RESUMEN
The Nottingham prognostic index plus (NPI+) is based on the assessment of biological class combined with established clinicopathologic prognostic variables providing improved patient outcome stratification for breast cancer superior to the traditional NPI. This study aimed to determine prognostic capability of the NPI+ in predicting risk of development of distant disease. A well-characterised series of 1073 primary early-stage BC cases treated in Nottingham and 251 cases from Budapest were immunohistochemically assessed for cytokeratin (Ck)5/6, Ck18, EGFR, oestrogen receptor (ER), progesterone receptor, HER2, HER3, HER4, Mucin 1 and p53 expression. NPI+ biological class and prognostic scores were assigned using individual algorithms for each biological class incorporating clinicopathologic parameters and investigated in terms of prediction of distant metastases-free survival (MFS). The NPI+ identified distinct prognostic groups (PG) within each molecular class which were predictive of MFS providing improved patient outcome stratification superior to the traditional NPI. NPI+ PGs, between series, were comparable in predicting patient outcome between series in luminal A, basal p53 altered and HER2+/ER+ (p > 0.01) tumours. The low-risk groups were similarly validated in luminal B, luminal N, basal p53 normal tumours (p > 0.01). Due to small patient numbers the remaining PGs could not be validated. NPI+ was additionally able to predict a higher risk of metastases at certain distant sites. This study may indicate the NPI+ as a useful tool in predicting the risk of metastases. The NPI+ provides accurate risk stratification allowing improved individualised clinical decision making for breast cancer.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Adulto , Anciano , Anciano de 80 o más Años , Receptores ErbB/metabolismo , Femenino , Humanos , Queratinas/metabolismo , Persona de Mediana Edad , Mucina-1/metabolismo , Metástasis de la Neoplasia , Pronóstico , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Receptor ErbB-4/metabolismo , Receptores de Estrógenos/metabolismo , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Epithelial-mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-ß signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-ß signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-ß canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-ß signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit.
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Transición Epitelial-Mesenquimal , Proteína de la Leucemia Promielocítica/metabolismo , Neoplasias de la Próstata/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Transporte Activo de Núcleo Celular , Línea Celular Tumoral , Movimiento Celular , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Humanos , Immunoblotting , Estimación de Kaplan-Meier , Carioferinas/genética , Carioferinas/metabolismo , Masculino , Invasividad Neoplásica , Fosforilación , Proteína de la Leucemia Promielocítica/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Proteína Exportina 1RESUMEN
BACKGROUND: Beta-blockers have potential antiangiogenic and antimigratory activity. Studies have demonstrated a survival benefit in patients with malignant melanoma treated with beta-blockers. OBJECTIVES: To investigate the association between postdiagnostic beta-blocker usage and risk of melanoma-specific mortality in a population-based cohort of patients with malignant melanoma. METHODS: Patients with incident malignant melanoma diagnosed between 1998 and 2010 were identified within the U.K. Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with malignant melanoma with a melanoma-specific death (cases) recorded by the Office of National Statistics were matched on year of diagnosis, age and sex to four malignant melanoma controls (who lived at least as long after diagnosis as their matched case). A nested case-control approach was used to investigate the association between postdiagnostic beta-blocker usage and melanoma-specific death and all-cause mortality. Conditional logistic regression was applied to generate odds ratios (ORs) and 95% confidence intervals (CIs) for beta-blocker use determined from general practitioner prescribing. RESULTS: Beta-blocker medications were prescribed after malignant melanoma diagnosis to 20·2% of 242 patients who died from malignant melanoma (cases) and 20·3% of 886 matched controls. Consequently, there was no association between beta-blocker use postdiagnosis and cancer-specific death (OR 0·99, 95% CI 0·68-1·42), which did not markedly alter after adjustment for confounders including stage (OR 0·87, 95% CI 0·56-1·34). No significant associations were detected for individual beta-blocker types, by defined daily doses of use or for all-cause mortality. CONCLUSIONS: Contrary to some previous studies, beta-blocker use after malignant melanoma diagnosis was not associated with reduced risk of death from melanoma in this U.K. population-based study.
