Publications by authors named "Michael Quante"

75 Publications

The complexity of cancer origins at the gastro-oesophageal junction.

Best Pract Res Clin Gastroenterol 2021 Mar-Apr;50-51:101729. Epub 2021 Feb 14.

UCL Cancer Institute, London, United Kingdom.

Chronic acid-biliary reflux and Helicobacter pylori infection are instrumental environmental drivers of cancer initiation and progression in the upper gastrointestinal tract. Remarkably, although these environmental carcinogens are quite dissimilar, the tumour progression cascade these carcinogens engender is highly comparable. For this reason, studies of malignant progression occurring at the anatomic borderland between the oesophagus and the stomach have traditionally lumped junctional adenocarcinomas with either oesophageal adenocarcinoma or gastric adenocarcinoma. Whilst studies have revealed remarkable epidemiological and genetic similarities of these cancers and their associated premalignant conditions, these works have also revealed some key differences. This highlights that further scientific effort demands a dedicated focus on the understanding of the cell-cell interaction between the epithelium and the local microenvironment in this anatomic region. We here review available evidence with regards to tumour progression occurring at the gastro-oesophageal junction and contrast it with available data on cancer evolution in the metaplastic oesophagus and distal stomach.
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http://dx.doi.org/10.1016/j.bpg.2021.101729DOI Listing
May 2021

Identification of TLR2 Signalling Mechanisms Which Contribute to Barrett's and Oesophageal Adenocarcinoma Disease Progression.

Cancers (Basel) 2021 Apr 25;13(9). Epub 2021 Apr 25.

School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland.

Chronic inflammation plays an important role in the pathogenesis of oesophageal adenocarcinoma (EAC) and its only known precursor, Barrett's oesophagus (BE). Recent studies have shown that oesophageal TLR2 levels increase from normal epithelium towards EAC. TLR2 signalling is therefore likely to be important during EAC development and progression, which requires an inflammatory microenvironment. Here, we show that, in response to TLR2 stimulation, BE organoids and early-stage EAC cells secrete pro-inflammatory cytokines and chemokines which recruit macrophages to the tumour site. Factors secreted from TLR2-stimulated EAC cells are shown to subsequently activate TLR2 on naïve macrophages, priming them for inflammasome activation and inducing their differentiation to an M2/TAM-like phenotype. We identify the endogenous TLR2 ligand, HMGB1, as the factor secreted from EAC cells responsible for the observed TLR2-mediated effects on macrophages. Our results indicate that HMGB1 signalling between EAC cells and macrophages creates an inflammatory tumour microenvironment to facilitate EAC progression. In addition to identifying HMGB1 as a potential target for early-stage EAC treatment, our data suggest that blocking TLR2 signalling represents a mechanism to limit HMGB1 release, inflammatory cell infiltration and inflammation during EAC progression.
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http://dx.doi.org/10.3390/cancers13092065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123271PMC
April 2021

Anti-inflammatory chemoprevention attenuates the phenotype in a mouse model of esophageal adenocarcinoma.

Carcinogenesis 2021 Apr 20. Epub 2021 Apr 20.

Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany.

Barrett´s Esophagus (BE) is the main known precursor condition of Esophageal Adenocarcinoma (EAC). BE is defined by the presence of metaplasia above the normal squamous columnar junction and has mainly been attributed to gastroesophageal reflux disease (GERD) and chronic reflux esophagitis. Thus, the rising incidence of EAC in the Western world is likely mediated by chronic esophageal inflammation, secondary to GERD in combination with environmental risk factors such as a Western diet and obesity. However, (at present) risk prediction tools and endoscopic surveillance have shown limited effectiveness. Chemoprevention as an adjunctive approach remains an attractive option to reduce the incidence of neoplastic disease. Here, we investigate the feasibility of chemopreventive approaches in BE and EAC via inhibition of inflammatory signaling in a transgenic mouse model of BE and EAC (L2-IL1B mice), with accelerated tumor formation on a high fat diet (HFD). L2-IL1B mice were treated with the IL-1 receptor antagonist Anakinra and the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin or Sulindac. Interleukin-1b antagonism reduced tumor progression in L2-IL1B mice with or without a HFD, while both NSAIDs were effective chemoprevention agents in the accelerated HFD fed L2-IL1B mouse model. Sulindac treatment also resulted in a marked change in the immune profile of L2-IL-1B mice. In summary, anti-inflammatory treatment of HFD-treated L2-IL1B mice acted protectively on disease progression. These results from a mouse model of BE support results from clinical trials that suggest that anti-inflammatory medication may be effective in the chemoprevention of EAC.
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http://dx.doi.org/10.1093/carcin/bgab032DOI Listing
April 2021

PALLD mutation in a European family conveys a stromal predisposition for familial pancreatic cancer.

