RESUMEN
COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.
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COVID-19/patología , COVID-19/virología , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/virología , Macrófagos/patología , Macrófagos/virología , SARS-CoV-2/fisiología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , COVID-19/diagnóstico por imagen , Comunicación Celular , Estudios de Cohortes , Fibroblastos/patología , Regulación de la Expresión Génica , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Fibrosis Pulmonar Idiopática/genética , Células Madre Mesenquimatosas/patología , Fenotipo , Proteoma/metabolismo , Receptores de Superficie Celular/metabolismo , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/virología , Tomografía Computarizada por Rayos X , Transcripción GenéticaRESUMEN
17p13 deletions including TP53 and other genes represent a common cause for reduced/lost p53 function in tumor cells. In this study, we analyzed the impact of 17p13 (TP53) deletions and p53 expression on tumor aggressiveness and patient prognosis in urothelial carcinoma. The 17p13 copy number status was analyzed by fluorescence in situ hybridization (FISH) on more than 2700 urothelial bladder carcinomas in a tissue microarray format. 17p13 deletion data were compared to p53 expression data measured by immunohistochemistry (IHC) in a previous study. Different types of p53 alterations were compared with tumor phenotype and clinical outcome data. Deletions of 17p13 occurred in 23% of 2185 analyzable carcinomas. The fraction of tumors with 17p13 deletions increased from pTa G2 low (9%) to pTa G3 (24%, p < 0.0001). In muscle-invasive carcinomas, 17p13 deletions were associated with advanced pT stage (p = 0.0246), but unrelated to patient prognosis (p > 0.5). 17p13 deletions were significantly related to p53 immunostaining (p = 0.0375). 17p13 deletions were most common in tumors with complete lack of p53 staining (31%), which supports the concept that many of these tumors have a complete loss of p53 function (p53 null phenotype). 17p13 deletions were also increased in tumors with high p53 staining (25%). In conclusion, 17p13 deletions were most commonly seen in p53 negative cancers, supporting their role as a cause for the p53 null phenotype in urothelial cancer. The association of 17p13 deletions with high grade and advanced pT stage may reflect increasing genomic instability going along with stage and grade progression.
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Deleción Cromosómica , Cromosomas Humanos Par 17 , Fenotipo , Proteína p53 Supresora de Tumor , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Pronóstico , Cromosomas Humanos Par 17/genética , Proteína p53 Supresora de Tumor/genética , Masculino , Femenino , Hibridación Fluorescente in Situ , Anciano , Persona de Mediana EdadRESUMEN
Tumors of the major and minor salivary glands histologically encompass a diverse and partly overlapping spectrum of frequent diagnostically challenging neoplasms. Despite recent advances in molecular testing and the identification of tumor-specific mutations or gene fusions, there is an unmet need to identify additional diagnostic biomarkers for entities lacking specific alterations. In this study, we collected a comprehensive cohort of 363 cases encompassing 20 different salivary gland tumor entities and explored the potential of DNA methylation to classify these tumors. We were able to show that most entities show specific epigenetic signatures and present a machine learning algorithm that achieved a mean balanced accuracy of 0.991. Of note, we showed that cribriform adenocarcinoma is epigenetically distinct from classical polymorphous adenocarcinoma, which could support risk stratification of these tumors. Myoepithelioma and pleomorphic adenoma form a uniform epigenetic class, supporting the theory of a single entity with a broad but continuous morphologic spectrum. Furthermore, we identified a histomorphologically heterogeneous but epigenetically distinct class that could represent a novel tumor entity. In conclusion, our study provides a comprehensive resource of the DNA methylation landscape of salivary gland tumors. Our data provide novel insight into disputed entities and show the potential of DNA methylation to identify new tumor classes. Furthermore, in future, our machine learning classifier could support the histopathologic diagnosis of salivary gland tumors.
