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AIMS: of this investigation were to quantify copper (Cu), iron (Fe) and zinc (Zn) along with sulphur (S) and phosphorus (P) in hepatocytes and connective tissue in liver section from patients with Wilson´s disease (WD) by micro Synchrotron X-ray fluorescence (µ-SRXRF). Secondly to establish two-dimensional µ-SRXRF element mappings for comparison with histologically prepared slices, and thirdly to assess whether elemental distributions are associated. METHODS: Archival liver tissues from twelve patients with end-stage cirrhosis or fulminant WD were investigated. Mutations in ATP7B have been classified before. For control seven archived normal liver tissues were investigated. µ-SRXRF measurements were performed at the DORIS III storage ring at HASYLAB/DESY (Hamburg, Germany). Two-dimensional element distribution were compared with histologically prepared slices about 20-30 µm apart from those investigated by µ-SRXRF. RESULTS: Elementary copper (Cu) could be demonstrated in all investigated liver sections simultaneously with Fe, Zn, P and S. In WD mean Cu was 20 fold increased in hepatocytes and threefold in fibrotic areas in comparison with controls. In regeneration nodules Cu was strikingly inhomogeneous distributed. Cu concentrations measured by µ-SRXRF correlated with those measured by atom absorption spectroscopy. Strong associations in their regional distribution existed between Zn and Cu or Fe and S. Moreover, differences in Cu/S were found between hepatocytes and fibrotic areas. An increase of Fe could only be documented in hepatocytes compared to fibrotic areas. With a beam size of 15 x 15 µm two-dimensional distributions of these elements are morphologically comparable with histological section with a magnification of about 25x optic microscope. CONCLUSIONS: µ-SRXRF investigations are a valuable tool for quantifying element concentrations in biological tissues and further provide 2-dimensional information of element distribution and elemental association in a biological tissues, thus speeding up basic knowledge in a synopsis with biological and clinical data.
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Degeneración Hepatolenticular/metabolismo , Hígado/química , Espectrometría por Rayos X , Oligoelementos/análisis , Adolescente , Adulto , Niño , Femenino , Humanos , Hígado/patología , Masculino , Persona de Mediana Edad , Sincrotrones , Adulto JovenRESUMEN
BACKGROUND: Refractory coeliac disease, enteropathy associated T-cell lymphoma and small bowel adenocarcinoma are rare but prognostically important complications in coeliac disease. AIM: To analyse potential changes in occurrence of complicated coeliac disease over the last 25 years. METHODS: One thousand one hundred and thirty eight patients were included and evaluated based on their time of first presentation at the Medical University of Vienna, Austria. Occurrences of refractory coeliac disease and associated malignancies were evaluated for 5-year intervals from January 1990 until December 2014 and were compared over time. RESULTS: 2.6% (n = 29) were diagnosed with refractory coeliac disease (females 65.6%, mean age at diagnosis 62.8 years). The proportion of those patients was 2.6%, 3.1%, 3.3%, 2.7% and 0.5% for the 5 year intervals from 1990 onwards. Thus, the number of refractory cases has been decreasing since 2000 (P = 0.024). The number of patients presenting with lymphoma (n = 7) was 0.6%, 0.4%, 1.1%, 0.8% and 0% from 1990 to 2014. Similarly the number of patients with adenocarcinoma (n = 4) decreased to 0% until 2014. Overall mortality in patients suffering from refractory disease was 48%. Of all patients diagnosed with lymphoma 71.4% died with a 5-year survival rate of 28.6%. CONCLUSIONS: Over the past 15 years the occurrence of complicated coeliac disease has been decreasing. This possibly reflects a higher awareness of coeliac disease and optimised diagnosis and treatment with avoidance of long-term immunological disease activity. Symptomatic disease and a delay in diagnosis are risk factors for refractory coeliac disease and related cancer.
