RESUMO
Metabolic reprogramming is a hallmark of cancer and is crucial for cancer progression, making it an attractive therapeutic target. Understanding the role of metabolic reprogramming in cancer initiation could help identify prevention strategies. To address this, we investigated metabolism during acinar-to-ductal metaplasia (ADM), the first step of pancreatic carcinogenesis. Glycolytic markers were elevated in ADM lesions compared with normal tissue from human samples. Comprehensive metabolic assessment in three mouse models with pancreas-specific activation of KRAS, PI3K, or MEK1 using Seahorse measurements, nuclear magnetic resonance metabolome analysis, mass spectrometry, isotope tracing, and RNA sequencing analysis revealed a switch from oxidative phosphorylation to glycolysis in ADM. Blocking the metabolic switch attenuated ADM formation. Furthermore, mitochondrial metabolism was required for de novo synthesis of serine and glutathione (GSH) but not for ATP production. MYC mediated the increase in GSH intermediates in ADM, and inhibition of GSH synthesis suppressed ADM development. This study thus identifies metabolic changes and vulnerabilities in the early stages of pancreatic carcinogenesis. Significance: Metabolic reprogramming from oxidative phosphorylation to glycolysis mediated by MYC plays a crucial role in the development of pancreatic cancer, revealing a mechanism driving tumorigenesis and potential therapeutic targets. See related commentary by Storz, p. 2225.
Assuntos
Metaplasia , Neoplasias Pancreáticas , Animais , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Camundongos , Metaplasia/metabolismo , Metaplasia/patologia , Glicólise , Carcinogênese/metabolismo , Células Acinares/metabolismo , Células Acinares/patologia , Fosforilação Oxidativa , Glutationa/metabolismo , Reprogramação Celular , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Reprogramação MetabólicaRESUMO
BACKGROUND: Pulmonary carcinoids are rare, low-grade malignant tumors characterized by neuroendocrine differentiation and relatively indolent clinical behavior. Most cases present as a slow-growing polypoidal mass in the major bronchi leading to hemoptysis and pulmonary infection due to blockage of the distal bronchi. Carcinoid syndrome is a paraneoplastic syndrome caused by the systemic release of vasoactive substances that presents in 5% of patients with neuroendocrine tumors. Due to such nonspecific presentation, most patients are misdiagnosed or diagnosed late and may receive several courses of antibiotics to treat recurrent pneumonia before the tumor is diagnosed. CASE SUMMARY: We report the case of a 48-year-old male who presented with cough, dyspnea, a history of recurrent pneumonitis, and therapy-refractory ulcerative colitis that completely subsided after the resection of a pulmonary carcinoid. CONCLUSION: We report and emphasize pulmonary carcinoid as a differential diagnosis in patients with nonresponding inflammatory bowel diseases and recurrent pneumonia.
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Adenoma , Tumor Carcinoide , Carcinoma Neuroendócrino , Colite Ulcerativa , Neoplasias Pulmonares , Síndrome do Carcinoide Maligno , Masculino , Humanos , Pessoa de Meia-Idade , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/cirurgia , Síndrome do Carcinoide Maligno/diagnóstico , Síndrome do Carcinoide Maligno/etiologia , Tumor Carcinoide/complicações , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/cirurgia , Intestinos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirurgiaRESUMO
BACKGROUND: Ecthyma gangrenosum (EG) is a cutaneous infectious disease characterized by eschar-like skin ulcers typically caused by Pseudomonas aeruginosa. Here, we report a case of relapsing EG in a patient who had returned from a trip to Colombia, thus establishing EG as an important differential diagnosis of tropical diseases, and demonstrating that even long-term antibiotic treatment can result in only partial remission of EG. CASE PRESENTATION: A 77-year-old man with underlying chronic lymphocytic leukemia (CLL) on ibrutinib treatment was admitted because of a superinfected mosquito bite on the left ear and multiple partially necrotic skin lesions disseminated all over the entire body five days after returning from a trip to Colombia. The initial clinical suspicion of a tropical disease (leishmaniosis, systemic mycosis, or others) could not be confirmed. During the diagnostic workup, microbiological cultures of the skin biopsies and bronchoalveolar lavage revealed Pseudomonas aeruginosa, leading to a diagnosis of EG. Initial antibiotic treatment resulted in partial remission. However, the patient had to be re-admitted due to a relapse 3-4 weeks after the first episode. Finally, the patient was successfully treated with a combined approach consisting of antibiotics, recurrent surgical incisions, and administration of immunoglobulins. CONCLUSIONS: In conclusion, EG should be considered as a differential diagnosis in immunosuppressed patients presenting with eschar-like skin ulcers. A combined treatment approach seems to be the best choice to achieve clinical cure and avoid relapse.