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Innate myeloid cells especially neutrophils and their extracellular traps are known to promote intravascular coagulation and thrombosis formation in infections and various other conditions. Innate myeloid cell-dependent fibrin formation can support systemic immunity while its dysregulation enhances the severity of infectious diseases. Less is known about the immune mechanisms preventing dysregulation of fibrin homeostasis in infection. During experimental systemic infections local fibrin deposits in the liver microcirculation cause rapid arrest of CD4+ T cells. Arrested T-helper cells mostly represent Th17 cells that partially originate from the small intestine. Intravascular fibrin deposits activate mouse and human CD4+ T cells which can be mediated by direct fibrin-CD4+ T-cell interactions. Activated CD4+ T cells suppress fibrin deposition and microvascular thrombosis by directly counteracting coagulation activation by neutrophils and classical monocytes. T-cell activation, which is initially triggered by IL-12p40- and MHC-II-dependent mechanisms, enhances intravascular fibrinolysis via LFA-1. Moreover, CD4+ T cells disfavor the association of the thrombin-activatable fibrinolysis inhibitor (TAFI) with fibrin whereby fibrin deposition is increased by TAFI in the absence but not in the presence of T cells. In human infections thrombosis development is inversely related to microvascular levels of CD4+ T cells. Thus, fibrin promotes LFA-1-dependent T-helper cell activation in infections which drives a negative feedback cycle that rapidly restricts intravascular fibrin and thrombosis development.
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Linfocitos T CD4-Positivos , Fibrina , Humanos , Fibrina/metabolismo , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Infecciones/inmunología , Activación de Linfocitos/inmunología , Trombosis/etiología , Trombosis/inmunologíaRESUMEN
BACKGROUND: A high level of PD-L1 expression is the most relevant predictive parameter for response to immune checkpoint inhibitor (CPI) therapy in urinary bladder cancer. Existing data on the relationship between PD-L1 expression and the natural course of disease are controversial and sparse. METHODS: To expand our understanding of the relationship between PD-L1 expression and parameters of cancer aggressiveness, PD-L1 was analyzed on tissue microarrays containing 2710 urothelial bladder carcinomas including 512 patients with follow-up data who underwent radical cystectomy and follow-up therapies in the pre-immune checkpoint inhibitor therapy era. RESULTS: Tumor cell positivity in ≥10% of cells were seen in 513 (20%) and an immune cell positivity occurred in 872 (34%) of 2566 interpretable cancers. PD-L1 positivity in tumor cells increased from pTaG2 low grade (0.9% positive) to pTaG3 high grade (4.1%; p = 0.0255) and was even higher in muscle-invasive (pT2-4) carcinomas (29.3%; p < 0.0001). However, within pT2-4 carcinomas, PD-L1 positivity was linked to low pT stage (p = 0.0028), pN0 (p < 0.0001), L0 status (p = 0.0005), and a better prognosis within 512 patients with cystectomy who never received CPIs (p = 0.0073 for tumor cells and p = 0.0086 for inflammatory cells). PD-L1 staining in inflammatory cells was significantly linked to PD-L1 staining in tumor cells (p < 0.0001) and both were linked to a positive p53 immunostaining (p < 0.0001). CONCLUSION: It cannot be fully excluded that the strong statistical link between PD-L1 status and favorable histological tumor features as well as better prognosis could influence the outcome of studies evaluating CPIs in muscle-invasive urothelial carcinoma.