JCI Insight 2021 Mar 25;6(8). Epub 2021 Mar 25.

Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

BACKGROUNDPancreatic cancer is one of the deadliest cancers, with low long-term survival rates. Despite recent advances in treatment, it is important to identify and screen high-risk individuals for cancer prevention. Familial pancreatic cancer (FPC) accounts for 4%-10% of pancreatic cancers. Several germline mutations are related to an increased risk and might offer screening and therapy options. In this study, we aimed to identity of a susceptibility gene in a family with FPC.METHODSWhole exome sequencing and PCR confirmation was performed on the surgical specimen and peripheral blood of an index patient and her sister in a family with high incidence of pancreatic cancer, to identify somatic and germline mutations associated with familial pancreatic cancer. Compartment-specific gene expression data and immunohistochemistry were also queried.RESULTSThe identical germline mutation of the PALLD gene (NM_001166108.1:c.G154A:p.D52N) was detected in the index patient with pancreatic cancer and the tumor tissue of her sister. Whole genome sequencing showed similar somatic mutation patterns between the 2 sisters. Apart from the PALLD mutation, commonly mutated genes that characterize pancreatic ductal adenocarcinoma were found in both tumor samples. However, the 2 patients harbored different somatic KRAS mutations (G12D and G12V). Healthy siblings did not have the PALLD mutation, indicating a disease-specific impact. Compartment-specific gene expression data and IHC showed expression in cancer-associated fibroblasts (CAFs).CONCLUSIONWe identified a germline mutation of the palladin (PALLD) gene in 2 siblings in Europe, affected by familial pancreatic cancer, with a significant overexpression in CAFs, suggesting that stromal palladin could play a role in the development, maintenance, and/or progression of pancreatic cancer.FUNDINGDFG SFB 1321.
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http://dx.doi.org/10.1172/jci.insight.141532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119201PMC
March 2021

Notch signaling drives development of Barrett's metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa.

Sci Rep 2021 Feb 24;11(1):4509. Epub 2021 Feb 24.

Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany.

Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.
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http://dx.doi.org/10.1038/s41598-021-84011-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904766PMC
February 2021

Microbiota alteration at different stages in gastric lesion progression: a population-based study in Linqu, China.

Am J Cancer Res 2021 1;11(2):561-575. Epub 2021 Feb 1.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute Beijing, China.

In addition to Helicobacter pylori (H.pylori), gastric microbiota may be involved in carcinogenesis process. However, the longitudinal study to assess changes in the gastric microbiota associated with the development of gastric carcinogenesis is still limited. The aim of this study is to explore dynamic microbial alterations in gastric cancer (GC) development based on a 4-year endoscopic follow-up cohort in Linqu County, China. Microbial alterations were investigated by deep sequencing of the microbial 16S ribosomal RNA gene in 179 subjects with various gastric lesions, and validated in paired gastric biopsies prospectively collected before and after lesion progression and in non-progression controls. Significant differences were found in microbial diversity and community structure across various gastric lesions, with 62 candidate differential taxa between at least two lesion groups. Further validations identified Helicobacter, Bacillus, Capnocytophaga and Prevotella to be associated with lesion progression-to-dysplasia (DYS)/GC (all P < 0.05), especially for subjects progressing from intestinal metaplasia (IM) to DYS/GC. The combination of the four genera in a microbial dysbiosis index showed a significant difference after lesion progression-to-DYS/GC compared to controls (P = 0.027). The panel including the four genera identified subjects after progression-to-DYS/GC with an area under the receiver-operating curve (AUC) of 0.941. Predictive significance was found before lesion progression-to-DYS/GC with an AUC = 0.776 and an even better AUC (0.927) for subjects progressing from IM to DYS/GC. Microbiota may play different roles at different stages in gastric carcinogenesis. A panel of bacterial genera associated with gastric lesions may help to assess gastric microbial dysbiosis and show potential predictive values for lesion progression. Our findings provide new clues for the microbial mechanism of H.pylori-associated carcinogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868750PMC
February 2021

Mucosal-Associated Invariant T (MAIT) Cells Are Highly Activated and Functionally Impaired in COVID-19 Patients.

Viruses 2021 02 3;13(2). Epub 2021 Feb 3.

Department of Internal Medicine II, University Hospital Rechts der Isar, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany.