Assuntos
Ectima/diagnóstico , Úlcera Cutânea/diagnóstico , Adenina/análogos & derivados , Adenina/uso terapêutico , Administração Intravenosa , Idoso , Antibacterianos/uso terapêutico , Líquido da Lavagem Broncoalveolar/microbiologia , Colômbia , Diagnóstico Diferencial , Ectima/tratamento farmacológico , Ectima/microbiologia , Ectima/cirurgia , Humanos , Hospedeiro Imunocomprometido , Imunoglobulinas/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Piperidinas/uso terapêutico , Pseudomonas aeruginosa/isolamento & purificação , Úlcera Cutânea/microbiologia , Úlcera Cutânea/cirurgiaRESUMO
Dendritic cells (DC) play a key role in the adaptive immune response due to their ability to present antigens and stimulate naïve T cells. Many bacteria and viruses can efficiently target DC, resulting in impairment of their immunostimulatory function or elimination. Hence, the DC compartment requires replenishment following infection to ensure continued operational readiness of the adaptive immune system. Here, we investigated the molecular and cellular mechanisms of inflammation-induced DC generation. We found that infection with viral and bacterial pathogens as well as Toll-like receptor 9 (TLR9) ligation with CpG-oligodeoxynucleotide (CpG-ODN) expanded an erythropoietin (EPO)-dependent TER119+CD11a+ cell population in the spleen that had the capacity to differentiate into TER119+CD11chigh and TER119-CD11chigh cells both in vitro and in vivo. TER119+CD11chigh cells contributed to the conventional DC pool in the spleen and specifically increased in lymph nodes draining the site of local inflammation. Our results reveal a so far undescribed inflammatory EPO-dependent pathway of DC differentiation and establish a mechanistic link between innate immune recognition of potential immunosuppressive pathogens and the maintenance of the DC pool during and after infection.
Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Eritropoetina/metabolismo , Imunidade Inata , Infecções/etiologia , Infecções/metabolismo , Animais , Biomarcadores , Antígenos de Grupos Sanguíneos/genética , Antígenos de Grupos Sanguíneos/metabolismo , Antígeno CD11c/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Eritropoetina/farmacologia , Feminino , Hematopoese Extramedular/efeitos dos fármacos , Hematopoese Extramedular/imunologia , Imunofenotipagem , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Transgênicos , Oligodesoxirribonucleotídeos/farmacologia , Baço/imunologia , Baço/metabolismo , Baço/patologiaRESUMO
Several studies have suggested an oncogenic role for the neural Wiskott-Aldrich syndrome protein (N-WASP, encoded by the Wasl gene), but thus far, little is known about its function in pancreatic ductal adenocarcinoma (PDAC). In this study, we performed in silico analysis of WASL expression in PDAC patients and found a correlation between low WASL expression and prolonged survival. To clarify the role of Wasl in pancreatic carcinogenesis, we used 2 oncogenic Kras-based PDAC mouse models with pancreas-specific Wasl deletion. In line with human data, both mouse models had an increased survival benefit due to either impaired tumor development in the presence of the tumor suppressor Trp53 or the delayed tumor progression and senescent phenotype upon genetic ablation of Trp53. Mechanistically, loss of Wasl resulted in cell-autonomous senescence through displacement of the N-WASP binding partners WASP-interacting protein (WIP) and p120ctn; vesicular accumulation of GSK3ß, as well as YAP1 and phosphorylated ß-catenin, which are components of the destruction complex; and upregulation of Cdkn1a(p21), a master regulator of senescence. Our findings, thus, indicate that Wasl functions in an oncogenic manner in PDAC by promoting the deregulation of the p120-catenin/ß-catenin/p21 pathway. Therefore, strategies to reduce N-WASP activity might improve the survival outcomes of PDAC patients.