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Antígeno B7-H1 , Carcinoma de Células Transicionales , Inhibidores de Puntos de Control Inmunológico , Invasividad Neoplásica , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Antígeno B7-H1/análisis , Antígeno B7-H1/biosíntesis , Masculino , Femenino , Pronóstico , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/metabolismo , Anciano , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Anciano de 80 o más Años , Estudios RetrospectivosRESUMEN
Cytokeratin 20 (CK20) expression is limited to umbrella cells in the normal urothelium. Since CK20 is often upregulated in neoplastic urothelial cells including dysplasia and carcinoma in situ, immunohistochemical CK20 analysis is often used for the assessment of bladder biopsies. CK20 expression is a feature of luminal bladder cancer subtype, but its prognostic relevance is disputed. In this study, we investigated CK20 on >2700 urothelial bladder carcinomas in a tissue microarray format by immunohistochemistry. Cytoplasmic and membranous CK20 staining was seen in 1319 (51.8%) cancers. The fraction of CK20 positive and especially strongly positive cases increased from pTaG2 low grade (44.5% strongly positive) and pTaG2 high grade (57.7%) to pTaG3 high grade (62.3%; p = 0.0006) but was lower in muscle-invasive (pT2-4) carcinomas (51.1% in all pTa vs. 29.6% in pT2-4; p < 0.0001). Within pT2-4 carcinomas, CK20 positivity was linked to nodal metastasis and lymphatic vessel invasion (p < 0.0001 each) and to venous invasion (p = 0.0177). CK20 staining was unrelated to overall patient survival if all 605 pT2-4 carcinomas were jointly analyzed but subgroup analyses revealed a significant association of CK20 positivity with favorable prognosis in 129 pT4 carcinomas (p = 0.0005). CK20 positivity was strongly linked to the expression of GATA3 (p < 0.0001), another feature of luminal bladder cancer. The combined analysis of both parameters showed best prognosis for luminal A (CK20+/GATA3+, CK20+/GATA3-) and worst outcome for luminal B (CK20-/GATA3+) and basal/squamous (CK20-/GATA3-) in pT4 urothelial carcinomas (p = 0.0005). In summary, the results of our study demonstrate a complex role of CK20 expression in urothelial neoplasms including neoexpression in pTa tumors, a subsequent loss of CK20 expression in a subset of tumors progressing to muscle-invasion, and a stage dependent prognostic role in muscle-invasive cancers.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Queratina-20/metabolismo , Vejiga Urinaria/metabolismo , Biomarcadores de Tumor/metabolismo , Urotelio/química , Urotelio/metabolismo , Urotelio/patologíaRESUMEN
BACKGROUND: Most inactivating p53 mutations result in a nuclear p53 accumulation - detectable by immunohistochemistry (IHC). p53 alterations leading to a complete lack of p53 protein and absence of immunostaining do also occur - not easily detectable by IHC. p16 is upregulated in p53 inactivated cells. We hypothesized that a positive p16 IHC may help to distinguish p53 inactivation in IHC negative cases. MATERIAL AND METHODS: We investigated p53 and p16 immunostaining on 2710 urothelial bladder carcinomas in a tissue microarray format to understand their impact in relation to clinicopathological parameters of disease progression and patient outcome. RESULTS: p16 immunostaining was absent in normal urothelium but occurred in 63.5% (30.4% strong) of cancers. p16 strongly positive cases increased from pTaG2 low-grade (9.6%) to pTaG3 high-grade tumors (46.5%, p < .0001) but decreased from pTaG3 to pT4 (33.3%; p = .0030). Among pT2-4 carcinomas, p16 positivity was linked to high-grade (p = .0005) but unrelated to overall survival. p53 staining was negative in 8.4%, very weak in 15.4%, weak in 55.3%, strong in 4.7%, and very strong in 16.2% cancers. p53 negative (potentially p53 null phenotype), strong, and very strong p53 positivity increased from pTaG2 low-grade to pTaG3 high-grade tumors (p < .0001) and from pTaG3 to pT2-4 cancers (p = .0007). p53 staining was largely unrelated to histopathological parameters or patient prognosis among pT2-4 carcinomas, except of p53 strong/very strong immunostaining. p16 expression predominated in tumors with very strong, strong, and negative p53 staining and the combination of p53 negative/p16 strongly positive cancers was linked to features of tumor aggressiveness. CONCLUSION: Aberrant p53 and p16 immunostaining increases during grade and stage progression although p53 negative and p16 positive immunostaining lack prognostic significance in pT2-4 carcinomas. Potential diagnostic features are that high level p16 expression is limited to neoplastic urothelium and p53 null phenotype to aggressive cancers (grade 3 and invasive).
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Proteína p53 Supresora de Tumor/genética , Biomarcadores de Tumor/genética , Pronóstico , Músculos/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genéticaRESUMEN
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive. METHODS: Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate ex vivo results. RESULTS: We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, ex vivo infected human lungs and COVID-19 autopsy samples showed that alveolar macrophages were frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake and a related inflammatory and anti-viral activation, especially in "inflammatory alveolar macrophages", comparable to those induced by SARS-CoV and MERS-CoV, but different from NL63 or influenza virus infection. CONCLUSIONS: Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment.
