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1.
Cell ; 170(6): 1096-1108.e13, 2017 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-28886380

RESUMEN

Regulatory T cells (Tregs) play a pivotal role in the inhibition of anti-tumor immune responses. Understanding the mechanisms governing Treg homeostasis may therefore be important for development of effective tumor immunotherapy. We have recently demonstrated a key role for the canonical nuclear factor κB (NF-κB) subunits, p65 and c-Rel, in Treg identity and function. In this report, we show that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors. Using mouse models, we demonstrate that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs. Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy. Our studies therefore establish inhibition of NF-κB c-Rel as a viable therapeutic approach for enhancing checkpoint-targeting immunotherapy protocols.


Asunto(s)
Inmunoterapia/métodos , Melanoma/inmunología , Melanoma/patología , FN-kappa B/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-rel/antagonistas & inhibidores , Linfocitos T Reguladores/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Melanoma/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo
2.
Cell ; 152(1-2): 25-38, 2013 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-23273993

RESUMEN

Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-κB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-κB's function in tumor-initiating cells has not been examined yet. Using a genetic model of intestinal epithelial cell (IEC)-restricted constitutive Wnt-activation, which comprises the most common event in the initiation of colon cancer, we demonstrate that NF-κB modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-κB signaling enhances Wnt activation and induces dedifferentiation of nonstem cells that acquire tumor-initiating capacity. Thus, our data support the concept of bidirectional conversion and highlight the importance of inflammatory signaling for dedifferentiation and generation of tumor-initiating cells in vivo.


Asunto(s)
Desdiferenciación Celular , Transformación Celular Neoplásica , Neoplasias del Colon/patología , Células Madre Neoplásicas/patología , Animales , Colon/patología , Células Epiteliales/patología , Femenino , Humanos , Masculino , Ratones , FN-kappa B/metabolismo , Vía de Señalización Wnt
3.
Immunity ; 47(3): 450-465.e5, 2017 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-28889947

RESUMEN

Both conventional T (Tconv) cells and regulatory T (Treg) cells are activated through ligation of the T cell receptor (TCR) complex, leading to the induction of the transcription factor NF-κB. In Tconv cells, NF-κB regulates expression of genes essential for T cell activation, proliferation, and function. However the role of NF-κB in Treg function remains unclear. We conditionally deleted canonical NF-κB members p65 and c-Rel in developing and mature Treg cells and found they have unique but partially redundant roles. c-Rel was critical for thymic Treg development while p65 was essential for mature Treg identity and maintenance of immune tolerance. Transcriptome and NF-κB p65 binding analyses demonstrated a lineage specific, NF-κB-dependent transcriptional program, enabled by enhanced chromatin accessibility. These dual roles of canonical NF-κB in Tconv and Treg cells highlight the functional plasticity of the NF-κB signaling pathway and underscores the need for more selective strategies to therapeutically target NF-κB.


Asunto(s)
Linaje de la Célula/genética , FN-kappa B/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Transcripción Genética , Animales , Autoinmunidad/genética , Autoinmunidad/inmunología , Sitios de Unión , Biomarcadores , Diferenciación Celular , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Análisis por Conglomerados , Citocinas/metabolismo , Eliminación de Gen , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Homeostasis/genética , Homeostasis/inmunología , Tolerancia Inmunológica , Inmunofenotipificación , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Activación de Linfocitos , Ratones , Ratones Transgénicos , FN-kappa B/genética , Motivos de Nucleótidos , Fenotipo , Unión Proteica , Transducción de Señal , Linfocitos T Reguladores/citología , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Transcriptoma
4.
J Gastroenterol Hepatol ; 39(9): 1876-1884, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38837839

RESUMEN

BACKGROUND AND AIM: Patients with liver cirrhosis often face a grave threat from infected ascites (IA). However, a well-established prognostic model for this complication has not been established in routine clinical practice. Therefore, we aimed to assess mortality risk in patients with liver cirrhosis and IA. METHODS: We conducted a retrospective study across three tertiary hospitals, enrolling 534 adult patients with cirrhotic liver and IA, comprising 465 with spontaneous bacterial peritonitis (SBP), 34 with bacterascites (BA), and 35 with secondary peritonitis (SP). To determine the attributable mortality risk linked to IA, these patients were matched with 122 patients with hydropic decompensated liver cirrhosis but without IA. Clinical, laboratory, and microbiological parameters were assessed for their relation to mortality using univariable analyses and a multivariable random forest model (RFM). Least absolute shrinkage and selection operator (Lasso) regression model was used to establish an easy-to-use mortality prediction score. RESULTS: The in-hospital mortality risk was highest for SP (39.0%), followed by SBP (26.0%) and BA (25.0%). Besides illness severity markers, microbiological parameters, such as Candida spp., were identified as the most significant indicators for mortality. The Lasso model determined 15 parameters with corresponding scores, yielding good discriminatory power (area under the receiver operating characteristics curve = 0.89). Counting from 0 to 83, scores of 20, 40, 60, and 80 corresponded to in-hospital mortalities of 3.3%, 30.8%, 85.2%, and 98.7%, respectively. CONCLUSION: We developed a promising mortality prediction score for IA, highlighting the importance of microbiological parameters in conjunction with illness severity for assessing patient outcomes.