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Antagonistas Adrenérgicos beta/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , Neoplasias Cutáneas/mortalidad , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Current management of breast cancer (BC) relies on risk stratification based on well-defined clinicopathologic factors. Global gene expression profiling studies have demonstrated that BC comprises distinct molecular classes with clinical relevance. In this study, we hypothesised that molecular features of BC are a key driver of tumour behaviour and when coupled with a novel and bespoke application of established clinicopathologic prognostic variables can predict both clinical outcome and relevant therapeutic options more accurately than existing methods. METHODS: In the current study, a comprehensive panel of biomarkers with relevance to BC was applied to a large and well-characterised series of BC, using immunohistochemistry and different multivariate clustering techniques, to identify the key molecular classes. Subsequently, each class was further stratified using a set of well-defined prognostic clinicopathologic variables. These variables were combined in formulae to prognostically stratify different molecular classes, collectively known as the Nottingham Prognostic Index Plus (NPI+). The NPI+ was then used to predict outcome in the different molecular classes. RESULTS: Seven core molecular classes were identified using a selective panel of 10 biomarkers. Incorporation of clinicopathologic variables in a second-stage analysis resulted in identification of distinct prognostic groups within each molecular class (NPI+). Outcome analysis showed that using the bespoke NPI formulae for each biological BC class provides improved patient outcome stratification superior to the traditional NPI. CONCLUSION: This study provides proof-of-principle evidence for the use of NPI+ in supporting improved individualised clinical decision making.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/diagnóstico , Toma de Decisiones , Índice de Severidad de la Enfermedad , Adulto , Anciano , Biomarcadores de Tumor/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Femenino , Perfilación de la Expresión Génica , Humanos , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Transcriptoma , Carga TumoralRESUMEN
BACKGROUND: Breast cancer is a heterogeneous disease characterised by complex molecular alterations underlying the varied behaviour and response to therapy. However, translation of cancer genetic profiling for use in routine clinical practice remains elusive or prohibitively expensive. As an alternative, immunohistochemical analysis applied to routinely processed tissue samples could be used to identify distinct biological classes of breast cancer. METHODS: In this study, 1073 archival breast tumours previously assessed for 25 key breast cancer biomarkers using immunohistochemistry and classified using clustering algorithms were further refined using naïve Bayes classification performance. Criteria for class membership were defined using the expression of a reduced panel of 10 proteins able to identify key molecular classes. We examined the association between these breast cancer classes with clinicopathological factors and patient outcome. RESULTS: We confirm patient classification similar to established genotypic biological classes of breast cancer in addition to novel sub-divisions of luminal and basal tumours. Correlations between classes and clinicopathological parameters were in line with expectations and showed highly significant association with patient outcome. Furthermore, our novel biological class stratification provides additional prognostic information to the Nottingham Prognostic Index. CONCLUSION: This study confirms that distinct molecular phenotypes of breast cancer can be identified using robust and routinely available techniques and both the luminal and basal breast cancer phenotypes are heterogeneous and contain distinct subgroups.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de la Mama/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Proteínas de Neoplasias/análisis , Fenotipo , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
BACKGROUND: Epidemiological and laboratory studies suggest that ß-blockers may reduce cancer progression in various cancer sites. The aim of this study was to conduct the first epidemiological investigation of the effect of post-diagnostic ß-blocker usage on colorectal cancer-specific mortality in a large population-based colorectal cancer patient cohort. PATIENTS AND METHODS: A nested case-control analysis was conducted within a cohort of 4794 colorectal cancer patients diagnosed between 1998 and 2007. Patients were identified from the UK Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with a colorectal cancer- specific death (data from the Office of National Statistics death registration system) were matched to five controls. Conditional logistic regression was applied to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) according to ß-blocker usage (data from GP-prescribing records). RESULTS: Post-diagnostic ß-blocker use was identified in 21.4% of 1559 colorectal cancer-specific deaths and 23.7% of their 7531 matched controls, with little evidence of an association (OR = 0.89 95% CI 0.78-1.02). Similar associations were found when analysing drug frequency, ß-blocker type or specific drugs such as propranolol. There was some evidence of a weak reduction in all-cause mortality in ß-blocker users (adjusted OR = 0.88; 95% CI 0.77-1.00; P = 0.04) which was in part due to the marked effect of atenolol on cardiovascular mortality (adjusted OR = 0.62; 95% CI 0.40-0.97; P = 0.04). CONCLUSIONS: In this novel, large UK population-based cohort of colorectal cancer patients, there was no evidence of an association between post-diagnostic ß-blocker use and colorectal cancer-specific mortality. CLINICAL TRIALS NUMBER: NCT00888797.