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COVID-19 , Gripe Humana , Adulto , Humanos , Enzima Convertidora de Angiotensina 2 , Pulmón/patología , Macrófagos Alveolares/metabolismo , Peptidil-Dipeptidasa A/metabolismo , SARS-CoV-2 , Tropismo ViralRESUMEN
OBJECTIVES: Multiparametric MRI with Prostate Imaging Reporting and Data System (PI-RADS) assessment is sensitive but not specific for detecting clinically significant prostate cancer. This study validates the diagnostic accuracy of the recently suggested fractal dimension (FD) of perfusion for detecting clinically significant cancer. MATERIALS AND METHODS: Routine clinical MR imaging data, acquired at 3 T without an endorectal coil including dynamic contrast-enhanced sequences, of 72 prostate cancer foci in 64 patients were analyzed. In-bore MRI-guided biopsy with International Society of Urological Pathology (ISUP) grading served as reference standard. Previously established FD cutoffs for predicting tumor grade were compared to measurements of the apparent diffusion coefficient (25th percentile, ADC25) and PI-RADS assessment with and without inclusion of the FD as separate criterion. RESULTS: Fractal analysis allowed prediction of ISUP grade groups 1 to 4 but not 5, with high agreement to the reference standard (κFD = 0.88 [CI: 0.79-0.98]). Integrating fractal analysis into PI-RADS allowed a strong improvement in specificity and overall accuracy while maintaining high sensitivity for significant cancer detection (ISUP > 1; PI-RADS alone: sensitivity = 96%, specificity = 20%, area under the receiver operating curve [AUC] = 0.65; versus PI-RADS with fractal analysis: sensitivity = 95%, specificity = 88%, AUC = 0.92, p < 0.001). ADC25 only differentiated low-grade group 1 from pooled higher-grade groups 2-5 (κADC = 0.36 [CI: 0.12-0.59]). Importantly, fractal analysis was significantly more reliable than ADC25 in predicting non-significant and clinically significant cancer (AUCFD = 0.96 versus AUCADC = 0.75, p < 0.001). Diagnostic accuracy was not significantly affected by zone location. CONCLUSIONS: Fractal analysis is accurate in noninvasively predicting tumor grades in prostate cancer and adds independent information when implemented into PI-RADS assessment. This opens the opportunity to individually adjust biopsy priority and method in individual patients. KEY POINTS: ⢠Fractal analysis of perfusion is accurate in noninvasively predicting tumor grades in prostate cancer using dynamic contrast-enhanced sequences (κFD = 0.88). ⢠Including the fractal dimension into PI-RADS as a separate criterion improved specificity (from 20 to 88%) and overall accuracy (AUC from 0.86 to 0.96) while maintaining high sensitivity (96% versus 95%) for predicting clinically significant cancer. ⢠Fractal analysis was significantly more reliable than ADC25 in predicting clinically significant cancer (AUCFD = 0.96 versus AUCADC = 0.75).
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Próstata , Neoplasias de la Próstata , Fractales , Humanos , Biopsia Guiada por Imagen/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Próstata/patología , Neoplasias de la Próstata/patología , Estudios RetrospectivosRESUMEN
OBJECTIVES: Multiparametric MRI has high diagnostic accuracy for detecting prostate cancer, but non-invasive prediction of tumor grade remains challenging. Characterizing tumor perfusion by exploiting the fractal nature of vascular anatomy might elucidate the aggressive potential of a tumor. This study introduces the concept of fractal analysis for characterizing prostate cancer perfusion and reports about its usefulness for non-invasive prediction of tumor grade. METHODS: We retrospectively analyzed the openly available PROSTATEx dataset with 112 cancer foci in 99 patients. In all patients, histological grading groups specified by the International Society of Urological Pathology (ISUP) were obtained from in-bore MRI-guided biopsy. Fractal analysis of dynamic contrast-enhanced perfusion MRI sequences was performed, yielding fractal dimension (FD) as quantitative descriptor. Two-class and multiclass diagnostic accuracy was analyzed using area under the curve (AUC) receiver operating characteristic analysis, and optimal FD cutoffs were established. Additionally, we compared fractal analysis to conventional apparent diffusion coefficient (ADC) measurements. RESULTS: Fractal analysis of perfusion allowed accurate differentiation of non-significant (group 1) and clinically significant (groups 2-5) cancer with a sensitivity of 91% (confidence interval [CI]: 83-96%) and a specificity of 86% (CI: 73-94%). FD correlated linearly with ISUP groups (r2 = 0.874, p < 0.001). Significant groupwise differences were obtained between low, intermediate, and high ISUP group 1-4 (p ≤ 0.001) but not group 5 tumors. Fractal analysis of perfusion was significantly more reliable than ADC in predicting non-significant and clinically significant cancer (AUCFD = 0.97 versus AUCADC = 0.77, p < 0.001). CONCLUSION: Fractal analysis of perfusion MRI accurately predicts prostate cancer grading in low-, intermediate-, and high-, but not highest-grade, tumors. KEY POINTS: ⢠In 112 prostate carcinomas, fractal analysis of MR perfusion imaging accurately differentiated low-, intermediate-, and high-grade cancer (ISUP grade groups 1-4). ⢠Fractal analysis detected clinically significant prostate cancer with a sensitivity of 91% (83-96%) and a specificity of 86% (73-94%). ⢠Fractal dimension of perfusion at the tumor margin may provide an imaging biomarker to predict prostate cancer grading.