Asunto(s)
Ascitis , Cirrosis Hepática , Peritonitis , Humanos , Cirrosis Hepática/mortalidad , Cirrosis Hepática/complicaciones , Cirrosis Hepática/microbiología , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Pronóstico , Ascitis/mortalidad , Ascitis/microbiología , Peritonitis/mortalidad , Peritonitis/microbiología , Peritonitis/diagnóstico , Anciano , Mortalidad Hospitalaria , Infecciones Bacterianas/mortalidad , Medición de Riesgo , Índice de Severidad de la Enfermedad , Riesgo , Adulto
5.
Nature ; 554(7690): 62-68, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29364867

RESUMEN

The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest KrasMUT levels underlying aggressive undifferentiated phenotypes. We also identify alternative oncogenic gains (Myc, Yap1 or Nfkb2), which collaborate with heterozygous KrasMUT in driving tumorigenesis, but have lower metastatic potential. Mechanistically, different oncogenic gains and dosages evolve along distinct evolutionary routes, licensed by defined allelic states and/or combinations of hallmark tumour suppressor alterations (Cdkn2a, Trp53, Tgfß-pathway). Thus, evolutionary constraints and contingencies direct oncogenic dosage gain and variation along defined routes to drive the early progression of PDAC and shape its downstream biology. Our study uncovers universal principles of Ras-driven oncogenesis that have potential relevance beyond pancreatic cancer.


Asunto(s)
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Evolución Molecular , Dosificación de Gen , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Alelos , Animales , Carcinogénesis/genética , Proteínas de Ciclo Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Progresión de la Enfermedad , Femenino , Genes myc , Genes p53 , Humanos , Masculino , Ratones , Mutación , Subunidad p52 de NF-kappa B/genética , Metástasis de la Neoplasia/genética , Proteínas Nucleares/genética , Fenotipo , Fosfoproteínas/genética , Factores de Transcripción/genética , Transcriptoma/genética , Factor de Crecimiento Transformador beta1/genética , Proteínas Señalizadoras YAP
6.
Z Gastroenterol ; 62(2): 193-198, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37758037

RESUMEN

BACKGROUND: Development of esophageal strictures is common after the total laryngectomy of head and neck cancer patients. While endoscopic techniques like dilatation by balloon or Salvary bougies are well established, risk factors and pathophysiology for development of refractory strictures are less well understood. OBJECTIVE: To evaluate risk factors associated with occurrence and recurrence of total-laryngectomy-associated esophageal strictures in head and neck cancer patients. METHODS: We analyzed retrospectively a cohort of 170 head and neck squamous cell carcinoma patients, who underwent total laryngectomy between 2007 and 2017. The outcome measure was laryngectomy-associated proximal esophageal stricture needing an endoscopic dilatation by using a balloon or Savary dilators. RESULTS: Of the 170 patients in the cohort, 32 (18.8%) developed strictures. Mean time between surgery and first endoscopic intervention was 24.4 months. Significant predictive factors were age ≥ 65 (p=0.017), nodal status N> 1 (p=0.003), continued alcohol abuse after surgery (p=0.005) and diabetes mellitus (p=0.005). In a subgroup, 17 of 32 patients developed refractory strictures and needed more than three dilatations to relieve dysphagia. Postoperative mean (p=0.016) and maximum (p=0.015) C-reactive protein (CRP) were predictive for refractory strictures. CONCLUSION: Symptomatic strictures occurred in 18.8% of the cases. Age, nodal status N>1, continued alcohol abuse and diabetes mellitus were predictive factors. For refractory stenosis (>3 dilatations needed) mean and maximum postoperative CRP were predictive. This may indicate that systemic inflammatory response post-surgery is involved in the stricture formation process.