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Adenocarcinoma/epidemiología , Enfermedad Celíaca/epidemiología , Neoplasias Intestinales/epidemiología , Linfoma de Células T/epidemiología , Adenocarcinoma/diagnóstico , Adenocarcinoma/etiología , Adulto , Anciano , Austria/epidemiología , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/diagnóstico , Femenino , Humanos , Neoplasias Intestinales/diagnóstico , Neoplasias Intestinales/etiología , Intestino Delgado/patología , Linfoma de Células T/diagnóstico , Linfoma de Células T/etiología , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Reactivation of persistent human adenoviruses (HAdVs) is associated with high morbidity and mortality in paediatric haematopoietic stem cell transplant (HSCT) recipients. Although invasive HAdV infections mainly arise from the gastrointestinal (GI) tract, the specific sites of HAdV persistence are not well characterised. We prospectively screened biopsies from 143 non-HSCT paediatric patients undergoing GI endoscopy and monitored serial stool specimens from 148 paediatric HSCT recipients for the presence of HAdV by real-time PCR. Persistence of HAdV in the GI tract was identified in 31% of children, with the highest prevalence in the terminal ileum. In situ hybridisation and immunohistochemistry identified HAdV persistence in lymphoid cells of the lamina propria, whereas biopsies from five transplant recipients revealed high numbers of replicating HAdV in intestinal epithelial cells. The prevalence of HAdV species, the frequencies of persistence in the GI tract and reactivations post transplant indicated a correlation of intestinal HAdV shedding pre-transplant with high risk of invasive infection. HAdV persistence in the GI tract is a likely origin of infectious complications in immunocompromised children. Intestinal lymphocytes represent a reservoir for HAdV persistence and reactivation, whereas the intestinal epithelium is the main site of viral proliferation preceding dissemination. The findings have important implications for assessing the risk of life-threatening invasive HAdV infections.
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Adenovirus Humanos/aislamiento & purificación , Adenovirus Humanos/fisiología , Tracto Gastrointestinal/virología , Activación Viral , Infecciones por Adenoviridae , Adolescente , Biopsia , Niño , Preescolar , Heces/virología , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Huésped Inmunocomprometido , Lactante , Mucosa Intestinal/virología , Linfocitos/virología , Masculino , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto JovenRESUMEN
BACKGROUND: IgE-mediated allergy is a common disease characterized by a harmful immune response towards otherwise harmless environmental antigens. Induction of specific immunological non-responsiveness towards allergens would be a desirable goal. Blockade of costimulatory pathways is a promising strategy to modulate the immune response in an antigen-specific manner. Recently, OX40 (CD134) was identified as a costimulatory receptor important in Th2-mediated immune responses. Moreover, synergy between OX40 blockade and 'conventional' costimulation blockade (anti-CD40L, CTLA4Ig) was observed in models of alloimmunity. OBJECTIVE: We investigated the potential of interfering with OX40 alone or in combination with CD40/CD28 signals to influence the allergic immune response. METHODS: The OX40 pathway was investigated in an established murine model of IgE-mediated allergy where BALB/c mice are repeatedly immunized with the clinically relevant grass pollen allergen Phl p 5. Groups were treated with combinations of anti-OX40L, CTLA4Ig and anti-CD40L. In selected mice, Tregs were depleted with anti-CD25. RESULTS: Blockade of OX40L alone at the time of first or second immunization did not modulate the allergic response on the humoral or effector cell levels but slightly on T cell responses. Administration of a combination of anti-CD40L/CTLA4Ig delayed the allergic immune response, but antibody production could not be inhibited after repeated immunization even though the allergen-specific T cell response was suppressed in the long run. Notably, additional blockade of OX40L had no detectable supplementary effect. Immunomodulation partly involved regulatory T cells as depletion of CD25(+) cells led to restored T cell proliferation. CONCLUSIONS AND CLINICAL RELEVANCE: Collectively, our data provide evidence that the allergic immune response towards Phl p 5 is independent of OX40L, although reduction on T cell responses and slightly on the asthmatic phenotype was detectable. Besides, no relevant synergistic effect of OX40L blockade in addition to CD40L/CD28 blockade could be detected. Thus, the therapeutic potential of OX40L blockade for IgE-mediated allergy appears to be ineffective in this setting.