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprises mild courses of disease as well as progression to severe disease, characterised by lung and other organ failure. The immune system is considered to play a crucial role for the pathogenesis of COVID-19, although especially the contribution of innate-like T cells remains poorly understood. Here, we analysed the phenotype and function of mucosal-associated invariant T (MAIT) cells, innate-like T cells with potent antimicrobial effector function, in patients with mild and severe COVID-19 by multicolour flow cytometry. Our data indicate that MAIT cells are highly activated in patients with COVID-19, irrespective of the course of disease, and express high levels of proinflammatory cytokines such as IL-17A and TNFα ex vivo. Of note, expression of the activation marker HLA-DR positively correlated with SAPS II score, a measure of disease severity. Upon MAIT cell-specific in vitro stimulation, MAIT cells however failed to upregulate expression of the cytokines IL-17A and TNFα, as well as cytolytic proteins, that is, granzyme B and perforin. Thus, our data point towards an altered cytokine expression profile alongside an impaired antibacterial and antiviral function of MAIT cells in COVID-19 and thereby contribute to the understanding of COVID-19 immunopathogenesis.
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http://dx.doi.org/10.3390/v13020241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913667PMC
February 2021

Elimination of NF-κB signaling in Vimentin+ stromal cells attenuates tumorigenesis in a mouse model of Barrett's Esophagus.

Carcinogenesis 2021 04;42(3):405-413

Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany.

Chronic inflammation induces Barrett's Esophagus (BE) which can advance to esophageal adenocarcinoma. Elevated levels of interleukin (IL)-1b, IL-6 and IL-8 together with activated nuclear factor-kappaB (NF-κB), have been identified as important mediators of tumorigenesis. The inflammatory milieu apart from cancer cells and infiltrating immune cells contains myofibroblasts (MFs) that express aSMA and Vimentin. As we observed that increased NF-κB activation and inflammation correlates with increased MF recruitment and an accelerated phenotype we here analyze the role of NF-κB in MF during esophageal carcinogenesis in our L2-IL-1B mouse model. To analyze the effect of NF-κB signaling in MFs, we crossed L2-IL-1B mice to tamoxifen inducible Vim-Cre (Vim-CreTm) mice and floxed RelA (p65fl/fl) mice to specifically eliminate NF-κB signaling in MF (IL-1b.Vim-CreTm.p65fl/fl). The interaction of epithelial cells and stromal cells was further analyzed in mouse BE organoids and patient-derived human organoids. Histological scoring of IL-1b.Vim-CreTm.p65fl/fl mice showed a significantly attenuated phenotype compared with L2-IL-1B mice, with mild inflammation, decreased metaplasia and no dysplasia. This correlated with decreased proliferation and increased differentiation in cardia tissue of IL-1b.Vim-CreTm.p65fl/fl compared with L2-IL-1B mice. Distinct changes of cytokines and chemokines within the local microenvironment in IL-1b.Vim-CreTm.p65fl/fl mice reflected the histopathological abrogated phenotype. Co-cultured NF-κB inhibitor treated MF with mouse BE organoids demonstrated NF-κB-dependent growth and migration. MFs are essential to form an inflammatory and procarcinogenic microenvironment and NF-κB signaling in stromal cells emerges as an important driver of esophageal carcinogenesis. Our data suggest anti-inflammatory approaches as preventive strategies during surveillance of BE patients.
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http://dx.doi.org/10.1093/carcin/bgaa109DOI Listing
April 2021

Characterizing caspase-1 involvement during esophageal disease progression.

Cancer Immunol Immunother 2020 Dec 1;69(12):2635-2649. Epub 2020 Jul 1.

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

Barrett's esophagus (BE) is an inflammatory condition and a neoplastic precursor to esophageal adenocarcinoma (EAC). Inflammasome signaling, which contributes to acute and chronic inflammation, results in caspase-1 activation leading to the secretion of IL-1β and IL-18, and inflammatory cell death (pyroptosis). This study aimed to characterize caspase-1 expression, and its functional importance, during disease progression to BE and EAC. Three models of disease progression (Normal-BE-EAC) were employed to profile caspase-1 expression: (1) a human esophageal cell line model; (2) a murine model of BE; and (3) resected tissue from BE-associated EAC patients. BE patient biopsies and murine BE organoids were cultured ex vivo in the presence of a caspase-1 inhibitor, to determine the importance of caspase-1 for inflammatory cytokine and chemokine secretion.Epithelial caspase-1 expression levels were significantly enhanced in BE (p < 0.01). In contrast, stromal caspase-1 levels correlated with histological inflammation scores during disease progression (p < 0.05). Elevated secretion of IL-1β from BE explanted tissue, compared to adjacent normal tissue (p < 0.01), confirmed enhanced activity of caspase-1 in BE tissue. Caspase-1 inhibition in LPS-stimulated murine BE organoids caused a significant reduction in IL-1β (p < 0.01) and CXCL1 (p < 0.05) secretion, confirming the importance of caspase-1 in the production of cytokines and chemokines associated with disease progression from BE to EAC. Targeting caspase-1 activity in BE patients should therefore be tested as a novel strategy to prevent inflammatory complications associated with disease progression.
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http://dx.doi.org/10.1007/s00262-020-02650-4DOI Listing
December 2020

Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma.