Asunto(s)
Alcoholismo , Diabetes Mellitus , Estenosis Esofágica , Neoplasias de Cabeza y Cuello , Humanos , Estenosis Esofágica/diagnóstico , Estenosis Esofágica/epidemiología , Estenosis Esofágica/etiología , Constricción Patológica/cirugía , Constricción Patológica/complicaciones , Estudios Retrospectivos , Alcoholismo/complicaciones , Laringectomía/efectos adversos , Resultado del Tratamiento , Esofagoscopía/métodos , Neoplasias de Cabeza y Cuello/complicaciones , Factores de Riesgo
7.
Endoscopy ; 55(5): 415-422, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36323331

RESUMEN

BACKGROUND: Risk stratification and recommendation for surgery for intraductal papillary mucinous neoplasm (IPMN) are currently based on consensus guidelines. Risk stratification from presurgery histology is only potentially decisive owing to the low sensitivity of fine-needle aspiration. In this study, we developed and validated a deep learning-based method to distinguish between IPMN with low grade dysplasia and IPMN with high grade dysplasia/invasive carcinoma using endoscopic ultrasound (EUS) images. METHODS: For model training, we acquired a total of 3355 EUS images from 43 patients who underwent pancreatectomy from March 2015 to August 2021. All patients had histologically proven IPMN. We used transfer learning to fine-tune a convolutional neural network and to classify "low grade IPMN" from "high grade IPMN/invasive carcinoma." Our test set consisted of 1823 images from 27 patients, recruiting 11 patients retrospectively, 7 patients prospectively, and 9 patients externally. We compared our results with the prediction based on international consensus guidelines. RESULTS: Our approach could classify low grade from high grade/invasive carcinoma in the test set with an accuracy of 99.6 % (95 %CI 99.5 %-99.9 %). Our deep learning model achieved superior accuracy in prediction of the histological outcome compared with any individual guideline, which have accuracies between 51.8 % (95 %CI 31.9 %-71.3 %) and 70.4 % (95 %CI 49.8-86.2). CONCLUSION: This pilot study demonstrated that deep learning in IPMN-EUS images can predict the histological outcome with high accuracy.


Asunto(s)
Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Aprendizaje Profundo , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/patología , Estudios Retrospectivos , Neoplasias Intraductales Pancreáticas/diagnóstico por imagen , Proyectos Piloto , Adenocarcinoma Mucinoso/patología , Neoplasias Pancreáticas/patología
8.
Eur Radiol ; 33(10): 6892-6901, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37133518

RESUMEN

OBJECTIVES: To examine the effect of high-b-value computed diffusion-weighted imaging (cDWI) on solid lesion detection and classification in pancreatic intraductal papillary mucinous neoplasm (IPMN), using endoscopic ultrasound (EUS) and histopathology as a standard of reference. METHODS: Eighty-two patients with known or suspected IPMN were retrospectively enrolled. Computed high-b-value images at b = 1000 s/mm2 were calculated from standard (b = 0, 50, 300, and 600 s/mm2) DWI images for conventional full field-of-view (fFOV, 3 × 3 × 4 mm3 voxel size) DWI. A subset of 39 patients received additional high-resolution reduced-field-of-view (rFOV, 2.5 × 2.5 × 3 mm3 voxel size) DWI. In this cohort, rFOV cDWI was compared against fFOV cDWI additionally. Two experienced radiologists evaluated (Likert scale 1-4) image quality (overall image quality, lesion detection and delineation, fluid suppression within the lesion). In addition, quantitative image parameters (apparent signal-to-noise ratio (aSNR), apparent contrast-to-noise ratio (aCNR), contrast ratio (CR)) were assessed. Diagnostic confidence regarding the presence/absence of diffusion-restricted solid nodules was assessed in an additional reader study. RESULTS: High-b-value cDWI at b = 1000 s/mm2 outperformed acquired DWI at b = 600 s/mm2 regarding lesion detection, fluid suppression, aCNR, CR, and lesion classification (p = < .001-.002). Comparing cDWI from fFOV and rFOV revealed higher image quality in high-resolution rFOV-DWI compared to conventional fFOV-DWI (p ≤ .001-.018). High-b-value cDWI images were rated non-inferior to directly acquired high-b-value DWI images (p = .095-.655). CONCLUSIONS: High-b-value cDWI may improve the detection and classification of solid lesions in IPMN. Combining high-resolution imaging and high-b-value cDWI may further increase diagnostic precision. CLINICAL RELEVANCE STATEMENT: This study shows the potential of computed high-resolution high-sensitivity diffusion-weighted magnetic resonance imaging for solid lesion detection in pancreatic intraductal papillary mucinous neoplasia (IPMN). The technique may enable early cancer detection in patients under surveillance. KEY POINTS: • Computed high-b-value diffusion-weighted imaging (cDWI) may improve the detection and classification of intraductal papillary mucinous neoplasms (IPMN) of the pancreas. • cDWI calculated from high-resolution imaging increases diagnostic precision compared to cDWI calculated from conventional-resolution imaging. • cDWI has the potential to strengthen the role of MRI for screening and surveillance of IPMN, particularly in view of the rising incidence of IPMNs combined with now more conservative therapeutic approaches.