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Antialérgicos/farmacología , Hipersensibilidad/inmunología , Inmunidad Celular/inmunología , Inmunidad Humoral/inmunología , Ligando OX40/inmunología , Polen/inmunología , Abatacept/farmacología , Alérgenos/inmunología , Animales , Ligando de CD40/antagonistas & inhibidores , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ligando OX40/antagonistas & inhibidores , Phleum/inmunología , Ratas , Hipersensibilidad Respiratoria/inmunologíaRESUMEN
BACKGROUND: Tumor dormancy has been described as a state of hibernation. Dormancy can be switched to proliferation by different pathways, which may play a critical role in tumor recurrence. In this study, we investigated genetic variations within genes involved in tumor dormancy and their association with recurrence and outcome in patients with colorectal liver metastases (CLM) who underwent neoadjuvant bevacizumab-based chemotherapy. PATIENTS AND METHODS: Genomic DNA was extracted from resected CLM (FFPE) from 149 patients. Single-nucleotide polymorphisms (SNPs) in 14 genes associated with dormancy were analyzed by direct Sanger DNA sequencing and evaluated for response, recurrence-free survival (RFS), overall survival (OS) and recurrence patterns. RESULTS: NME1 rs34214448 C>A was significantly associated with RFS in univariable analysis (P = 0.039) and with intrahepatic recurrence (P = 0.014). NOTCH3 rs1044009 T>C and CD44 rs8193 C>T showed a significant difference in 3-year OS rates (P = 0.004 and P = 0.042, respectively). With respect to radiological response, CD44 rs8193 C>T variant genotypes were associated with a significantly higher response rate (P = 0.033). Recursive partitioning analyses revealed that Dll4 rs12441495 C>G, NME1 rs34214448 C>A and NOTCH3 rs1044009 T>C were the dominant SNPs predicting histological response, RFS and OS, respectively. CONCLUSION: Our data suggest that gene variations within genes involved in tumor dormancy pathways are associated with response and outcome in patients with resected CLM. These data may lead to new and more effective treatment strategies targeting tumor dormancy.
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Carcinoma/genética , Neoplasias Colorrectales/genética , Neoplasias Hepáticas/genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Unión al Calcio , Carcinoma/secundario , Carcinoma/cirugía , Neoplasias Colorrectales/patología , Bases de Datos Factuales , Supervivencia sin Enfermedad , Femenino , Humanos , Receptores de Hialuranos/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Masculino , Metastasectomía , Persona de Mediana Edad , Nucleósido Difosfato Quinasas NM23/genética , Polimorfismo de Nucleótido Simple , Pronóstico , Receptor Notch3 , Receptores Notch/genéticaRESUMEN
In patients with colorectal liver metastases (CLM), liver resection offers the possibility of cure and long-term survival. The liver is a highly immunogenic organ harboring ~80% of the body's tissue macrophages. Emerging data demonstrate a critical role of the immune response for cancer treatment. We investigated variations within genes involved in immune response checkpoints and their association with outcomes in patients with CLM who underwent neoadjuvant chemotherapy including bevacizumab and liver resection. Single-nucleotide polymorphisms (SNPs) in nine genes (CCL2, CCR2, LAG3, NT5E, PDCD1, CD274, IDO1, CTLA4 and CD24) were analyzed in genomic DNA from 149 patients with resected bevacizumab-pretreated CLM by direct Sanger DNA sequencing, and correlated with response, recurrence-free survival (RFS), overall survival (OS), probability of cure and recurrence patterns. IDO1 (indoleamine 2, 3-dioxygenase) rs3739319 G>A and CD24 rs8734 G>A showed a significant difference in 3-year OS rates. In addition, IDO1 rs3739319 G>A was significantly associated with extrahepatic recurrence. Recursive partitioning analyses revealed that IDO1 rs3739319 G>A was the dominant SNP predicting RFS and OS. Our data suggest that variants within genes involved in immune response checkpoints are associated with outcomes in patients with resected CLM and might lead to improved treatment strategies modulating anti-tumor immune response by targeting novel immune checkpoints.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Genes MHC Clase II/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/administración & dosificación , Quimioterapia Adyuvante/métodos , Neoplasias Colorrectales/tratamiento farmacológico , Supervivencia sin Enfermedad , Femenino , Hepatectomía/métodos , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Pronóstico , Tasa de SupervivenciaRESUMEN
The mixed chimerism approach achieves donor-specific tolerance in organ transplantation, but clinical use is inhibited by the toxicities of current bone marrow (BM) transplantation (BMT) protocols. Blocking the CD40:CD154 pathway with anti-CD154 monoclonal antibodies (mAbs) is exceptionally potent in inducing mixed chimerism, but these mAbs are clinically not available. Defining the roles of donor and recipient CD40 in a murine allogeneic BMT model, we show that CD4 or CD8 activation through an intact direct or CD4 T cell activation through the indirect pathway is sufficient to trigger BM rejection despite CTLA4Ig treatment. In the absence of CD4 T cells, CD8 T cell activation via the direct pathway, in contrast, leads to a state of split tolerance. Interruption of the CD40 signals in both the direct and indirect pathway of allorecognition or lack of recipient CD154 is required for the induction of chimerism and tolerance. We developed a novel BMT protocol that induces mixed chimerism and donor-specific tolerance to fully mismatched cardiac allografts relying on CD28 costimulation blockade and mTOR inhibition without targeting the CD40 pathway. Notably, MHC-mismatched/minor antigen-matched skin grafts survive indefinitely whereas fully mismatched grafts are rejected, suggesting that non-MHC antigens cause graft rejection and split tolerance.