Gastroenterology 2020 08 20;159(2):575-590. Epub 2020 Apr 20.

Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.

Background & Aims: Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis.

Methods: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5 (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB.

Results: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5 cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5 cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5 cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation.

Conclusions: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.
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http://dx.doi.org/10.1053/j.gastro.2020.04.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484392PMC
August 2020

[Barrett Esophagus - Update of clinical management and therapy options].

Dtsch Med Wochenschr 2020 04 1;145(7):429-435. Epub 2020 Apr 1.

II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München.

Pathogenesis: Adenocarcinomas of the esophagus are very similar to those of the stomach and most likely develop in the gastric cardia, from where proliferating cells expand into the esophagus and form benign Barrett's mucosa. An additional genomic instability leads to the clonal evolution of certain cells, which can lead to the development of adenocarcinoma.

Risk Factors: A clear definition of factors is urgently needed for better risk stratification and the establishment of preventive strategies. Current prediction models, which include overweight, diet or tobacco consumption, have not yet been able to establish themselves in clinical application.

Diagnostics And Monitoring: Current guidelines exist for diagnostics and monitoring. The diagnosis of Barrett's esophagus is performed histopathologically from 4-quadrant biopsies. In addition, macroscopically conspicuous areas of the Barrett mucosa should be biopsies. The detection of neoplastic areas can be improved by using chromoendoscopy in combination with magnification endoscopy and staining techniques (methylene blue or acetic acid).

Therapy: The curatively intended endoscopic resection is the standard therapy for dysplastic Barrett's metaplasia, mucosal (T1a m) and superficial submucosal (T1a sm1) adenocarcinoma. Here, cap and ligature resection as well as endoscopic submucosal dissection (ESD) represent the recommended resection techniques and, in combination with radiofrequency ablation, the therapy according to guidelines.
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http://dx.doi.org/10.1055/a-0968-6699DOI Listing
April 2020

Epidemiologic Risk Factors in a Comparison of a Barrett Esophagus Registry (BarrettNET) and a Case-Control Population in Germany.

Cancer Prev Res (Phila) 2020 04 17;13(4):377-384. Epub 2020 Feb 17.

Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany.

Endoscopic screening for Barrett's esophagus as the major precursor lesion for esophageal adenocarcinoma is mostly offered to patients with symptoms of gastroesophageal reflux disease (GERD). However, other epidemiologic risk factors might affect the development of Barrett's esophagus and esophageal adenocarcinoma. Therefore, efforts to improve the efficiency of screening to find the Barrett's esophagus population "at risk" compared with the normal population are needed. In a cross-sectional analysis, we compared 587 patients with Barrett's esophagus from the multicenter German BarrettNET registry to 1976 healthy subjects from the population-based German KORA cohort, with and without GERD symptoms. Data on demographic and lifestyle factors, including age, gender, smoking, alcohol consumption, body mass index, physical activity, and symptoms were collected in a standardized epidemiologic survey. Increased age, male gender, smoking, heavy alcohol consumption, low physical activity, low health status, and GERD symptoms were significantly associated with Barrett's esophagus. Surprisingly, among patients stratified for GERD symptoms, these associations did not change. Demographic, lifestyle, and clinical factors as well as GERD symptoms were associated with Barrett's esophagus development in Germany, suggesting that a combination of risk factors could be useful in developing individualized screening efforts for patients with Barrett's esophagus and GERD in Germany.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0474DOI Listing
April 2020

Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche.

Nat Commun 2020 01 8;11(1):111. Epub 2020 Jan 8.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA.

The enteric neurotransmitter acetylcholine governs important intestinal epithelial secretory and immune functions through its actions on epithelial muscarinic Gq-coupled receptors such as M3R. Its role in the regulation of intestinal stem cell function and differentiation, however, has not been clarified. Here, we find that nonselective muscarinic receptor antagonism in mice as well as epithelial-specific ablation of M3R induces a selective expansion of DCLK1-positive tuft cells, suggesting a model of feedback inhibition. Cholinergic blockade reduces Lgr5-positive intestinal stem cell tracing and cell number. In contrast, Prox1-positive endocrine cells appear as primary sensors of cholinergic blockade inducing the expansion of tuft cells, which adopt an enteroendocrine phenotype and contribute to increased mucosal levels of acetylcholine. This compensatory mechanism is lost with acute irradiation injury, resulting in a paucity of tuft cells and acetylcholine production. Thus, enteroendocrine tuft cells appear essential to maintain epithelial homeostasis following modifications of the cholinergic intestinal niche.
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http://dx.doi.org/10.1038/s41467-019-13850-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949263PMC
January 2020

Effect of on gastrointestinal microbiota: a population-based study in Linqu, a high-risk area of gastric cancer.