Asunto(s)
Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Humanos , Estudios Retrospectivos , Neoplasias Pancreáticas/diagnóstico por imagen , Relación Señal-Ruido , Imagen de Difusión por Resonancia Magnética/métodos , Páncreas
9.
Crit Care ; 27(1): 201, 2023 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-37237287

RESUMEN

BACKGROUND: A quantitative assessment of pulmonary edema is important because the clinical severity can range from mild impairment to life threatening. A quantitative surrogate measure, although invasive, for pulmonary edema is the extravascular lung water index (EVLWI) extracted from the transpulmonary thermodilution (TPTD). Severity of edema from chest X-rays, to date is based on the subjective classification of radiologists. In this work, we use machine learning to quantitatively predict the severity of pulmonary edema from chest radiography. METHODS: We retrospectively included 471 X-rays from 431 patients who underwent chest radiography and TPTD measurement within 24 h at our intensive care unit. The EVLWI extracted from the TPTD was used as a quantitative measure for pulmonary edema. We used a deep learning approach and binned the data into two, three, four and five classes increasing the resolution of the EVLWI prediction from the X-rays. RESULTS: The accuracy, area under the receiver operating characteristic curve (AUROC) and Mathews correlation coefficient (MCC) in the binary classification models (EVLWI < 15, ≥ 15) were 0.93 (accuracy), 0.98 (AUROC) and 0.86(MCC). In the three multiclass models, the accuracy ranged between 0.90 and 0.95, the AUROC between 0.97 and 0.99 and the MCC between 0.86 and 0.92. CONCLUSION: Deep learning can quantify pulmonary edema as measured by EVLWI with high accuracy.


Asunto(s)
Aprendizaje Profundo , Edema Pulmonar , Humanos , Edema Pulmonar/diagnóstico por imagen , Edema Pulmonar/etiología , Rayos X , Estudios Retrospectivos , Agua Pulmonar Extravascular/diagnóstico por imagen , Radiografía , Termodilución
10.
Colorectal Dis ; 25(5): 943-953, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36748436

RESUMEN

AIM: Appendiceal neoplasms are rare subtypes of colorectal tumours that mainly affect younger patients some 20 years earlier than other colon tumours. The aim of this study was to gain more insight into the histological subtypes of this rare disease and include cases previously excluded, such as mucinous neoplasia. METHOD: The cohort study included 1097 patients from the Munich Cancer Registry (MCR) diagnosed between 1998 and 2020. Joinpoint analysis was used to determine trend in incidence. Baseline demographic comparisons and survival analyses using competing risk and univariate/multivariate methods were conducted according to tumour histology: adenocarcinoma (ADENO), neuroendocrine neoplasia (NEN), mixed adeno-neuroendocrine carcinoma (MANEC), and low- (LAMN) and high-grade mucinous neoplasia (HAMN). RESULTS: Up to 2016 the number of cases increased significantly [annual per cent change (APC) = 6.86, p < 0.001] followed by a decline in the following years (APC = -14.82, p = 0.014; average APC = 2.5, p = 0.046). Comparison of all patients showed that NEN (48.4%) and mucinous neoplasms (11.6%) had a considerably better prognosis than ADENO (36.0%) and MANEC (3.0%, p < 0.0001). A multivariate analysis within the NEN and ADENO subgroups revealed that further histological classification was not prognostically relevant, while older age and regional tumour spread at diagnosis were associated with a poor prognosis. ADENO histology with high tumour grade and appendectomy only was also associated with poorer survival. CONCLUSION: Appendiceal neoplasms are histologically heterogeneous; however, this diversity becomes less relevant compared with the marked difference from cancers of the remaining colon. The previously observed increase in cases appears to be abating; fewer cases of appendicitis and/or appendectomies or changes in histopathological assessment may be behind this trend.