Assuntos
Neoplasias Experimentais/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteína Neuronal da Síndrome de Wiskott-Aldrich/deficiência , Animais , Humanos , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Neuronal da Síndrome de Wiskott-Aldrich/metabolismoRESUMO
OBJECTIVE: Most patients with hepatocellular carcinoma are diagnosed at intermediate or advanced stages (BCLC B or C) and undergo palliative local treatments such as transarterial chemoembolization or selective internal radiation therapy, also called radioembolization. In terms of liver function and tumor extent, stages BCLC B and C comprise a wide spectrum of tumor manifestations. Predictors of survival in these patients undergoing transarterial chemoembolization and selective internal radiation therapy might help stratification into different prognostic groups and help to select the optimal treatment modality. METHODS: In this retrospective study, all patients with hepatocellular carcinoma who underwent transarterial chemoembolization between January 2010 and December 2014 and all hepatocellular carcinoma patients who underwent selective internal radiation therapy between August 2012 and December 2016 were recruited. The prognostic value of pretherapeutic clinical and laboratory parameters for the prediction of overall survival was analyzed using uni- and multi-variable Cox regression models. RESULTS: We enrolled 129 patients in the transarterial chemoembolization group and 34 patients in the selective internal radiation therapy group. The predictive value of the albumin-bilirubin grade was validated for both the transarterial chemoembolization and the selective internal radiation therapy group. Multivariable analysis identified albumin-bilirubin grade and tumor size as independent predictors for the transarterial chemoembolization group and tumor size, serum albumin and serum sodium as independent predictors for the selective internal radiation therapy group. CONCLUSION: While measures of liver dysfunction predicted survival similarly in both cohorts, we found tumor size to predict survival differently in transarterial chemoembolization- and selective internal radiation therapy-treated patients. Tumor size might help to select the most appropriate treatment in hepatocellular carcinoma patients, although this finding has to be validated in further studies.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/efeitos adversos , Humanos , Neoplasias Hepáticas/terapia , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
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.
Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Neoplasias Esofágicas/patologia , Microbioma Gastrointestinal/fisiologia , Interleucina-8/metabolismo , Obesidade/patologia , Adenocarcinoma/imunologia , Adulto , Idoso , Animais , Esôfago de Barrett/imunologia , Carcinogênese/imunologia , Carcinogênese/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Neoplasias Esofágicas/imunologia , Esôfago/imunologia , Esôfago/patologia , Fezes/microbiologia , Feminino , Voluntários Saudáveis , Humanos , Interleucina-8/genética , Interleucina-8/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/imunologia , Organoides , Soro/imunologia , Soro/metabolismo , Fatores de Tempo , Técnicas de Cultura de TecidosRESUMO
Assessment of peripheral perfusion and comparison of surface and body core temperature (BST; BCT) are diagnostic cornerstones of critical care. Infrared non-contact thermometers facilitate the accurate measurement of BST. Additionally, a corrected measurement of BST on the forehead provides an estimate of BCT (BCT_Forehead). In clinical routine BCT is measured by ear thermometers (BCT_Ear). The PiCCO-device (PiCCO: Pulse contour analysis) provides thermodilution-derived Cardiac Index (CI_TD) using an arterial catheter with a thermistor tip in the distal aorta. Therefore, the PiCCO-catheter might be used for continuous BCT-measurement (BCT_PiCCO) in addition to intermittent CI-measurement. To the best of our knowledge, BCT_PiCCO has not been validated compared to standard techniques of BCT-measurement including measurement of urinary bladder temperature (BCT_Bladder). Therefore, we compared BCT_PiCCO to BCT_Ear and BCT_Bladder in 52 patients equipped with the PiCCO-device (Pulsion; Germany). Furthermore, this setting allowed to compare different BSTs and their differences to BCT with CI_TD. BCT_PiCCO, BCT_Ear (ThermoScan; Braun), BCT_Bladder (UROSID; ASID BONZ), BCT_Forehead and BSTs (Thermofocus; Tecnimed) were measured four times within 24h. BSTs were determined on the great toe, finger pad and forearm. Immediately afterwards TPTD was performed to obtain CI_TD. 32 (62%) male, 20 (38%) female patients; APACHE-II 23.8 ±8.3. Bland-Altman-analysis demonstrated low bias and percentage error (PE) values for the comparisons of BCT_PiCCO vs. BCT_Bladder (bias 0.05 ±0.27° Celsius; PE = 1.4%), BCT_PiCCO vs. BCT_Ear (bias 0.08 ±0.38° Celsius; PE = 2.0%) and BCT_Ear vs. BCT_Bladder (bias 0.04 ±0.42° Celsius; PE = 2.2). While BCT_PiCCO, BCT_Ear and BCT_Bladder can be considered interchangeable, Bland-Altman-analyses of BCT_Forehead vs. BCT_PiCCO (bias =-0.63 ±0.75° Celsius; PE = 3.9%) Celsisus, BCT_Ear (bias = -0.58 ±0.68° Celsius; PE = 3.6%) and BCT_Bladder (bias = -0.55 ±0.74° Celsius; PE = 3.9%) demonstrate a substantial underestimation of BCT by BCT_Forehead. BSTs and differences between BCT and BST (DCST) significantly correlated with CI_TD with r-values between 0.230 and 0.307 and p-values between 0.002 and p < 0.001. The strongest association with CI_TD was found for BST_forearm (r = 0.307; p < 0.001). In a multivariate analysis regarding CI_TD and including biometric data, BSTs and and their differences to core-temperatures (DCST), only higher temperatures on the forearm and the great toe, young age, low height and male gender were independently associated with CI_TD. The estimate of CI based on this model (CI_estimated) correlated with CI_TD (r = 0.594; p < 0.001). CI_estimated provided large ROC-areas under the curve (AUC) regarding the critical thresholds of CI_TD ≤ 2.5 L/min/m2 (AUC = 0.862) and CI_TD ≥ 5.0 L/min/m2 (AUC = 0.782). 1.) BCT_PiCCO, BCT_Ear and BCT_Bladder are interchangeable. 2.) BCT_Forehead significantly underestimates BCT by about 0.5° Celsius. 3.) All measured BSTs and DCSTs were significantly associated with CI_TD. 4.) CI_estimated is promising, in particular for the prediction of critical thresholds of CI.