Gut 2020 09 19;69(9):1598-1607. Epub 2019 Dec 19.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China

Objective: Gastrointestinal microbiota may be involved in associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential dysbiosis arising from infection.

Design: Deep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti- treatment, relative to 49 negative subjects.

Results: In positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between and , , , , were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased after successful eradication and more upregulated drug-resistant functional orthologs after failed treatment.

Conclusion: infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.
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http://dx.doi.org/10.1136/gutjnl-2019-319696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456744PMC
September 2020

Post-neoadjuvant cellular dissociation grading based on tumour budding and cell nest size is associated with therapy response and survival in oesophageal squamous cell carcinoma.

Br J Cancer 2019 12 6;121(12):1050-1057. Epub 2019 Nov 6.

Institute of Pathology, Technical University Munich, Munich, Germany.

Background: Cellular Dissociation Grade (CDG) composed of tumour budding and cell nest size has been shown to independently predict prognosis in pre-therapeutic biopsies and primary resections of oesophageal squamous cell carcinoma (ESCC). Here, we aimed to evaluate the prognostic impact of CDG in ESCC after neoadjuvant therapy.

Methods: We evaluated cell nest size and tumour budding activity in 122 post-neoadjuvant ESCC resections, correlated the results with tumour regression groups and patient survival and compared the results with data from primary resected cases as well as pre-therapeutic biopsies.

Results: CDG remained stable when results from pre-therapeutic biopsies and post-therapeutic resections from the same patient were compared. CDG was associated with therapy response and a strong predictor of overall, disease-specific (DSS) and disease-free (DFS) survival in univariate analysis and-besides metastasis-remained the only significant survival predictor for DSS and DFS in multivariate analysis. Multivariate DFS hazard ratios reached 3.3 for CDG-G2 and 4.9 for CDG-G3 neoplasms compared with CDG-G1 carcinomas (p = 0.016).

Conclusions: CDG is the only morphology-based grading algorithm published to date, which in concert with regression grading, is able to contribute relevant prognostic information in the post-neoadjuvant setting of ESCC.
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http://dx.doi.org/10.1038/s41416-019-0623-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964693PMC
December 2019

BarrettNET-a prospective registry for risk estimation of patients with Barrett's esophagus to progress to adenocarcinoma.

Dis Esophagus 2019 Aug;32(8)

Klinik und Poliklinik für Innere Medizin II, University Hospital rechts der Isar, Technical University of Munich.

Risk stratification in patients with Barrett's esophagus (BE) to prevent the development of esophageal adenocarcinoma (EAC) is an unsolved task. The incidence of EAC and BE is increasing and patients are still at unknown risk. BarrettNET is an ongoing multicenter prospective cohort study initiated to identify and validate molecular and clinical biomarkers that allow a more personalized surveillance strategy for patients with BE. For BarrettNET participants are recruited in 20 study centers throughout Germany, to be followed for progression to dysplasia (low-grade dysplasia or high-grade dysplasia) or EAC for >10 years. The study instruments comprise self-administered epidemiological information (containing data on demographics, lifestyle factors, and health), as well as biological specimens, i.e., blood-based samples, esophageal tissue biopsies, and feces and saliva samples. In follow-up visits according to the individual surveillance plan of the participants, sample collection is repeated. The standardized collection and processing of the specimen guarantee the highest sample quality. Via a mobile accessible database, the documentation of inclusion, epidemiological data, and pathological disease status are recorded subsequently. Currently the BarrettNET registry includes 560 participants (23.1% women and 76.9% men, aged 22-92 years) with a median follow-up of 951 days. Both the design and the size of BarrettNET offer the advantage of answering research questions regarding potential causes of disease progression from BE to EAC. Here all the integrated methods and materials of BarrettNET are presented and reviewed to introduce this valuable German registry.
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http://dx.doi.org/10.1093/dote/doz024DOI Listing
August 2019

High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via Interleukin 8 and Alterations to the Gut Microbiome.

Gastroenterology 2019 08 15;157(2):492-506.e2. Epub 2019 Apr 15.

Irvine Cancer Research Center, Columbia University, New York, New York.

Background & Aims: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice.

Methods: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions.

Results: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development.

Conclusions: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.
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http://dx.doi.org/10.1053/j.gastro.2019.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662596PMC
August 2019

Cellular Dissociation Grading Based on the Parameters Tumor Budding and Cell Nest Size in Pretherapeutic Biopsy Specimens Allows for Prognostic Patient Stratification in Esophageal Squamous Cell Carcinoma Independent From Clinical Staging.

Am J Surg Pathol 2019 05;43(5):618-627

Institute of Pathology.