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Antagonistas Adrenérgicos beta/uso terapéutico , Antihipertensivos/uso terapéutico , Atenolol/uso terapéutico , Neoplasias Colorrectales/mortalidad , Propranolol/uso terapéutico , Antagonistas Adrenérgicos beta/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Antihipertensivos/farmacología , Atenolol/farmacología , Estudios de Casos y Controles , Neoplasias Colorrectales/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Propranolol/farmacología , Estudios Prospectivos , Sistema de Registros , Reino UnidoRESUMEN
Breast cancer mortality is frequently associated with metastatic disease. Metastasis models have shown adrenoceptor (AR) stimulation induces cell migration which is inhibited by adrenoceptor antagonist drugs. We investigated adrenoceptor protein expression in clinical breast tumours and its association with disease progression and prognosis. Immunohistochemistry on tissue microarrays was used to characterise α1b, α2c and ß(2)2 adrenoceptor protein expression in operable breast tumours. Associations with tumour-relevant biological markers and clinical outcome were statistically assessed. Strong α1b expression occurred in large high grade (P < 0.0001), HER2+ (P < 0.0001) or basal-like (CK5/6, P = 0.0005; CK14, P = 0.0001; EGFR, P = 0.003) cancers, showing increased proliferation (Mib1, P = 0.002), decreased apoptosis (Bcl2, P < 0.0001) and poor NPI membership (P = 0.001). α1b expression correlated with poor cancer-specific survival (LR = 7.628, P = 0.022) and tumour recurrence (LR = 6.128, P = 0.047). Strong α2c was over-expressed in high grade (P = 0.007), HER3+ (P = 0.002) and HER4+ (P < 0.0001) cancers with borderline increase in EGFR, p53 and MIB1 proteins, and inverse association with hormonal (PgR, P = 0.002) phenotype. In contrast, strong ß(2) expression occurred in small-size, luminal-like (ER+, P < 0.001) tumours of low grade (P < 0.001) and lymph node stage (P = 0.027) that showed poor prognosis when hormonal treatment was withheld. Adrenoceptors were not found to be independent predictors of clinical outcome. Alpha1b and α2c AR is over-expressed in basal-like breast tumours of poor prognosis. Strong ß(2) adrenoceptor expression is seen in patients with a luminal (ER+) tumour phenotype and good prognosis, due to benefits derived from hormonal therapy. These findings suggest a possible role for targeted therapy using adrenoceptor antagonists.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Adulto , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/secundario , Carcinoma Lobular/mortalidad , Carcinoma Lobular/secundario , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Receptores de Estrógenos/metabolismo , Carga TumoralRESUMEN
Allergy is defined as an immediate hypersensitivity type I immunological disease, which can be IgE or non-IgE driven, and in the latter case may be antibody or cell mediated. Atopy is a term used to describe individuals with a genetic predisposition for developing IgE-mediated allergic disease. But more recently, it has become evident that IgE-mediated disease can occur in non-atopic subjects. While it is now generally accepted that mucosal local IgE has a role in the expression of atopic allergic disease, the concept of 'local allergy' in non-atopic subjects has been proposed, with the term 'entopy' given to this condition. Although there is increasing evidence supporting this paradigm, entopy is only applicable to a proportion of non-atopic patients, suggesting that other disease mechanisms exist to explain non-atopic disease. This review considers the evidence for local mucosal allergy in atopic and non-atopic individuals with an emphasis on diseases affecting the upper airways and eye. Furthermore, the diagnosis, treatment and relationship between local allergy and conventional (systemic) allergy are discussed, and alternative disease mechanisms predominantly involving antibodies or their sub-components (free light chain Igs) are postulated to explain the 'entopy' paradigm. This review is intended to provide an improved understanding of the mechanisms and causes of local mucosal hypersensitivity.
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Hipersensibilidad Inmediata/inmunología , Membrana Mucosa/inmunología , Linfocitos B/inmunología , Humanos , Inmunoglobulina E/metabolismo , Células Th2/inmunologíaRESUMEN
The basal-like or basal phenotype (BP) class of breast cancers have recently attracted attention as a poor prognostic form of breast cancer. However, BP appears to encompass biologically and clinically heterogeneous tumours, resulting in a lack of consensus definition of BP. We analysed 48,000 gene transcripts in 132 invasive breast carcinomas to identify two novel genes (OATP2 and FABP7) significantly associated with BP [defined by cytokeratin (CK)5/6 and/or CK14 positivity]. Using a series of invasive breast carcinoma cases (n = 899), prepared as tissue microarrays, we assessed OATP2 and FABP7 protein expression using immunohistochemistry to investigate associations with clinicopathological variables, patients' outcome and ability to refine BP classification. A total of 7.9 and 15.6% cases were OATP2 and FABP7 positive, respectively. OATP2 was associated with tumours of high histological grade (p < 0.01), ER and PgR negativity (p < 0.01) and shorter breast cancer-specific survival (p = 0.04). FABP7 expression was associated with lower lymph node stage (p < 0.01), ER and PgR negativity (p < 0.01). BP tumours which were FABP7 positive had a significantly longer BCSS (p = 0.05) and disease-free survival (p = 0.01) compared with FABP7 negative basal tumours (p < 0.01). OATP2 positive tumours were associated with adverse survival and increased risk of early recurrence. This study confirms the biological and clinical heterogeneity of the BP in breast cancer. We have identified a novel subgroup of basal tumours showing FABP7 expression that have significantly better clinical outcome. Further studies analysing the role of FABP7 are therefore warranted.