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Abatacept/farmacología , Anticuerpos Monoclonales/farmacología , Antígenos CD40/antagonistas & inhibidores , Ligando de CD40/antagonistas & inhibidores , Quimera/inmunología , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Animales , Trasplante de Médula Ósea , Antígenos CD40/efectos de los fármacos , Antígenos CD40/fisiología , Ligando de CD40/efectos de los fármacos , Ligando de CD40/fisiología , Sinergismo Farmacológico , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Modelos Animales , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Acondicionamiento Pretrasplante/métodos , Tolerancia al Trasplante/inmunologíaRESUMEN
OBJECTIVES: We aimed to determine the prognostic significance of receptor activator of nuclear factor kappa-B ligand (RANKL), RANK and osteoprotegerin (OPG) in patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The protein expression of RANKL, RANK and OPG was assessed by immunohistochemistry on pretreatment biopsies of 93 patients with locally advanced OSCC who received preoperative chemoradiotherapy (CRT). The primary endpoint was cancer-specific survival. Secondary endpoints were correlation of biomarkers with bone invasion and pathological tumor response. Kaplan-Meier curves and Cox regression models were used for survival analyses. RESULTS: A significantly higher OPG expression was demonstrated in patients with malignant bone invasion and non-responders to CRT as compared to patients without bone invasion and responders (p=0.032 and p=0.033, respectively). Multivariate analysis revealed that higher OPG expression was independently associated with shorter cancer-specific survival (p=0.04). The expression status of RANKL and RANK was not significantly related to clinicopathological characteristics and had no impact on survival of OSCC patients. CONCLUSION: Upregulation of OPG expression is associated with bone invasion, poor pathological tumor regression to neoadjuvant CRT, and worse long-term cancer-specific survival in patients with locally advanced OSCC. Our results indicate that OPG may be a novel prognostic biomarker in oral cancer.
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Neoplasias Óseas/patología , Carcinoma de Células Escamosas/patología , Neoplasias de la Boca/patología , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/metabolismo , Neoplasias Óseas/terapia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Femenino , Humanos , Masculino , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/terapia , Pronóstico , Análisis de SupervivenciaRESUMEN
Current endoscopic anatomy interposes the gastric cardia between the tubular oesophagus and the proximal stomach. In contrast to that, recent evidence unfolds a different view. Using "PubMed" and "Scopus" searches, we examined if the novel understanding regarding the cardia goes in line with the concept of unfolding, as described by Heidegger based on the ancient didactic poetry of Parmenides. What has been taken as gastric cardia in fact represents reflux-damaged, dilated, columnar lined oesophagus (CLO): dilated distal oesophagus (DDO). Due to its macroscopic gastric appearance it cannot be discriminated from the stomach by endoscopy. Differentiation between DDE and proximal stomach requires the histopathology of measured multi-level biopsies obtained from the DDO and the proximal stomach. Cardaic, onxytocardiac mucosa and intestinal metaplasia (IM; Barrett's oesophagus) define CLO and thus the oesophageal location, while oxyntic mucosa (OM) of the proximal stomach verifies a gastric biopsy location. Endoscopically visible CLO and DDO define the morphological manifestation of reflux: the squamo-oxyntic gap (SOG). Biopsies obtained from the level of the diaphragmatic impressions allow differentiation between an enlarged hiatus with normal anatomic content (CLO; oesophagus) vs. hernia with abnormal content (OM; stomach). Non-dysplastic Barrett's oesophagus exists in 10â%-17â% of asymptomatic and in 20â%-100â% (with increasing CLO length) of reflux symptom-positive individuals (annual cancer risk: 0.2â%-0.7â%). These data justify biopsy of an endoscopically normal appearing squamocolumnar junction for the exclusion of Barrett's oesophagus and cancer risk. In the absence of contraindications, cancer risk-based therapy of dysplastic Barrett's oesophagus includes radiofrequency ablation (RFA) ± endoscopic resection. The perception of the cardia as reflux damaged DDO mirrors the concept of unfolding, as described by the interpretation of the didactic poem of Parmenides by Heidegger. Our data recommend to omit the term "cardia" and allocate morphology either to the oesophagus (CLO, DDO) or to the proximal stomach or indicate that allocation is impossible (i.âe.. tumour-induced). Future studies will have to test the value of this novel concept for diagnosis, treatment of gastro-oesophageal reflux disease and cancer prevention.
