They were treated with LAN 120 mg every 14 days for up to 96 weeks (midgut cohort) or 48 weeks (panNET cohort). The primary end-point was centrally assessed progression-free survival (PFS). PFS by Ki-67 categories was analysed post hoc. Secondary end-points included quality of life (QoL) and safety. Results: Ninety-nine patients were enrolled (midgut, N = 51; panNET, N = 48). Median (95% CI) PFS was 8.3 (5.6–11.1) and 5.6 (5.5–8.3) months, respectively. In patients with Ki-67 ≤ 10%, median (95% CI) PFS was 8.6 (5.6–13.8) and 8.0 (5.6–8.3) months in the midgut and panNET cohorts, respectively. Patients’ QoL did not deteriorate during the study. There were no treatment-related serious adverse events and only two withdrawals for treatment-related adverse events (both in the panNET cohort). Conclusions: In patients with progressive NETs following standard-regimen LAN, reducing the dosing interval to every 14 days provided encouraging PFS, particularly in patients with a Ki-67 ≤ 10% (post hoc); no safety concerns and no deterioration in QoL were observed. Increasing LAN dosing frequency could therefore be considered before escalation to less well-tolerated therapies.
CRIS-Team Scopus Importer:2021-10-08
Keywords: Lanreotide; Neuroendocrine tumours; Progression-free survival; Receptors; Somatostatin

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma - Scheiner, Bernhard; Roessler, Daniel; Phen, Samuel; Lim, Mir; Pomej, Katharina; Pressiani, Tiziana; Cammarota, Antonella; Fründt, Thorben W.; von Felden, Johann; Schulze, Kornelius; Himmelsbach, Vera; Finkelmeier, Fabian; et al. (JHEP Reports, 2023)
Background & Aims: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. Methods: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. Results: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. Conclusions: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. Impact and implications: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy.
CRIS-Team Scopus Importer:2023-01-06
Keywords: Immune checkpoint blocker; Immunotherapy; Liver cancer; Systemic therapy

Efficacy and safety of lanreotide autogel (LAN) 120 mg every 14 days in progressive pancreatic or midgut neuroendocrine tumours (NETs): CLARINET FORTE study results - Pavel, Marianne Ellen; Cwikla, J. B.; Lombard-Bohas, C.; Borbath, I.; Shah, T.; Pape, U-F.; Thanh, X-M. Truong; Houchard, A.; Ruszniewski, P. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-10-30