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Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteínas Portadoras/biosíntesis , Transportador 1 de Anión Orgánico Específico del Hígado/biosíntesis , Proteínas Supresoras de Tumor/biosíntesis , Adulto , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/genética , Proteínas Portadoras/genética , Supervivencia sin Enfermedad , Proteína de Unión a los Ácidos Grasos 7 , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Persona de Mediana Edad , Estadificación de Neoplasias , Fenotipo , Pronóstico , Análisis de Matrices Tisulares , Resultado del Tratamiento , Proteínas Supresoras de Tumor/genéticaRESUMEN
Gene expression microarrays allow for the high throughput analysis of huge numbers of gene transcripts and this technology has been widely applied to the molecular and biological classification of cancer patients and in predicting clinical outcome. A potential handicap of such data intensive molecular technologies is the translation to clinical application in routine practice. In using an artificial neural network bioinformatic approach, we have reduced a 70 gene signature to just 9 genes capable of accurately predicting distant metastases in the original dataset. Upon validation in a follow-up cohort, this signature was an independent predictor of metastases free and overall survival in the presence of the 70 gene signature and other factors. Interestingly, the ANN signature and CA9 expression also split the groups defined by the 70 gene signature into prognostically distinct groups. Subsequently, the presence of protein for the principal prognosticator gene was categorically assessed in breast cancer tissue of an experimental and independent validation patient cohort, using immunohistochemistry. Importantly our principal prognosticator, CA9, showed that it is capable of selecting an aggressive subgroup of patients who are known to have poor prognosis.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , Metástasis de la Neoplasia/genética , Redes Neurales de la Computación , Adulto , Anciano , Antígenos de Neoplasias/biosíntesis , Área Bajo la Curva , Neoplasias de la Mama/patología , Anhidrasa Carbónica IX , Anhidrasas Carbónicas/biosíntesis , Biología Computacional/métodos , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Pronóstico , Curva ROC , Sensibilidad y Especificidad , Análisis de Matrices TisularesRESUMEN
MicroRNAs (miRNAs) are a highly abundant class of endogenous small non-coding RNAs (18-25 nucleotides in length) that regulate gene expression by targeting protein-coding mRNAs post-transcriptionally. miRNAs have been implicated in cancer development and progression. As miRNAs and their regulatory functions are further revealed, the more the importance of miRNA-directed gene regulation is emphasised. In the human genome, 695 mature miRNAs have been identified, although computational calculation predicts that this may increase to >1000. Deregulation of miRNA expression profiles is thought to be implicated in the pathogenesis of many human cancers including breast tumours. Breast cancer subtypes are observed to have deranged miRNA expression signatures, which makes miRNAs important targets for developing a novel molecular classification of breast cancer and opening avenues for more individualised treatment strategies for patients with breast cancer.
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Neoplasias de la Mama/genética , MicroARNs/genética , ARN Mensajero/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/diagnóstico , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , PronósticoRESUMEN
Caveolin-1 (CAV1) and caveolin 2 (CAV2) are the principal structural proteins of caveolae, sphingolipid and cholesterol-rich invaginations of the plasma membrane involved in vesicular trafficking and signal transduction. Over the recent years there has been controversy about their role in breast cancer and their suitability as markers of basal-like phenotype. Caveolin-1 and CAV2 protein expression was assessed on a tissue microarray containing 880 unselected invasive breast cancer cases, by means of immunohistochemistry. Caveolin-1 and CAV2 expression was observed in 13.4 and 5.9% of all breast cancer, respectively. Their expression was strongly associated with high histological grade, lack of steroid hormone receptor positivity (ER and PR), and expression of basal markers (basal cytokeratins, P63, P-cadherin). Furthermore, there was a significant association between CAV1 and CAV2 expression and basal-like phenotype. On univariate analysis only CAV2 had a prognostic impact on breast cancer-specific survival; however, this was not independent from other traditional markers on multivariate analysis. Our results demonstrate that both CAV1 and CAV2 are associated with basal-like phenotype. Further studies are warranted to determine whether they play an oncogenic role in basal-like/triple-negative breast cancer development or are just surrogate markers for this subgroup.