Asunto(s)
Adenocarcinoma , Neoplasias del Apéndice , Apéndice , Neoplasias del Colon , Tumores Neuroendocrinos , Humanos , Neoplasias del Apéndice/patología , Estudios de Cohortes , Estudios Retrospectivos , Neoplasias del Colon/epidemiología , Neoplasias del Colon/cirugía , Neoplasias del Colon/patología , Tumores Neuroendocrinos/epidemiología , Tumores Neuroendocrinos/cirugía , Tumores Neuroendocrinos/patología , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Pronóstico , Apendicectomía , Apéndice/patología
11.
Digestion ; 104(5): 391-399, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37331350

RESUMEN

INTRODUCTION: Cold snare polypectomy (CSP) is a safe and effective procedure for small colorectal polyps ≤9 mm. There are only limited data regarding CSP of larger neoplastic lesions. This study evaluated the efficacy and safety of CSP for polyps between 10 and 15 mm in size. METHODS: In this prospective single-arm observational pilot study, patients with a least one polyp 10-15 mm were included. These polyps were preferably removed by CSP using a dedicated hybrid snare. The primary outcome was the histological complete resection rate (CRR) determined by pathologically negative margins of the specimen and no neoplastic tissue obtained from biopsies of the resection site margin. Secondary outcomes were en bloc resection rate, failure of CSP, and incidence of adverse events. RESULTS: A total of 61 neoplastic polyps were removed from 39 patients. Overall CRR was 80.3% (49/61). CSP was feasible in 78.7% (48/61) of polyps and the CRR in this group was 85.4% (41/48). When CSP failed (13/61; 21.3%), lesions were successfully resected by immediate HSP using the same snare with a CRR of 61.5% (8/13) in this group. One patient presented delayed hemorrhage after HSP of a polyp but successful hemostasis was achieved with two hemoclips. No other adverse events occurred. No recurrence was seen on follow-up colonoscopy in cases with incomplete resected polyps. CONCLUSION: CSP seems to be efficient and safe in removing colorectal polyps up to 15 mm. A hybrid snare seems to be particularly advantageous for these polyps as it allows immediate conversion to HSP if CSP might fail in larger polyps. This trial is registered at ClinicalTrials.gov (NCT04464837).


Asunto(s)
Pólipos del Colon , Neoplasias Colorrectales , Humanos , Colonoscopía/efectos adversos , Colonoscopía/métodos , Pólipos del Colon/cirugía , Pólipos del Colon/patología , Estudios Prospectivos , Proyectos Piloto , Resultado del Tratamiento , Márgenes de Escisión , Neoplasias Colorrectales/patología
12.
Z Gastroenterol ; 2023 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-37875129

RESUMEN

INTRODUCTION: Colorectal cancer is the second most common cause of cancer death worldwide. Screening colonoscopy is a very effective measure to prevent colorectal cancer and can reduce mortality at the population level. However, the participation rates of screening programs are low.To provide easily accessible information on screening colonoscopy and to increase the participation rates of screening programs, we developed a questionnaire for asymptomatic patients based on the German guidelines to assess the indication for screening colonoscopy. We evaluated the questionnaire with reference to the indications given by specialists in gastroenterology. METHODS: Patients who visited a specialist in gastroenterology in an outpatient clinic of a tertiary hospital for other reasons than a colonoscopy were eligible for the study. A maximum of seven questions to assess the indication for screening colonoscopy were answered by the patients. Afterward, the indication for screening colonoscopy was given or not by a specialist in gastroenterology. The accuracy of the questionnaire was measured in terms of sensitivity, specificity, and predictive values. RESULTS: In total, 335 patients were included in the analyses, of whom 50 and 285 patients were given and were not given an indication for screening colonoscopy by the specialists, respectively. In 0/50 patients, the questionnaire was false negative and in 8/285 patients false positive. Thus, the questionnaire had a sensitivity of 100% (95% confidence interval: 93-100%), a specificity of 97% (95-99%), a negative predictive value of 100% (99-100%), and a positive predictive value of 86% (75-94%).A subgroup analysis including patients who had never had a colonoscopy (n=109) showed comparable results: sensitivity of 100% (92-100%), specificity of 92% (83-97%), negative predictive value of 100% (94-100%), and positive predictive value of 90% (87-97%). CONCLUSION: The self-assessment questionnaire for asymptomatic individuals to assess the recommendation for screening colonoscopy is very sensitive and specific compared to a specialist in gastroenterology.The questionnaire can be found at: https://www.interdisziplinaere-endoskopie.mri.tum.de/de/infos-patienten/index.php.

13.
Clin Infect Dis ; 75(1): e1063-e1071, 2022 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-34694375

RESUMEN

BACKGROUND: At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict coronavirus disease 2019 (COVID-19) illness. However, the results are not conclusive, as critical illness can drastically alter a patient's microbiome through multiple confounders. METHODS: To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multicenter, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate, and severe COVID-19 (n = 322 participants). RESULTS: In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features. CONCLUSIONS: In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.