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Próstata , Neoplasias de la Próstata , Fractales , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Clasificación del Tumor , Perfusión , Próstata/patología , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Estudios RetrospectivosRESUMEN
BACKGROUND: Minimally invasive, battery-powered drilling systems have become the preferred tool for obtaining representative samples from bone lesions. However, the heat generated during battery-powered bone drilling for bone biopsies has not yet been sufficiently investigated. Thermal necrosis can occur if the bone temperature exceeds a critical threshold for a certain period of time. PURPOSE: To investigate heat production as a function of femur temperature during and after battery-powered percutaneous bone drilling in a porcine in vivo model. METHODS: We performed 16 femur drillings in 13 domestic pigs with an average age of 22 weeks and an average body temperature of 39.7 °C, using a battery-powered drilling system and an intraosseous temperature monitoring device. The standardized duration of the drilling procedure was 20 s. The bone core specimens obtained were embedded in 4% formalin, stained with haematoxylin and eosin (H&E) and sent for pathological analysis of tissue quality and signs of thermal damage. RESULTS: No significant changes in the pigs' local temperature were observed after bone drilling with a battery-powered drill device. Across all measurements, the median change in temperature between the initial measurement and the temperature measured after drilling (at 20 s) was 0.1 °C. Histological examination of the bone core specimens revealed no signs of mechanical or thermal damage. CONCLUSION: Overall, this preliminary study shows that battery-powered, drill-assisted harvesting of bone core specimens does not appear to cause mechanical or thermal damage.
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Huesos , Calefacción , Animales , Fémur/diagnóstico por imagen , Fémur/cirugía , Calor , Humanos , PorcinosRESUMEN
Signaling pathways that drive bladder cancer (BC) progression may be promising and specific targets for systemic therapy. Here, we investigated the clinical significance and targetability of NOTCH and mitogen-activated protein kinase (MAPK) signaling for this aggressive malignancy. We assessed NOTCH1 and MAPK activity in 222 stage III and IV BC specimens of patients that had undergone radical cystectomy, and tested for clinical associations including cancer-specific and overall survival. We examined therapeutic effects of NOTCH and MAPK repression in a murine xenograft model of human bladder cancer cells and evaluated tumor growth and tumor cell plasticity. In BC, NOTCH1 and MAPK signaling marked two distinct tumor cell subpopulations. The combination of high NOTCH1 and high MAPK activity indicated poor cancer-specific and overall survival in univariate and multivariate analyses. Inhibition of NOTCH and MAPK in BC xenografts in vivo depleted targeted tumor cell subpopulations and revealed strong plasticity in signaling pathway activity. Combinatorial inhibition of NOTCH and MAPK signaling most strongly suppressed tumor growth. Our findings indicate that tumor cell subpopulations with high NOTCH and MAPK activity both contribute to tumor progression. Furthermore, we propose a new concept for BC therapy, which advocates specific and simultaneous targeting of these different tumor cell subpopulations through combined NOTCH and MAPK inhibition.