Assuntos
Hemodinâmica , Termodiluição , Boston , Catéteres , Feminino , Alemanha , Humanos , Masculino , Reprodutibilidade dos Testes , TemperaturaRESUMO
BACKGROUND: The incidence of Crohn's disease (CD) is rising, and still many patients have to undergo repeated surgery due to failure of pharmacologic therapy. RESULTS: While the introduction of anti-TNF agents started biologic therapy for CD and revolutionized the management of patients, the number of patients who do not respond to this treatment or lose their initial response to this treatment is still substantial. Therefore, the recent introduction of new therapeutic options with anti-integrins and new anti-cytokines was an important step to provide more effective treatment for our patients. Yet, next to new drugs also new treatment strategies have been proposed. CONCLUSION: In this article, we will review these new aspects of pharmacologic therapy for CD -patients.
RESUMO
BACKGROUND AND STUDY AIMS: Longer observation times are associated with increased adenoma detection rates (ADR) in the entire colon. However, adenomas in the proximal colon are at risk of being missed during colonoscopy. The aim of this study was to investigate the impact of observation time on detection of adenomatous polyps in the proximal colon. PATIENTS AND METHODS: This was a prospective study at a university hospital in Germany. Colonoscopies were conducted using magnetic endoscope imaging (MEI) in order to determine the exact position of the scope. Exact observation times spent for the detection of polyps in the proximal and distal colon segments were assessed. The primary outcome was adenoma detection in the proximal colon. ROC curves were generated in order to test the correlation between observation time and adenoma detection. Logistic regression analysis was used to check for interfering factors. RESULTS: A total 480 procedures with 538 polyps were available for analysis. The overall adenoma detection rate was 38.5â%. ADR in the proximal colon was 28.0â%. There was a significant association between observation time in the proximal colon and the detection of proximal adenomas ( P â<â0.001). The impact of the time factor on ADR was stronger in the proximal compared to the distal colon ( P â=â0.030). A net period of 4âmin 7 sec was found to be the minimum time span for sufficient adenoma detection in the proximal colon. CONCLUSION: Observation time is significant in terms of adenoma detection in the proximal colon. The impact of observation time on ADR is stronger in the proximal compared to the distal colon. In the proximal colon a minimum time span of 4 minutes should be spent in order to ensure adequate adenoma detection.
RESUMO
Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC.
Assuntos
Carcinoma Ductal Pancreático/metabolismo , Senescência Celular , Quimiocina CXCL1/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Interleucina-8B/metabolismo , Fator de Transcrição RelA/metabolismo , Proteínas ras/genética , Animais , Carcinogênese , Carcinoma Ductal Pancreático/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Genes ras , Masculino , Camundongos , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Oncogenes , Neoplasias Pancreáticas/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Proteínas ras/metabolismoRESUMO
BACKGROUND/OBJECTIVES: According to the widely accepted "Cambridge Classification", one of the morphological criteria for chronic pancreatitis (CP) is enlargement of the pancreas. Increased size seems to be an obvious feature of an inflammatory disease. However, it has never been validated so far, if CP is indeed accompanied by significant enlargement of the pancreas. METHODS: In this retrospective study, reference values for the size of the pancreas (head, body and tail measured in the transverse plane by transabdominal ultrasound) were established from 921 patients without pancreatic disease. Measurements were performed by a single investigator. Subsequently, the size of the pancreas from 72 patients with CP was compared to age- and sex-matched controls. RESULTS: Calculating the 5th and 95th percentile, reference values of the pancreatic size were as follows: head 1.5-3.1 cm (mean: 2.2); body 0.6-1.6 cm (mean: 1.1); tail 1.4-3.0 cm (mean: 2.1). The size of the pancreas correlated significantly with body height, weight and body mass index. Patients with CP had only a slightly but statistically significantly larger pancreas than controls. Mean values from the CP group were still between the 5th and 95th percentile of matched controls. CONCLUSIONS: Although the pancreas from patients with CP was statistically significantly larger compared to controls, the difference was only marginally. According to these data, it is at least questionable if pancreatic size is a helpful parameter for sonographic evaluation to discriminate chronic pancreatitis from healthy pancreas.