Asunto(s)
COVID-19 , Microbiota , Adulto , Enfermedad Crítica , Estudios Transversales , Disbiosis , Haemophilus , Humanos , Neisseria , SARS-CoV-2
14.
Gastroenterology ; 160(1): 346-361.e24, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33007300

RESUMEN

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibroblast-rich desmoplastic stroma. Cancer-associated fibroblasts (CAFs) have been shown to display a high degree of interconvertible states including quiescent, inflammatory, and myofibroblastic phenotypes; however, the mechanisms by which this plasticity is achieved are poorly understood. Here, we aim to elucidate the role of CAF plasticity and its impact on PDAC biology. METHODS: To investigate the role of mesenchymal plasticity in PDAC progression, we generated a PDAC mouse model in which CAF plasticity is modulated by genetic depletion of the transcription factor Prrx1. Primary pancreatic fibroblasts from this mouse model were further characterized by functional in vitro assays. To characterize the impact of CAFs on tumor differentiation and response to chemotherapy, various coculture experiments were performed. In vivo, tumors were characterized by morphology, extracellular matrix composition, and tumor dissemination and metastasis. RESULTS: Our in vivo findings showed that Prrx1-deficient CAFs remain constitutively activated. Importantly, this CAF phenotype determines tumor differentiation and disrupts systemic tumor dissemination. Mechanistically, coculture experiments of tumor organoids and CAFs showed that CAFs shape the epithelial-to-mesenchymal phenotype and confer gemcitabine resistance of PDAC cells induced by CAF-derived hepatocyte growth factor. Furthermore, gene expression analysis showed that patients with pancreatic cancer with high stromal expression of Prrx1 display the squamous, most aggressive, subtype of PDAC. CONCLUSIONS: Here, we define that the Prrx1 transcription factor is critical for tuning CAF activation, allowing a dynamic switch between a dormant and an activated state. This work shows that Prrx1-mediated CAF plasticity has significant impact on PDAC biology and therapeutic resistance.


Asunto(s)
Fibroblastos Asociados al Cáncer/fisiología , Carcinoma Ductal Pancreático/etiología , Carcinoma Ductal Pancreático/patología , Proteínas de Homeodominio/fisiología , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/patología , Animales , Plasticidad de la Célula/fisiología , Modelos Animales de Enfermedad , Ratones
15.
Gastroenterology ; 161(1): 318-332.e9, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33819482

RESUMEN

BACKGROUND & AIMS: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown. METHODS: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes. RESULTS: Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes. CONCLUSIONS: We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.


Asunto(s)
Proteínas del Linfoma 3 de Células B/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Células Madre Neoplásicas/metabolismo , Neoplasias Pancreáticas/metabolismo , Animales , Proteínas del Linfoma 3 de Células B/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/secundario , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Metabolismo Energético , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Invasividad Neoplásica , Células Madre Neoplásicas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Transducción de Señal , Carga Tumoral , Células Tumorales Cultivadas
16.
Eur J Immunol ; 51(5): 1182-1194, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33521935

RESUMEN

Stringent regulation of the inflammatory response is crucial for normal tissue regeneration. Here, we analyzed the role of Toll-like receptor 3 (TLR3) in pancreatic regeneration after acute pancreatitis (AP). AP was induced by caerulein treatment in mice with global TLR3 deficiency (TLR3OFF ) or in mice re-expressing TLR3 exclusively in the myeloid cell lineage (TLR3Mye ). Compared to WT mice, TLR3OFF mice had a markedly increased formation of acinar-to-ductal metaplasia (ADM) that persisted until day 7 after initiation of AP. Pancreatic tissue of WT mice was completely regenerated after 5 days with no detectable ADM structures. The enhancing effect of TLR3-deficiency on ADM formation was closely linked with an increased and prolonged accumulation of macrophages in pancreata of TLR3OFF mice. Importantly, the phenotype of TLR3OFF mice was rescued in TLR3Mye mice, demonstrating the causative role of myeloid cell selective TLR3 signaling. Moreover, in vitro stimulation of macrophages through TLR3 initiated cell death by a caspase-8-associated mechanism. Therefore, these findings provide evidence that TLR3 signaling in myeloid cells is sufficient to limit inflammation and ADM formation and to promote regeneration after AP. Notably, resolution of inflammation after AP was associated with macrophage sensitivity to TLR3-mediated cell death.