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Proteínas Quinasas Activadas por Mitógenos/metabolismo , Receptor Notch1/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Anciano , Análisis de Varianza , Animales , Bencimidazoles/uso terapéutico , Línea Celular Tumoral , Dibenzazepinas/uso terapéutico , Progresión de la Enfermedad , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Pronóstico , Receptor Notch1/antagonistas & inhibidores , Análisis de Regresión , Transducción de Señal , Análisis de Matrices Tisulares/métodos , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The detection of severe acute respiratory syndrome coronavirus (SARS-CoV-2) is challenging, particularly in post-mortem human tissues. However, there is increasing evidence for viral SARS-CoV-2 manifestation in non-respiratory tissues. In this context, it is a current matter of debate, whether SARS-CoV-2 shows hepatotropism. CASE PRESENTATION: Here, we report a case of an 88-year-old women with massive SARS-CoV-2 viremia, severe jaundice and clinical signs of an acute hepatitis, who died within a few days from an acute liver failure without showing any clinical signs of pneumonia. Autopsy revealed a severe chronic and acute liver damage with bile duct infestation by SARS-CoV-2 that was accompanied by higher expressions of angiotensin-converting enzyme-2 (ACE2), Cathepsin L and transmembrane serine protease 2 (TMPRSS2). CONCLUSION: Our findings indicate an enhanced biliary susceptibility to viral infection with SARS-CoV-2, that might have resulted from pre-existing severe liver damage. Furthermore, our findings emphasize the differential diagnosis of coronavirus disease 2019 (COVID-19)-associated liver failure in the clinical setting of an inexplicable jaundice.
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COVID-19 , Fallo Hepático Agudo , Anciano de 80 o más Años , Femenino , Humanos , Cirrosis Hepática/complicaciones , Fallo Hepático Agudo/etiología , Peptidil-Dipeptidasa A , SARS-CoV-2RESUMEN
As new biomarkers, circular RNAs (circRNAs) have been largely unexplored in prostate cancer (PCa). Using an integrative approach, we aimed to evaluate the potential of circRNAs and their linear transcripts (linRNAs) to act as (i) diagnostic biomarkers for differentiation between normal and tumor tissue and (ii) prognostic biomarkers for the prediction of biochemical recurrence (BCR) after radical prostatectomy. In a first step, eight circRNAs (circATXN10, circCRIM1, circCSNK1G3, circGUCY1A2, circLPP, circNEAT1, circRHOBTB3, and circSTIL) were identified as differentially expressed via a genome-wide circRNA-based microarray analysis of six PCa samples. Additional bioinformatics and literature data were applied for this selection process. In total, 115 malignant PCa and 79 adjacent normal tissue samples were examined using robust RT-qPCR assays specifically established for the circRNAs and their linear counterparts. Their diagnostic and prognostic potential was evaluated using receiver operating characteristic curves, Cox regressions, decision curve analyses, and C-statistic calculations of prognostic indices. The combination of circATXN10 and linSTIL showed a high discriminative ability between malignant and adjacent normal tissue PCa. The combination of linGUCY1A2, linNEAT1, and linSTIL proved to be the best predictive RNA-signature for BCR. The combination of this RNA signature with five established reference models based on only clinicopathological factors resulted in an improved predictive accuracy for BCR in these models. This is an encouraging study for PCa to evaluate circRNAs and their linRNAs in an integrative approach, and the results showed their clinical potential in combination with standard clinicopathological variables.
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Biomarcadores de Tumor/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , ARN Circular/genética , Anciano , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Prostatectomía , Neoplasias de la Próstata/cirugía , ARN Largo no Codificante/genética , Curva ROC , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Lymph vessels play a crucial role in immune reactions in health and disease. In oncology the inhibition of lymphangiogenesis is an established therapeutic concept for reducing metastatic spreading of tumor cells. During allogeneic tissue transplantation, the inhibition of lymphangiogenesis has been successfully used to attenuate graft rejection. Despite its critical importance for tumor growth, alloimmune responses, and inflammation, the role of lymphangiogenesis has not been investigated during allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that acute graft-versus-host disease (aGVHD) is associated with lymphangiogenesis in murine allo-HSCT models as well as in patient intestinal biopsies. Inhibition of aGVHD-associated lymphangiogenesis by monoclonal antibodies against vascular endothelial growth factor receptor 3 (VEGFR-3) ameliorated aGVHD and improved survival in murine models. The administration of anti-VEGFR-3 antibodies did not interfere with hematopoietic engraftment and improved immune reconstitution in allo-HSCT recipients with aGVHD. Anti-VEGFR-3 therapy had no significant impact on growth of malignant lymphoma after allo-HSCT. We conclude that aGVHD is associated with lymphangiogenesis in intestinal lesions and in lymph nodes. Our data show that anti-VEGFR-3 treatment ameliorates lethal aGVHD and identifies the lymphatic vasculature as a novel therapeutic target in the setting of allo-HSCT.