Assuntos
Pâncreas/diagnóstico por imagem , Pancreatite Crônica/diagnóstico por imagem , Adulto , Estatura , Índice de Massa Corporal , Peso Corporal , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite Crônica/diagnóstico , Valores de Referência , Estudos Retrospectivos , UltrassonografiaRESUMO
BACKGROUND AND STUDY AIM: The aim of the study was to compare the latest narrow-band imaging (NBI) device with high-definition white light (HDWL) endoscopy for accuracy of real-time optical diagnosis of small colorectal polyps. PATIENTS AND METHODS: We conducted a randomized, prospective, multicenter trial at three study sites in Germany. In the NBI arm, endoscopists used NBI for the prediction of polyp pathology on the basis of the NBI International Colorectal Endoscopic classification. In the HDWL arm, NBI was not used for optical classification of polyp histology. The primary outcome was accuracy of optical diagnoses (neoplastic vs. non-neoplastic) in small polyps measuring <â10âmm. Secondary end points included sensitivity and negative predictive value (NPV). RESULTS: A total of 380 patients were randomized 1:1 to either the NBI or HDWL arm. A total of 421 polyps measuring <â10âmm were detected (55.8â% neoplastic, 44.2â% non-neoplastic). Accuracy, sensitivity, and NPV were 73.7â%, 82.4â%, and 75.5â%, respectively, in the NBI arm and 79.2â%, 79.8â%, and 73.4â%, respectively, in the HDWL arm (Pâ=â0.225, Pâ=â0.667, Pâ=â0.765). More polyps were assessed with high confidence in the HDWL arm (82.6â%) than in the NBI arm (73.7â%; Pâ=â0.038). The NPV of the prediction of neoplastic histology in diminutive polyps (≤â5âmm) rated with high confidence was 90.3â% in the NBI arm. We detected significant differences between the participating study sites in the performance data of predictions. CONCLUSION: The levels of accuracy for real-time prediction of polyp histology (<â10âmm) did not differ between NBI and HDWL for optical diagnosis. Variation in the performance of optical diagnosis was apparent between study centers. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02009774).
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Pólipos do Colo , Colonoscopia , Erros de Diagnóstico/prevenção & controle , Imagem de Banda Estreita , Transiluminação , Adulto , Idoso , Biópsia/métodos , Biópsia/normas , Pólipos do Colo/diagnóstico , Pólipos do Colo/diagnóstico por imagem , Pólipos do Colo/patologia , Colonoscopia/métodos , Colonoscopia/normas , Pesquisa Comparativa da Efetividade , Precisão da Medição Dimensional , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Imagem de Banda Estreita/métodos , Imagem de Banda Estreita/normas , Valor Preditivo dos Testes , Transiluminação/métodos , Transiluminação/normas , Carga TumoralRESUMO
BACKGROUND AND STUDY AIM: The use of magnetic endoscope imaging (MEI) has been previously shown to facilitate colonoscopy procedures. We aimed to evaluate the benefits of MEI in terms of reduction in propofol dosage in patients undergoing routine colonoscopy. METHODS: We conducted a randomized prospective trial in a university hospital in Germany. Endoscopists were randomly assigned 1:1 to use MEI during colonoscopy (MEI arm) or to conduct colonoscopy without the use of MEI (standard arm). The desired level of sedation was conscious sedation as assessed using the Observer's Assessment of Alertness and Sedation scores. After complete recovery, patient satisfaction was assessed using a numeric rating scale (NRS) ranging from 1 to 10 points. The primary outcome was total propofol dosage. Secondary outcome measures were patient satisfaction, patients' cooperation, and complication rates, as well as cecal intubation time and adenoma detection. RESULTS: Among 334 randomized patients, no severe adverse events were observed. Median propofol dosage was significantly lower in the MEI arm compared with the standard arm (150âmg vs. 180 mg; Pâ=â0.04). Deep sedation was observed in 7.8â% of patients in the MEI group and 3.6â% in the standard arm (Pâ=â0.10). Patient satisfaction scores were higher in the MEI arm compared with standard procedures (9.0 vs. 8.5; Pâ=â0.04). No significant differences in patients' cooperation, cecal intubation time, and adenoma detection were observed between the study arms. CONCLUSION: The use of MEI may be useful in reducing propofol dosage for colonoscopy and improving patient satisfaction.ClinicalTrials.gov identifier: NCT02121704.