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Cardias/patología , Endoscopía Gastrointestinal/métodos , Esófago/patología , Reflujo Gastroesofágico/clasificación , Reflujo Gastroesofágico/patología , Terminología como Asunto , Humanos , InternacionalidadRESUMEN
BACKGROUND: Vaccines consisting of allergen-derived peptides lacking IgE reactivity and allergen-specific T cell epitopes bound to allergen-unrelated carrier molecules have been suggested as candidates for allergen-specific immunotherapy. OBJECTIVE: To study whether prophylactic and therapeutic vaccination with carrier-bound peptides from the major birch pollen allergen Bet v 1 lacking allergen-specific T cell epitopes has influence on Bet v 1-specific T cell responses. METHODS: Three Bet v 1-derived peptides, devoid of Bet v 1-specific T cell epitopes, were coupled to KLH and adsorbed to aluminium hydroxide to obtain a Bet v 1-specific allergy vaccine. Groups of BALB/c mice were immunized with the peptide vaccine before or after sensitization to Bet v 1. Bet v 1- and peptide-specific antibody responses were analysed by ELISA. T cell and cytokine responses to Bet v 1, KLH, and the peptides were studied in proliferation assays. The effects of peptide-specific and allergen-specific antibodies on T cell responses and allergic lung inflammation were studied using specific antibodies. RESULTS: Prophylactic and therapeutic vaccination with carrier-bound Bet v 1 peptides induced a Bet v 1-specific IgG antibody response without priming/boosting of Bet v 1-specific T cells. Prophylactic and therapeutic vaccination of mice with the peptide vaccine induced Bet v 1-specific antibodies which suppressed Bet v 1-specific T cell responses and allergic lung inflammation. CONCLUSION AND CLINICAL RELEVANCE: Vaccination with carrier-bound allergen-derived peptides lacking allergen-specific T cell epitopes induces allergen-specific IgG antibodies which suppress allergen-specific T cell responses and allergic lung inflammation.
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Anticuerpos Neutralizantes/inmunología , Antígenos de Plantas/farmacología , Betula , Epítopos de Linfocito T/farmacología , Péptidos/farmacología , Rinitis Alérgica Estacional , Vacunación , Vacunas/farmacocinética , Adyuvantes Inmunológicos/farmacología , Hidróxido de Aluminio/farmacología , Animales , Antígenos de Plantas/inmunología , Epítopos de Linfocito T/inmunología , Femenino , Ratones , Ratones Endogámicos BALB C , Péptidos/inmunología , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/prevención & control , Vacunas/inmunologíaRESUMEN
We evaluated p16INK4A as a reliable option to detect human papilloma virus (HPV) DNA in penile tumor specimens. Formalin-fixed paraffin embedded samples of 26 patients with penile cancer and another 18 cases with non-tumorigenic lesions were stained by three different widely used commercially available chromogenic in-situ hybridization assays high-risk HPV CISH Y1443 (Genpoint, DAKO), pan HPV CISH Y1404 (Genpoint, DAKO), INFORM HPV III (Ventana, Tucson, Arizona) and p16INK4A immunohistochemistry, then compared to the known gold standard polymerase chain reaction detecting HPV 16, 18, 31, and 33. Immunoreactivity for p16INK4A was evaluated by using a 4-tiered (0, 1, 2, and 3) pattern based system. 19 cases were positive for p16INK4A, 13 of which showed a continuous transepithelial staining (pattern 3). Pan HPV ISH showed positivity in 9 cases, high-risk HPV ISH in 7 cases and INFORM HPVIII ISH in 7 cases. p16INK4A IHC pattern 3 versus pattern 0, 1 and 2 exhibited a specificity and positive predictive value of 100 percent, with a sensitivity and negative predictive value of 72 and 62 percent, respectively, which was much better than all HPV in-situ hybridization methods referred to polymerase chain reaction. p16INK4A seems to be a superior marker for the detection of HPV-associated penile squamous cell carcinoma compared to CISH tests, but is not recommend for the detection of non-tumorigenic lesions, where PCR should be used for the initial assessment.