Initial treatment planning in esophageal squamous cell carcinoma mainly relies on clinical staging. Recently, a highly prognostic grading system based on the cellular dissociation parameters Tumor Budding and Cell Nest Size has been proposed for resected esophageal squamous cell carcinoma. To probe for the transferability and relevance of this established novel grading system in the pretreatment setting, we evaluated Tumor Budding/Cell Nest Size in pretherapeutic biopsies of either primarily resected (cohort 1, n=80) or neoadjuvantly treated (cohort 2, n=75) esophageal squamous cell carcinoma. Grading data were correlated with clinicopathologic and survival parameters. High Tumor Budding Activity and small Cell Nest Size in pretherapeutic biopsies were strongly associated with shortened overall survival, disease-free survival, and disease-specific survival in both cohorts. A modified histopathologic grading system incorporating both factors termed "Cellular Dissociation Grade" showed excellent prognostic demarcation between well (G1), moderately (G2), and poorly differentiated (G3) carcinomas in both scenarios (overall survival: cohort 1: P<0.001; cohort 2: P=0.009) and was predictive for a high pathologic tumor stage and the presence of nodal metastases in primarily resected patients. Multivariate analyses revealed the Cellular Dissociation Grade to be a predictor of poor outcome in the pretherapeutic setting independent of clinical stage (overall survival, disease-free survival, and disease-specific survival: P<0.001). Hazard ratio for disease-free survival was 3.19 for G2 and 5.66 for G3 carcinomas compared with G1 neoplasms. Our data not only prove the transferability of histopathologic grading based on Tumor Budding/Cell Nest Size to biopsy specimens in esophageal squamous cell carcinoma, but also demonstrate that the Cellular Dissociation Grade is a strong outcome predictor in this entity even in the pretreatment scenario. Therefore, we believe that this novel type of grading has the ability to serve as a powerful histology-based pretherapeutic biomarker, that might supplement clinical staging for choosing the most suitable therapy decision.
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http://dx.doi.org/10.1097/PAS.0000000000001230DOI Listing
May 2019

Vimentin-Induced Cardiac Mesenchymal Stem Cells Proliferate in the Acute Ischemic Myocardium.

Cells Tissues Organs 2018 10;206(1-2):35-45. Epub 2019 Jan 10.

Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), Rostock University Medical Center, Rostock, Germany.

In-depth knowledge of the mechanisms induced by early postischemic cardiac endogenous mesenchymal stem cells (MSCs) in the acutely ischemic heart could advance our understanding of cardiac regeneration. Herein, we aimed to identify, isolate, and initially characterize the origin, kinetics and fate of cardiac MSCs. This was facilitated by in vivo genetic cell fate mapping through green fluorescent protein (GFP) expression under the control of vimentin induction after acute myocardial infarction (MI). Following permanent ligation of the left anterior descending coronary artery in CreER+ mTom/mGFP+ mice, vimentin/GFP+ cells revealed ischemia-responsive activation, survival, and local enrichment inside the peri-infarction border zone. Fluorescence-activated cell sorting (FACS)-isolated vimentin/GFP+ cells could be strongly expanded in vitro with clonogenic precursor formation and revealed MSC-typical cell morphology. Flow-cytometric analyses demonstrated an increase in cardiac vimentin/GFP+ cells in the ischemic heart, from a 0.6% cardiac mononuclear cell (MNC) fraction at 24 h to 1.6% at 72 h following MI. Sca-1+CD45- cells within the vimentin/GFP+ subtype of this MNC fraction increased from 35.2% at 24 h to 74.6% at 72 h after MI. The cardiac postischemic vimentin/GFP+ MNC subtype showed multipotent adipogenic, chondrogenic, and osteogenic differentiation potential, which is distinctive for MSCs. In conclusion, we demonstrated a seemingly proliferative first response of vimentin- induced cardiac endogenous MSCs in the acutely ischemic heart. Genetically, GFP-targeted in vivo cell tracking, isolation, and in vitro expansion of this cardiac MSC subtype could help to clarify their reparative status in inflammation, fibrogenesis, cell turnover, tissue homeostasis, and myocardial regeneration.
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http://dx.doi.org/10.1159/000495527DOI Listing
September 2019

Association Between Gut Microbiota and -Related Gastric Lesions in a High-Risk Population of Gastric Cancer.

Front Cell Infect Microbiol 2018 19;8:202. Epub 2018 Jun 19.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China.