Asunto(s)
Expresión Génica , Células Mieloides/metabolismo , Pancreatitis/genética , Pancreatitis/metabolismo , Receptor Toll-Like 3/genética , Enfermedad Aguda , Animales , Biomarcadores , Proliferación Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inmunohistoquímica , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Noqueados , Células Mieloides/inmunología , Pancreatitis/inmunología , Pancreatitis/patología , Regeneración/genética , Transducción de Señal , Receptor Toll-Like 3/metabolismo
17.
Eur J Nucl Med Mol Imaging ; 49(6): 2049-2063, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34882260

RESUMEN

PURPOSE: The incidence of esophageal adenocarcinoma (EAC) has been increasing for decades without significant improvements in treatment. Barrett's esophagus (BE) is best established risk factor for EAC, but current surveillance with random biopsies cannot predict progression to cancer in most BE patients due to the low sensitivity and specificity of high-definition white light endoscopy. METHODS: Here, we evaluated the membrane-bound highly specific Hsp70-specific contrast agent Tumor-Penetrating Peptide (Hsp70-TPP) in guided fluorescence molecular endoscopy biopsy. RESULTS: Hsp70 was significantly overexpressed as determined by IHC in dysplasia and EAC compared with non-dysplastic BE in patient samples (n = 12) and in high-grade dysplastic lesions in a transgenic (L2-IL1b) mouse model of BE. In time-lapse microscopy, Hsp70-TPP was rapidly taken up and internalized  by human BE dysplastic patient-derived organoids. Flexible fluorescence endoscopy of the BE mouse model allowed a specific detection of Hsp70-TPP-Cy5.5 that corresponded closely with the degree of dysplasia but not BE. Ex vivo application of Hsp70-TPP-Cy5.5 to freshly resected whole human EAC specimens revealed a high (> 4) tumor-to-background ratio and a specific detection of previously undetected tumor infiltrations. CONCLUSION: In summary, these findings suggest that Hsp70-targeted imaging using fluorescently labeled TPP peptide may improve tumor surveillance in BE patients.


Asunto(s)
Adenocarcinoma , Esófago de Barrett , Neoplasias Esofágicas , Adenocarcinoma/patología , Animales , Esófago de Barrett/diagnóstico por imagen , Esófago de Barrett/epidemiología , Biopsia , Neoplasias Esofágicas/diagnóstico por imagen , Esofagoscopía/métodos , Humanos , Ratones
18.
Scand J Gastroenterol ; 57(12): 1417-1422, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35771587

RESUMEN

BACKGROUND AND GOALS: Risk stratification for the need for therapeutic endoscopy and prediction of mortality in patients with upper gastrointestinal bleeding (UGIB) can be assessed by several scores. However, current scores are not validated for variceal bleeding and Intensive Care Unit (ICU) patients. The aim of this study was to evaluate potential parameters for the prediction of UGIB and patient outcomes. PATIENTS AND STUDY METHODS: In this monocenter retrospective observational study, data from all esophagogastroduodenoscopies (EGD) between November 2014 and February 2020 with suspected hemorrhage in our ICU were evaluated. RESULTS: Out of 345 included EGD, 42.3% of UGIB was diagnosed. 51.9% needed endoscopic intervention. Overall, 52.3% of included patients with UGIB died. Logistic regression showed that preceding variceal or non-variceal UGIB (p < .001), serum lactate (p = .001), heart rate (HR) (p = .005), and blood transfusions (p = .001) were significant predictors of UGIB. Previous UGIB (p < .001), male sex (p = .015), known varices (p < .001), serum albumin (p = .19) and use of catecholamines (p = .040) were significant predictors for the need of endoscopic intervention. Higher mortality was significantly associated with the usage of steroids (p < .001), malignant preconditions (p = .021), serum albumin (p = .020) and prolonged PTT (partial thromboplastin time) (p = .001). CONCLUSIONS: We were able to identify additional parameters that had previously not been included in existing scores to predict the risk of UGIB, the need for therapeutic endoscopy and mortality in ICU patients. Therefore, an extension of these scores is necessary. Further validation of identified parameters in multicenter trials is needed to improve risk scores for ICU patients.


Asunto(s)
Várices Esofágicas y Gástricas , Hemorragia Gastrointestinal , Humanos , Masculino , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/terapia , Várices Esofágicas y Gástricas/complicaciones , Várices Esofágicas y Gástricas/terapia , Factores de Riesgo , Estudios Retrospectivos , Albúmina Sérica , Unidades de Cuidados Intensivos , Medición de Riesgo
19.
Dig Dis ; 40(6): 777-786, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35100589