Assuntos
Neoplasias do Ceco , Colonoscopia , Imageamento por Ressonância Magnética/métodos , Propofol , Adulto , Idoso , Neoplasias do Ceco/diagnóstico por imagem , Neoplasias do Ceco/patologia , Colonoscopia/métodos , Colonoscopia/psicologia , Sedação Profunda/métodos , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Aumento da Imagem/métodos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Satisfação do Paciente , Propofol/administração & dosagem , Propofol/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Cardiac Index (CI) is a key-parameter of hemodynamic monitoring. Indicator-dilution is considered as gold standard and can be obtained by pulmonary arterial catheter or transpulmonary thermodilution (TPTD; CItd). Furthermore, CI can be estimated by Pulse-Contour-Analysis (PCA) using arterial wave-form analysis (CIpc). Obviously, adjustment of CIpc to CItd initially improves the accuracy of CIpc. Despite uncertainty after which time accuracy of CIpc might be inappropriate, recalibration by TPTD is suggested after a maximum of 8 h. We hypothesized that accuracy of CIpc might not only depend on time to last TPTD, but also on changes of the arterial wave curve detectable by PCA itself. Therefore, we tried to prospectively characterize predictors of accuracy and precision of CIpc (primary outcome). In addition to "time to last TPTD" we evaluated potential predictors detectable solely by pulse-contour-analysis. Finally, the study aimed to develop a pulse-contour-derived "calibration-index" suggesting recalibration and to validate these results in an independent collective. METHODS: In 28 intensive-care-patients with PiCCO-monitoring (Pulsion Medical-Systems, Germany) 56 datasets were recorded. CIpc-values at baseline and after intervals of 1 h, 2 h, 4 h, 6 h and 8 h were compared to CItd derived from immediately subsequent TPTD. Results from this evaluation-collective were validated in an independent validation-collective (49 patients, 67 datasets). RESULTS: Mean bias values CItd-CIpc after different intervals ranged between -0.248 and 0.112 L/min/m(2). Percentage-error after different intervals to last TPTD ranged between 18.6% (evaluation, 2 h-interval) and 40.3% (validation, 6 h-interval). In the merged data, percentage-error was below 30% after 1 h, 2 h, 4 h and 8 h, and exceeded 30% only after 6 h. "Time to last calibration" was neither associated to accuracy nor to precision of CIpc in any uni- or multivariate analysis. By contrast, the height of CIpc and particularly changes in CIpc compared to last thermodilution-derived CItd(base) univariately and independently predicted the bias CItd-CIpc in both collectives. Relative changes of CIpc compared to CItd(base) exceeding thresholds derived from the evaluation-collective (-11.6% < CIpc-CItd(base)/CItd(base) < 7.4%) were confirmed as significant predictors of a bias |CItd-CIpc| ≥ 20% in the validation-collective. CONCLUSION: Recalibration triggered by changes of CIpc compared to CItd(base) derived from last calibration should be preferred to fixed intervals.
Assuntos
Débito Cardíaco/fisiologia , Pulso Arterial/normas , Algoritmos , Pressão Sanguínea/fisiologia , Calibragem , Cuidados Críticos , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Estudos Prospectivos , Sensibilidade e Especificidade , Termodiluição/métodos , Resistência Vascular/fisiologiaRESUMO
OBJECTIVES: A functional vacuolar adenosine triphosphatase (v-ATPase) complex regulates canonical Wnt/ß-catenin signaling. The goal of this study was to identify the distribution of the v-ATPase in human and murine models of pancreatic intraepithelial neoplasms (PanINs) and assess its role in Wnt/ß-catenin signaling. METHODS: We evaluated the immunolabeling pattern of the v-ATPase in human PanIN specimens and murine PanIN-1 and PanIN-2 lesions obtained from Ptf1a(Cre/+); LSL-Kras(G12D) mice. Wnt/ß-catenin signaling was interrogated in primary PanIN cells by examining the phosphorylated levels of its surface coreceptor, low-density lipoprotein receptor-related protein-6 (LRP6), and its intracellular effector, nonphosphorylated ß-catenin. The response of primary PanIN cells to epidermal growth factor (EGF) was assessed in the absence and presence of the v-ATPase inhibitor, concanamycin. RESULTS: In advanced (PanIN-2), but not early (PanIN-1), lesions, the v-ATPase assumed a polarized phenotype. Blocking the v-ATPase disrupted Wnt/ß-catenin signaling in primary PanIN cells despite significantly higher levels of the total and activated Wnt cell surface coreceptor, LRP6. Vacuolar adenosine triphosphatase blockade significantly decreased the total and activated levels of EGF receptor, a determinant of PanIN progression. The activation of EGF receptor and its intracellular mediator, p44/42 mitogen-activated protein kinase, was also reduced by v-ATPase blockade. This led to diminished proliferation in response to EGF ligand. CONCLUSIONS: The v-ATPase regulates Wnt/ß-catenin and EGF receptor signaling in PanINs.