Eradication of has been found to be effective for gastric cancer prevention, but uncertainties remain about the possible adverse consequences such as the potential microbial dysbiosis. In our study, we investigated the association between gut microbiota and -related gastric lesions in 47 subjects by deep sequencing of microbial 16S ribosomal RNA (rRNA) gene in fecal samples. The dominant phyla in fecal samples were , and with average relative abundances of 54.77, 31.37 and 12.91%, respectively. Microbial diversity analysis showed that observed species and Shannon index were increased in subjects with past or current infection compared with negative subjects. As for the differential bacteria, the average relative abundance of was found to significantly decrease from negative (66.16%) to past infection group (33.01%, = 0.007), as well as from normal (76.49%) to gastritis (56.04%) and metaplasia subjects (46.83%, = 0.027). For and , the average relative abundances showed elevated trends in the past infection group (47.11, 20.53%) compared to negative group (23.44, 9.05%, = 0.068 and 0.246, respectively), and similar increased trends were also found from normal (18.23, 5.05%) to gastritis (35.31, 7.23%, = 0.016 and 0.294, respectively) or metaplasia subjects (32.33, 20.07%, both < 0.05). These findings suggest that the alterations of fecal microbiota, especially the dominant phyla of and , may be involved in the process of -related gastric lesion progression and provide hints for future evaluation of microbial changes after eradication.
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http://dx.doi.org/10.3389/fcimb.2018.00202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018392PMC
July 2019

Origins of Metaplasia in the Esophagus: Is This a GE Junction Stem Cell Disease?

Dig Dis Sci 2018 08;63(8):2013-2021

Department of Internal Medicine, Munich Technical University, Ismaninger Strasse 22, 81675, Munich, Germany.

The incidence of esophageal adenocarcinoma (EAC) and its precursor lesion Barrett's esophagus (BE) has been increasing steadily in the western world in recent decades. Understanding the cellular origins of BE and the conditions responsible for their malignant transformation would greatly facilitate risk assessment and identification of patients at risk of progression, but this topic remains a source of debate. Here, we review recent findings that have provided support for the gastroesophageal junction (GEJ) as the main source of stem cells that give rise to BE and EAC. These include both gastric cardia cells and transitional basal cells. Furthermore, we discuss the role of chronic injury and inflammation in a tumor microenvironment as a major factor in promoting stem cell expansion and proliferation as well as transformation of the GEJ-derived stem cells and progression to EAC. We conclude that there exists a large amount of empirical support for the GEJ as the likely source of BE stem cells. While BE seems to resemble a successful adaptation to esophageal damage, carcinogenesis appears as a consequence of natural selection at the level of GEJ stem cells, and later glands, that expand into the esophagus wherein the local ecology creates the selective landscape for cancer progression.
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http://dx.doi.org/10.1007/s10620-018-5152-yDOI Listing
August 2018

Genetic Biopsy for Prediction of Surveillance Intervals after Endoscopic Resection of Colonic Polyps: Results of the GENESIS Study.

United European Gastroenterol J 2018 Mar 28;6(2):290-299. Epub 2017 Jul 28.

Clinic for Internal Medicine I, Ulm University, Ulm, Germany.

Background And Objective: Current surveillance strategies for colorectal cancer following polypectomy are determined by endoscopic and histopathological factors. Such a distinction has been challenged. The present study was designed to identify molecular parameters in colonic polyps potentially defining new sub-groups at risk.

Methods: One hundred patients were enrolled in this multicentre study. Polyps biopsies underwent formalin-free processing (PAXgene, PreAnalytiX) and targeted next generation sequencing (38 genes (QIAGEN), NextSeq 500 platform (Illumina)). Genetic and histopathological analyses were done blinded to other data.

Results: In 100 patients, 224 polyps were removed. Significant associations of genetic alterations with endoscopic or histological polyp characteristics were observed for , , , and mutations. Multivariate analysis revealed that polyps ≥ 10 mm have a significant higher relative risk for harbouring oncogene mutations (relative risk 3.467 (1.742-6.933)). Adenomas and right-sided polyps are independent risk factors for mutations (relative risk 18.559 (2.371-145.245) and 12.987 (1.637-100.00)).

Conclusions: Assessment of the mutational landscape of polyps can be integrated in the workflow of current colonoscopy practice. There are distinct genetic patterns related to polyp size and location. These results suffice to optimise individual risk calculation and may help to better define surveillance intervals.
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http://dx.doi.org/10.1177/2050640617723810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833231PMC
March 2018

The metaplastic mosaic of Barrett's oesophagus.

Virchows Arch 2018 Jan 3;472(1):43-54. Epub 2018 Mar 3.

UCL Cancer Institute, London, UK.