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Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/diagnóstico , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , ADN Viral/análisis , Pruebas de ADN del Papillomavirus Humano , Inmunohistoquímica , Hibridación in Situ , Papillomaviridae/genética , Infecciones por Papillomavirus/diagnóstico , Neoplasias del Pene/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana Edad , Papillomaviridae/clasificación , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Neoplasias del Pene/química , Neoplasias del Pene/patología , Neoplasias del Pene/virología , Reacción en Cadena de la Polimerasa , Valor Predictivo de las PruebasRESUMEN
OBJECTIVE: The hepatocellular carcinoma-related protein 1 (HCRP1) is a key factor in the degradation of the epidermal growth factor receptor. In this study, we assessed the prognostic significance of HCRP1 expression in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). METHODS: HCRP1 expression was determined by immunohistochemistry on tissue biopsy sections of 111 patients with locally advanced OOSCC undergoing neoadjuvant chemoradiotherapy followed by surgery. The Kaplan-Meier method and Cox regression models were used for survival analyses. RESULTS: Low HCRP1 expression was associated with poor recurrence-free survival (P = 0.046) and overall survival (P = 0.03). Multivariate analysis revealed that low HCRP1 expression remained an independent risk factor for relapse (HR 2.98, 95% CI 1.19-7.49, P = 0.02) and death (HR 3.04, 95% CI 1.19-7.79, P = 0.02). CONCLUSION: Low HCRP1 expression was found to be of adverse prognostic significance in patients with OOSCC who received preoperative chemoradiotherapy.
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Carcinoma de Células Escamosas/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Neoplasias de la Boca/genética , Neoplasias Orofaríngeas/genética , Adulto , Anciano , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/terapia , Quimioradioterapia , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/terapia , Neoplasias Orofaríngeas/mortalidad , Neoplasias Orofaríngeas/terapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: The prognostic value of KRAS mutation in patients with colorectal cancer liver metastases (CLM) receiving neoadjuvant chemotherapy including bevacizumab before liver resection is unclear. METHODS: The KRAS and BRAF status of resected CLM was assessed in prospectively studied patients. Mutations were correlated with recurrence-free and overall survival. Only patients with remaining vital tumour cells in the resected specimen and those without disease progression were analysed; those with progressive disease did not undergo resection. RESULTS: A total of 60 patients were enrolled. Fifteen (25 per cent) had a KRAS mutation, but none of the 60 patients had a BRAF mutation. The radiological response to neoadjuvant chemotherapy including bevacizumab, assessed according to the Response Evaluation Criteria In Solid Tumours, was partial in 52 patients (87 per cent) and the remaining eight had stable disease. The partial response rate was similar in patients with a KRAS mutation and those with the wild-type gene (12 of 15 versus 40 of 45 patients; P = 0·400). KRAS mutation had a negative prognostic effect on recurrence-free survival (hazard ratio (HR) 2·48, 95 per cent confidence interval 1·26 to 4·89; P = 0·009) and overall survival (HR 3·51, 1·30 to 9·45; P = 0·013). CONCLUSION: This study provided further evidence for the prognostic importance of KRAS status in terms of recurrence-free and overall survival. Neoadjuvant chemotherapy including bevacizumab elicited a response, irrespective of KRAS status, in this selected group of patients with CLM.