Assuntos
Carcinoma Ductal Pancreático/enzimologia , Proteínas de Membrana/análise , Proteínas de Neoplasias/análise , Neoplasias Pancreáticas/enzimologia , ATPases Vacuolares Próton-Translocadoras/análise , Via de Sinalização Wnt/fisiologia , Adenocarcinoma in Situ/enzimologia , Adenocarcinoma in Situ/ultraestrutura , Azul Alciano , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/ultraestrutura , Linhagem Celular Tumoral , Polaridade Celular , Progressão da Doença , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/análise , Receptores ErbB/efeitos dos fármacos , Humanos , Ilhotas Pancreáticas/enzimologia , Ilhotas Pancreáticas/ultraestrutura , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/análise , Camundongos , Camundongos Mutantes , Proteína Quinase 3 Ativada por Mitógeno/análise , Proteína Quinase 3 Ativada por Mitógeno/fisiologia , Gradação de Tumores , Proteínas de Neoplasias/fisiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/ultraestrutura , Transporte Proteico , Coloração e Rotulagem , ATPases Vacuolares Próton-Translocadoras/fisiologiaRESUMO
Caveolin-1 (Cav1), a scaffold protein of membrane caveolae and coactivator of peroxisome proliferator-activated receptor gamma (PPARg), inhibits oncogenic signaling through Ras and wingless. However, the in vivo role of Cav1 in colorectal cancer (CRC) remained unknown. To test whether loss of Cav1 accelerates tumorigenesis, we generated a novel mouse model of CRC by crossing C57BL/6 Apc(min/+) with B6129 Cav1 knockout (Cav1-/-) mice. Apc(min/+) Cav1-/- mice developed large, microinvasive and vascularized intraepithelial adenocarcinomas in the distal colon and rectum with higher incidence than Apc(min/+) Cav1+/- and Apc(min/+) Cav1+/+ littermates. Intratumoral gene signatures related to Ras and wingless signaling were elevated, nuclear localization of PPARg protein and expression of PPARg-target genes were reduced independently of Cav1. The PPARg-agonist rosiglitazone prevented tumor formation in mice irrespectively of the Cav1 status and upregulated expression of the Ras-inhibitory protein docking protein-1. Thus, codeficiency of Cav1 and adenomatous polyposis coli facilitated formation of CRC, and activation of PPARg may offer novel strategies for treatment of CRC.
Assuntos
Carcinogênese/genética , Caveolina 1/genética , Neoplasias Colorretais/genética , Terapia de Alvo Molecular , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Animais , Caveolina 1/deficiência , Neoplasias Colorretais/patologia , Genes ras/genética , Humanos , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Transdução de Sinais , Proteína Wnt1/genética , Proteína Wnt1/metabolismoRESUMO
BACKGROUND & AIMS: The transcription factor nuclear factor-κB (NF-κB) (a heterodimer of NF-κB1p50 and RelA) is activated rapidly in acute pancreatitis (AP). However, it is not clear whether NF-κB promotes or protects against AP. We used the NF-κB inhibitor protein, inhibitor of κB (IκB)α, to study the roles of NF-κB in the development of AP in mice. METHODS: IκBα or the combination of IκBα and RelA selectively were deleted from pancreas of mice using the Cre/locus of cross-over P strategy; cerulein or L-arginine were used to induce AP. We performed microarray analyses of the IκBα- and RelA-deficient pancreata. DNA from healthy individuals and patients with acute or chronic pancreatitis were analyzed for variants in coding regions of alpha-1-antichymotrypsin. RESULTS: Mice with pancreas-specific deletion of IκBα had constitutive activation of RelA and a gene expression profile consistent with NF-κB activation; development of AP in these mice was attenuated and trypsin activation was impaired. However, AP was fully induced in mice with pancreas-specific deletion of IκBα and RelA. By using genome-wide expression analysis, we identified a cluster of NF-κB-regulated genes that might protect against the development of AP. The serine protease inhibitor 2A (Spi2a) was highly up-regulated in IκBα-deficient mice. Lentiviral-mediated expression of Spi2A reduced the development of AP in C57BL/6 and RelA-deficient mice. However, we did not correlate any variants of alpha-1-antichymotrypsin, the human homologue of Spi2a, with acute or chronic pancreatitis. CONCLUSIONS: Pancreas-specific deletion of IκBα results in nuclear translocation of RelA and reduces AP induction and trypsin activation in mice after administration of cerulein or L-arginine. Constitutive activation of RelA up-regulates Spi2A, which protects mice against the development of AP.