Barrett's oesophagus surveillance biopsies represent a significant share of the daily workload for a busy histopathology department. Given the emphasis on endoscopic detection and dysplasia grading, it is easy to forget that the benefits of these screening programs remain unproven. The majority of patients are at low risk of progression to oesophageal adenocarcinoma, and periodic surveillance of these patients is burdensome and costly. Here, we investigate the parallels in the development of Barrett's oesophagus and other scenarios of wound healing in the intestine. There is now increased recognition of the full range of glandular phenotypes that can be found in patients' surveillance biopsies, and emerging evidence suggests parallel pathways to oesophageal adenocarcinoma. Greater understanding of the conditions that favour progression to cancer in the distal oesophagus will allow us to focus resources on patients at increased risk.
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http://dx.doi.org/10.1007/s00428-018-2317-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849653PMC
January 2018

Is a Potential Target for Diagnostic PET/CT Imaging in Barrett's Dysplasia and Esophageal Adenocarcinoma.

Clin Cancer Res 2018 03 5;24(5):1048-1061. Epub 2017 Dec 5.

II. Medizinische Klinik, Technische Universitat München, Munich, Germany.

Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma. Here we utilized an transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis. IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4 columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer. In conclusion, the recruitment of CXCR4 immune cells and expansion of CXCR4 epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1756DOI Listing
March 2018

Insights Into the Pathophysiology of Esophageal Adenocarcinoma.

Gastroenterology 2018 01 14;154(2):406-420. Epub 2017 Oct 14.

University College London Cancer Institute, London, United Kingdom; University College London Hospital, London, United Kingdom.

Although researchers have identified genetic alterations that contribute to development of esophageal adenocarcinoma, we know little about features of patients or environmental factors that mediate progression of chronic acid biliary reflux to Barrett's esophagus and cancer. Increasing our understanding of the mechanisms by which normal squamous epithelium progresses to early-stage invasive cancer will help formulate rational surveillance guidelines and allow us to divest resources away from patients at low risk of malignancy. We review the cellular and genetic alterations that occur during progression of Barrett's esophagus, based on findings from clinical studies and mouse models of disease. We review the features of the luminal and mucosal microenvironment of Barrett's esophagus that promote, in a small proportion of patients, development of esophageal adenocarcinoma. Markers of clonal evolution can be used to determine patient risk for cancer and set surveillance intervals.
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http://dx.doi.org/10.1053/j.gastro.2017.09.046DOI Listing
January 2018

Dclk1-expressing tuft cells: critical modulators of the intestinal niche?

Am J Physiol Gastrointest Liver Physiol 2017 Oct 6;313(4):G285-G299. Epub 2017 Jul 6.

II. Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany;

-expressing tuft cells constitute a unique intestinal epithelial lineage that is distinct from enterocytes, Paneth cells, goblet cells, and enteroendocrine cells. Tuft cells express taste-related receptors and distinct transcription factors and interact closely with the enteric nervous system, suggesting a chemosensory cell lineage. In addition, recent work has shown that tuft cells interact closely with cells of the immune system, with a critical role in the cellular regulatory network governing responses to luminal parasites. Importantly, ablation of tuft cells severely impairs epithelial proliferation and tissue regeneration after injury, implicating tuft cells in the modulation of epithelial stem/progenitor function. Finally, tuft cells expand during chronic inflammation and in preneoplastic tissues, suggesting a possible early role in inflammation-associated tumorigenesis. Hence, we outline and discuss emerging evidence that strongly supports tuft cells as key regulatory cells in the complex network of the intestinal microenvironment.
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http://dx.doi.org/10.1152/ajpgi.00073.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668570PMC
October 2017

Cut-off optimization for C-urea breath test in a community-based trial by mathematic, histology and serology approach.

Sci Rep 2017 05 18;7(1):2072. Epub 2017 May 18.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, China.

The performance of diagnostic tests in intervention trials of Helicobacter pylori (H.pylori) eradication is crucial, since even minor inaccuracies can have major impact. To determine the cut-off point for C-urea breath test (C-UBT) and to assess if it can be further optimized by serologic testing, mathematic modeling, histopathology and serologic validation were applied. A finite mixture model (FMM) was developed in 21,857 subjects, and an independent validation by modified Giemsa staining was conducted in 300 selected subjects. H.pylori status was determined using recomLine H.pylori assay in 2,113 subjects with a borderline C-UBT results. The delta over baseline-value (DOB) of 3.8 was an optimal cut-off point by a FMM in modelling dataset, which was further validated as the most appropriate cut-off point by Giemsa staining (sensitivity = 94.53%, specificity = 92.93%). In the borderline population, 1,468 subjects were determined as H.pylori positive by recomLine (69.5%). A significant correlation between the number of positive H.pylori serum responses and DOB value was found (r = 0.217, P < 0.001). A mathematical approach such as FMM might be an alternative measure in optimizing the cut-off point for C-UBT in community-based studies, and a second method to determine H.pylori status for subjects with borderline value of C-UBT was necessary and recommended.
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http://dx.doi.org/10.1038/s41598-017-02180-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437005PMC
May 2017