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Neoplasias Colorrectales/genética , Genes ras/genética , Neoplasias Hepáticas/secundario , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Quimioterapia Adyuvante , Femenino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Estudios ProspectivosRESUMEN
A novel approach to the design of a semantic, low-dimensional, encoding for endoscopic imagery is proposed. This encoding is based on recent advances in scene recognition, where semantic modeling of image content has gained considerable attention over the last decade. While the semantics of scenes are mainly comprised of environmental concepts such as vegetation, mountains or sky, the semantics of endoscopic imagery are medically relevant visual elements, such as polyps, special surface patterns, or vascular structures. The proposed semantic encoding differs from the representations commonly used in endoscopic image analysis (for medical decision support) in that it establishes a semantic space, where each coordinate axis has a clear human interpretation. It is also shown to establish a connection to Riemannian geometry, which enables principled solutions to a number of problems that arise in both physician training and clinical practice. This connection is exploited by leveraging results from information geometry to solve problems such as (1) recognition of important semantic concepts, (2) semantically-focused image browsing, and (3) estimation of the average-case semantic encoding for a collection of images that share a medically relevant visual detail. The approach can provide physicians with an easily interpretable, semantic encoding of visual content, upon which further decisions, or operations, can be naturally carried out. This is contrary to the prevalent practice in endoscopic image analysis for medical decision support, where image content is primarily captured by discriminative, high-dimensional, appearance features, which possess discriminative power but lack human interpretability.
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Algoritmos , Inteligencia Artificial , Endoscopía/métodos , Interpretación de Imagen Asistida por Computador/métodos , Imagenología Tridimensional/métodos , Reconocimiento de Normas Patrones Automatizadas/métodos , Humanos , Aumento de la Imagen/métodos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Rare diseases with similar clinical presentation as more frequent gastrointestinal disorders might be challenging in the diagnostic and therapeutic management. In this case we report on a 47-year-old woman who was thought to suffer from Crohn's disease. Symptoms, macroscopic and histological aspects of the gastrointestinal tract, treatment response and clinical course had encouraged the wrong diagnosis over a period of 23 years. After the patient died in the context of a sudden clinical deterioration, fibromuscular dysplasia of the aorta was finally unmasked by post-mortem examination as underlying cause of all symptoms attributed to Crohn's disease. Re-evaluation of former diagnostic procedures revealed subtle aspects of fibromuscular dysplasia, even in biopsy samples from 23 years ago. This first case report of fibromuscular dysplasia of the aorta documents a rare pitfall in the diagnostic workup of a frequent clinical presentation in gastroenterology.
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Aorta/patología , Enfermedad de Crohn/diagnóstico , Errores Diagnósticos , Displasia Fibromuscular/diagnóstico , Autopsia , Enfermedad de Crohn/terapia , Diagnóstico Diferencial , Resultado Fatal , Femenino , Displasia Fibromuscular/patología , Humanos , Persona de Mediana Edad , Factores de TiempoRESUMEN
In this work we propose a method to extract shape-based features from endoscopic images for an automated classification of colonic polyps. This method is based on the density of pits as used in the pit pattern classification scheme which is commonly used for the classification of colonic polyps. For the detection of pits we employ a noise-robust variant of the LBP operator. To be able to be robust against local texture variations we extend this operator by an adaptive thresholding. Based on the detected pit candidates we compute a Delaunay triangulation and use the edge lengths of the resulting triangles to construct histograms. These are then used in conjunction with the k-NN classifier to classify images. We show that, compared to a previously developed method, we are not only able to almost always get higher classification results in our application scenario, but that the proposed method is also able to significantly outperform the previously developed method in terms of the computational demand.
Asunto(s)
Pólipos del Colon/diagnóstico , Colonoscopía/métodos , Anciano , Algoritmos , Automatización , Pólipos del Colon/patología , Simulación por Computador , Endoscopios , Endoscopía/métodos , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Informática Médica , Persona de Mediana Edad , Modelos Estadísticos , Distribución Normal , Reconocimiento de Normas Patrones Automatizadas/métodos , Pólipos , Reproducibilidad de los ResultadosRESUMEN
In this work we propose a novel method to describe local texture properties within color images with the aim of automated classification of endoscopic images. In contrast to comparable Local Binary Patterns operator approaches, where the respective texture operator is almost always applied to each color channel separately, we construct a color vector field from an image. Based on this field the proposed operator computes the similarity between neighboring pixels. The resulting image descriptor is a compact 1D-histogram which we use for a classification using the k-nearest neighbors classifier. To show the usability of this operator we use it to classify magnification-endoscopic images according to the pit pattern classification scheme. Apart from that, we also show that compared to previously proposed operators we are not only able to get competitive classification results in our application scenario, but that the proposed operator is also able to outperform the other methods either in terms of speed, feature compactness, or both.