Assuntos
Proteínas I-kappa B/genética , NF-kappa B/metabolismo , Pancreatite/genética , Pancreatite/metabolismo , Serpinas/genética , Fator de Transcrição RelA/genética , alfa 1-Antiquimotripsina/genética , Células Acinares , Animais , Arginina , Ceruletídeo , Citosol/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Vetores Genéticos , Genótipo , Proteínas I-kappa B/metabolismo , Lentivirus , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Inibidor de NF-kappaB alfa , Proteínas Nucleares/metabolismo , Pâncreas/enzimologia , Pancreatite/induzido quimicamente , Pancreatite/patologia , Fosforilação , Serpinas/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Tripsina/metabolismo , Regulação para CimaRESUMO
INTRODUCTION: Liver failure patients might be at risk for citrate accumulation during continuous venovenous hemodialysis (CVVHD) with regional citrate anticoagulation. The aim of this study was to investigate the predictive capability of baseline liver function parameters regarding citrate accumulation, expressed as an increase in the calcium total/calcium ionized (Ca(tot)/Ca(ion)) ratio ≥ 2.5, and to describe the feasibility of citrate CVVHD in liver failure patients. METHODS: We conducted a prospective observational study in medical ICU patients treated in a German university hospital. We performed 43 CVVHD runs using citrate for regional anticoagulation in 28 critically ill patients with decompensated liver cirrhosis or acute liver failure (maximum of two CVVHD runs per patient). Liver function was characterized before CVVHD using laboratory parameters, calculation of Child-Pugh and Model of End-stage Liver Disease scores, and determination of the plasma disappearance rate of indocyanine green. In addition to blood gas analysis, we measured total calcium and citrate in serum at baseline and after definitive time points for each CVVHD run. RESULTS: Accumulation of citrate in serum correlated with an increase in the Ca(tot)/Ca(ion) ratio. Although the critical upper threshold of Ca(tot)/Ca(ion) ratio ≥ 2.5 was exceeded 10 times in seven different CVVHD runs, equalization of initial metabolic acidosis was possible without major disturbances of acid-base and electrolyte status. Standard laboratory liver function parameters showed poor predictive capabilities regarding citrate accumulation in terms of an elevated Ca(tot)/Ca(ion) ratio ≥ 2.5. In contrast, serum lactate ≥ 3.4 mmol/l and prothrombin time ≤ 26% predicted an increase in the Ca(tot)/Ca(ion) ratio ≥ 2.5 with high sensitivity (86% for both lactate and prothrombin time) and specificity (86% for lactate, 92% for prothrombin time). CONCLUSIONS: Despite substantial accumulation of citrate in serum, CVVHD with regional citrate anticoagulation seems feasible in patients with severely impaired liver function. Citrate accumulation in serum is reflected by an increase in the Ca(tot)/Ca(ion) ratio. To identify patients at risk for citrate accumulation in terms of a Ca(tot)/Ca(ion) ratio ≥ 2.5, baseline serum lactate (threshold ≥ 3.4 mmol/l) and prothrombin time (threshold ≤ 26%) may be useful for risk prediction in daily clinical practice. Careful monitoring of electrolytes and acid-base status is mandatory to ensure patient safety.
Assuntos
Anticoagulantes/uso terapêutico , Ácido Cítrico/uso terapêutico , Falência Hepática/terapia , Diálise Renal/métodos , Equilíbrio Ácido-Base , Adolescente , Adulto , Idoso , Anticoagulantes/sangue , Cálcio/sangue , Ácido Cítrico/sangue , Eletrólitos/sangue , Feminino , Humanos , Concentração de Íons de Hidrogênio , Falência Hepática/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Primary myelofibrosis belongs to the group of myeloproliferative syndromes. Extramedullary hematopoiesis in the liver can lead to portal hypertension. PATIENT AND METHODS: We report a case of a patient with life-threatening, endoscopically not treatable bleeding from esophageal varices due to extramedullary hematopoiesis of the liver that was successfully treated with placement of a transjugular intrahepatic porto-systemic stent-shunt (TIPS). RESULTS: Therapy of variceal bleeding by TIPS insertion was successful. During a 29-month follow-up, no hepatic failure, hepatic encephalopathy, or further variceal bleeding episode occurred. CONCLUSION: TIPS placement is a well-established procedure for the treatment of complications due to portal hypertension mainly due to liver cirrhosis. This report illustrates that TIPS placement can also be a promising treatment option in patients with primary myelofibrosis and portal hypertension due to extramedullary hematopoiesis.