RESUMEN

BACKGROUND: Guidelines recommend empirical therapy with piperacillin/tazobactam (TZP) for spontaneous bacterial peritonitis (SBP) with low risk of multidrug-resistant organisms. Whether coverage of beta-lactam-resistant Gram-positive bacteria, such as ampicillin-resistant Enterococcus faecium, provides clinical benefit in such situations is unknown. METHODS: In this observational study, we investigated the real-world effectiveness of empirical therapy with TZP monotherapy versus TZP plus linezolid (LZD) combination therapy in patients with SBP from two centers. Treatment failure, defined as the need to escalate antibiotic therapy due to in vitro resistance, lack of neutrophil decrease in ascitic fluid, or clinical decision, and 30-day survival were retrospectively assessed. RESULTS: In the first cohort, 100 SBP episodes were empirically treated with TZP + LZD combination therapy (n = 50) or TZP monotherapy (n = 50). Treatment failure was recorded in 48% with TZP monotherapy compared with 16% with TZP + LZD combination therapy (p = 0.001), and this difference persisted after stratification for community-acquired versus hospital-acquired SBP. Although treatment failure after TZP therapy was associated with lower 30-day survival (56% vs. 82%; p = 0.04), 30-day survival with empirical TZP + LZD combination therapy was not different from empirical TZP monotherapy (Kaplan-Meier estimates 74% vs. 69%; p = 0.87). TZP concentrations in ascitic fluid were >32 mg/L in 94% samples after continuous administration. In a second cohort of 41 patients empirically treated with TZP, treatment failure was observed in 37%, which was also higher than in episodes treated with TZP + LZD in cohort 1 (p = 0.03). CONCLUSION: In this retrospective analysis, empirical TZP + LZD combination therapy for SBP was associated with fewer treatment failures without impact on short-term survival.


Asunto(s)
Peritonitis , Humanos , Linezolid/uso terapéutico , Estudios Retrospectivos , Combinación Piperacilina y Tazobactam/uso terapéutico , Peritonitis/tratamiento farmacológico , Peritonitis/microbiología , Antibacterianos/uso terapéutico
20.
J Intensive Care Med ; 37(1): 21-31, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33148110

RESUMEN

INTRODUCTION: Visualization of B-lines via lung ultrasound provides a non-invasive estimation of pulmonary hydration. Extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) assessed by transpulmonary thermodilution (TPTD) represent the most validated parameters of lung water and alveolocapillary permeability, but measurement is invasive and expensive. This study aimed to compare the correlations of B-lines scores from extensive 28-sector and simplified 4-sector chest scan with EVLWI and PVPI derived from TPTD in the setting of intensive care unit (primary endpoint). METHODS: We performed scoring of 28-sector and 4-sector B-Lines in 50 critically ill patients. TPTD was carried out with the PiCCO-2-device (Pulsion Medical Systems SE, Maquet Getinge Group). Median time exposure for ultrasound procedure was 12 minutes for 28-sector and 4 minutes for 4-sector scan. RESULTS: Primarily, we found close correlations of 28-sector as well as 4-sector B-Lines scores with EVLWI (R2 = 0.895 vs. R2 = 0.880) and PVPI (R2 = 0.760 vs. R2 = 0.742). Both B-lines scores showed high accuracy to identify patients with specific levels of EVLWI and PVPI. The extensive 28-sector B-lines score revealed a moderate advantage compared to simplified 4-sector scan in detecting a normal EVLWI ≤ 7 (28-sector scan: sensitivity = 81.8%, specificity = 94.9%, AUC = 0.939 versus 4-sector scan: sensitivity = 81.8%, specificity = 82.1%, AUC = 0.902). Both protocols were approximately equivalent in prediction of lung edema with EVLWI ≥ 10 (28-sector scan: sensitivity = 88.9%, specificity = 95.7%, AUC = 0.977 versus 4-sector scan: sensitivity = 81.5%, specificity = 91.3%, AUC = 0.958) or severe pulmonary edema with EVLWI ≥ 15 (28-sector scan: sensitivity = 91.7%, specificity = 97.4%, AUC = 0.995 versus 4-sector scan: sensitivity = 91.7%, specificity = 92.1%, AUC = 0.978). As secondary endpoints, our evaluations resulted in significant associations of 28-sector as well as simplified 4-sector B-Lines score with parameters of respiratory function. CONCLUSION: Both B-line protocols provide accurate non-invasive evaluation of lung water in critically ill patients. The 28-sector scan offers a marginal advantage in prediction of pulmonary edema, but needs substantially more time than 4-sector scan.


Asunto(s)
Agua Pulmonar Extravascular , Edema Pulmonar , Enfermedad Crítica , Agua Pulmonar Extravascular/diagnóstico por imagen , Humanos , Pulmón/diagnóstico por imagen , Edema Pulmonar/diagnóstico por imagen , Termodilución
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