Asunto(s)
Algoritmos , Pólipos del Colon/patología , Color , Colorimetría/métodos , Endoscopía Gastrointestinal/métodos , Interpretación de Imagen Asistida por Computador/métodos , Reconocimiento de Normas Patrones Automatizadas/métodos , Inteligencia Artificial , Humanos , Aumento de la Imagen/métodos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Some 10-15 per cent of patients with oesophageal cancer overexpress human epidermal growth factor receptor (HER) 2 at the primary tumour site, leading to the hope that specific targeted systemic therapy might favourably influence clinical and subclinical disease at locoregional and distant sites. This approach is based on primary tumour characteristics, without knowledge of expression patterns at metastatic sites. In oesophageal cancer, concordance between HER-2 status at the primary tumour and other sites is unknown. METHODS: The HER-2 status of primary tumours and corresponding metastatic sites (lymph node and distant) and local recurrence were evaluated in a series of patients with oesophageal cancer, using immunohistochemistry and dual colorimetric in situ hybridization. RESULTS: There were 97 adenocarcinomas (ACs) and 79 squamous cell carcinomas (SCCs). Some 14 per cent of primary ACs and 1 per cent of primary SCCs were staged as HER-2-positive. The HER-2 status was identical in the primary tumour and lymph node metastases in 95 per cent of ACs and 99 per cent of SCCs respectively (P = 0·375, sign test). Nineteen of 22 distant metastases from AC and all from SCC had identical HER-2 status to the primary tumour. In two of 22 patients with AC the primary tumour was classed as negative but distant metastases were HER-2-positive. CONCLUSION: With over 85 per cent concordance in HER-2 status between primary tumours and distant metastases in oesophageal cancer, routine HER-2 testing of metastases to confirm HER-2 positivity is not warranted. Assessment of HER-2 status at metastatic sites may be worthwhile in some patients with easily accessible metastases and negative HER-2 status at the primary tumour, or if adequate material cannot be obtained from the primary site.
Asunto(s)
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Genes erbB-2 , Receptor ErbB-2/metabolismo , Adenocarcinoma/metabolismo , Anciano , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Amplificación de Genes/genética , Humanos , Inmunohistoquímica , Metástasis Linfática , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Técnicas de Amplificación de Ácido Nucleico , Estudios ProspectivosRESUMEN
Coinfection with GBV-C/HGV in patients with chronic hepatitis C (CHC) may influence clinical course and response rates of antiviral therapy. Aim of the study was to investigate the prevalence of GBV-C/HGV/HCV coinfection and its influence on outcome of interferon/ribavirin combination therapy. Three hundred and four patients with CHC [m/f = 211/93, age: 42 (18-65)] were investigated. HGV RNA detection was performed by polymerase chain reaction prior to and 6 months after the end of antiviral therapy. HGV/HCV coinfection could be identified in 37/304 (12.2%) patients with intravenous drug abuse as the most common source of infection (N = 21, (56.8%)). The predominant HCV genotype in coinfected individuals was HCV-3a (HCV-3a: 51.4%, HCV-1: 37.8%, HCV-4: 10.8%). HGV coinfection was more prevalent in patients infected with HCV-3 compared to HCV-1 or HCV-4 [19/45 (42.2%) vs. 14/185 (7.6%) vs. 4/52 (7.7%), P < 0.01]. Patients with HGV/HCV coinfection were younger [35 (18-56) vs. 43 (19-65), years; P < 0.01], and advanced fibrosis (F3-F4) was less frequent (22.2% vs. 42.9%, P < 0.05). A sustained virological response was achieved more frequently in HGV/HCV coinfected patients [26/37 (70.3%)] than in monoinfected patients [120/267 (44.9%), P < 0.01]. HGV RNA was undetectable in 65.7% of the coinfected patients at the end of follow-up. Intravenous drug abuse seems to be a major risk factor for HGV coinfection in patients with chronic hepatitis C. Coinfection with HGV does not worsen the clinical course of chronic hepatitis C or diminish response of HCV to antiviral therapy. Interferon/ribavirin combination therapy also clears HGV infection in a high proportion of cases.