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Enfermedad Injerto contra Huésped/prevención & control , Linfangiogénesis , Receptor 3 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Enfermedades Intestinales , Ganglios Linfáticos/patología , Ratones , Trasplante Homólogo , Receptor 3 de Factores de Crecimiento Endotelial Vascular/inmunologíaRESUMEN
BACKGROUND: Budding is a complementary prognostic factor for colorectal cancer. In this study, we aimed to clarify the role of tumor budding in rectal cancer patients after preoperative chemoradiotherapy. METHODS: A total of 124 patients with rectal cancer treated with neoadjuvant chemoradiotherapy and consecutive surgery were included. Surgical specimens were evaluated for budding and routine clinicopathological features. Budding was evaluated on hematoxylin and eosin (H&E)-stained slides and by cytokeratin immunohistochemical (IHC) staining. RESULTS: A budding rate of 36.9% (n = 38) by H&E and 55.6% (n = 55) by IHC was observed. Budding was significantly associated with a high ypT and ypN status, poor differentiation, and low degrees of tumor regression. Moreover, budding was strongly predictive of a worse patient outcome, as measured by tumor recurrence or death. In multivariate analyses, budding remained the only significant parameter for overall survival and was even superior to the ypT and ypN status (budding in H&E: hazard ratio (HR) 2.72, 95% confidence interval (95% CI) 1.15-6.44, p = 0.023; budding in IHC: HR 5.19, 95% CI 1.62-16.61, p = 0.006). CONCLUSION: Budding is a strong prognostic predictor of survival in rectal cancer patients after neoadjuvant therapy. A standardized evaluation of tumor budding after neoadjuvant therapy may thus aid in risk stratification and guide the clinical management of patients with rectal cancer. Immunostaining can help to enhance the diagnostic accuracy and prognostic significance.
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Neoplasias del Recto/diagnóstico , Recto/patología , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular , Quimioradioterapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate the accuracy of clinical parameters and established pre-treatment risk stratification systems for prostate cancer (PCa) in predicting PSMA-positive metastases in men undergoing Ga-68-PSMA PET/CT as initial staging examination. MATERIALS AND METHODS: A retrospective analysis in 108 consecutive treatment-naïve patients with biopsy-proven PCa undergoing Ga-68-PSMA PET/CT (median age, 72 years [range, 49-82 years]) was performed. Prediction of PSMA-positive metastases by serum PSA, clinical T stage (cT), ISUP group, percentage of positive biopsy cores, and derived risk scores (D'Amico risk classification system, Roach [RF], Yale formula [YF], and Briganti nomogram [BN]) was examined with ROC analysis. RESULTS: Any PSMA-positive metastases were found in 36 of 108 patients, including LN metastases in 28 patients, extrapelvic LN metastases in 15 patients, and organ metastases in 19 patients (bone, 19; lung, 1). AUCs for PSA, cT, ISUP, and percentage of positive biopsy cores regarding PSMA-positive metastases did not differ significantly (range, 0.6-0.8; each P > 0.05). D'Amico (AUC, 0.61-0.64) was inferior to RF (0.76-0.83), YF (0.81-0.86), and BN (0.73 to 0.88; each P < 0.05). Among the 89 high-risk patients (D'Amico), decision for or against PET imaging based on RF (cut-off, >18.0), YF (>10.8), or BN (>8.0) would have prevented PSMA PET/CT in 4 (5%), 15 (17%), or 18 patients (20%), respectively, while preserving a sensitivity ≥95% for PSMA-positive metastases. CONCLUSIONS: Clinical parameters and established risk stratification systems for PCa can predict Ga-68-PSMA PET-positive metastases in treatment-naïve patients. Especially YF and BN may improve identification of patients with the highest probability of metastatic disease detected by Ga-68-PSMA PET/CT.