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Biomarcadores de Tumor/biosíntesis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Caveolina 1/biosíntesis , Caveolina 2/biosíntesis , Humanos , Inmunohistoquímica , Inmunofenotipificación , Invasividad Neoplásica , Estadificación de Neoplasias , PronósticoRESUMEN
This study investigated sonic hedgehog (Shh) signalling in gastric metaplasia in the insulin-gastrin (InsGas) hypergastrinaemic mouse +/- Helicobacter felis (H. felis) infection. Sonic hedgehog gene and protein expression was reduced in pre-metaplastic lesions from non-infected mice (90% gene reduction, P<0.01) compared to normal mucosa. Sonic hedgehog was reactivated in gastric metaplasia of H. felis-infected mice (3.5-fold increase, P<0.01) compared to pre-metaplastic lesions. Additionally, the Shh target gene, glioma-associated oncogene (Gli)-1, was significantly reduced in the gastric glands of InsGas mice (75% reduction, P<0.05) and reactivated with H. felis infection (P<0.05, base of glands, P<0.01 stroma of metaplastic glands). The ability of H. felis to activate the Shh pathway was investigated by measuring the effect of target cytokine, interleukin-8 (IL-8), on Shh expression in AGS and MGLVA1 cells, which was shown to induce Shh expression at physiological concentrations. H. felis induced the expression of NF-kappaB in inflammatory infiltrates in vivo, and the expression of the IL-8 mouse homologue, protein KC, in inflammatory infiltrates and metaplastic lesions. Sonic hedgehog pathway reactivation was paralleled with an increase in proliferation of metaplastic lesions (15.75 vs 4.39% in infected vs non-infected mice, respectively, P<0.001). Furthermore, Shh overexpression increased the growth rate of the gastric cancer cell line, AGS. The antiapoptotic protein, bcl-2, was expressed in the stroma of infected mice, along with a second Shh target gene, patched-1 (P=0.0001, stroma of metaplastic gland). This study provides evidence suggesting reactivation of Shh signalling from pre-metaplastic to advanced metaplastic lesions of the stomach and outlines the importance of the Shh pathway as a potential chemoprophylactic target for gastric carcinogenesis.
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Proteínas Hedgehog/genética , Adenocarcinoma , Animales , Línea Celular Tumoral , Mucosa Gástrica/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Reacción en Cadena de la Polimerasa , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
Prognostic signatures in breast cancer derived from microarray expression profiling have been reported by two independent groups. These signatures, however, have not been validated in external studies, making clinical application problematic. We performed microarray expression profiling of 135 early-stage tumors, from a cohort representative of the demographics of breast cancer. Using a recently proposed semisupervised method, we identified a prognostic signature of 70 genes that significantly correlated with survival (hazard ratio (HR): 5.97, 95% confidence interval: 3.0-11.9, P = 2.7e-07). In multivariate analysis, the signature performed independently of other standard prognostic classifiers such as the Nottingham Prognostic Index and the 'Adjuvant!' software. Using two different prognostic classification schemes and measures, nearest centroid (HR) and risk ordering (D-index), the 70-gene classifier was also found to be prognostic in two independent external data sets. Overall, the 70-gene set was prognostic in our study and the two external studies which collectively include 715 patients. In contrast, we found that the two previously described prognostic gene sets performed less optimally in external validation. Finally, a common prognostic module of 29 genes that associated with survival in both our cohort and the two external data sets was identified. In spite of these results, further studies that profile larger cohorts using a single microarray platform, will be needed before prospective clinical use of molecular classifiers can be contemplated.
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Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , Neoplasias de la Mama/mortalidad , Estudios de Cohortes , Femenino , Humanos , Pronóstico , Análisis por Matrices de Proteínas , Reproducibilidad de los Resultados , Análisis de SupervivenciaRESUMEN
In this review, we critically evaluate the evidence for local IgE production in allergic rhinitis mucosa and the concept of local allergy in non-atopic idiopathic rhinitis. Significantly, fewer studies have focused on the disease pathways associated with non-allergic rhinitis compared with their allergic counterparts. Recently, there's been a revival of the hypothesis concerning the existence of local tissue-specific allergic disease confined to the nasal mucosa of some systemically non-atopic rhinitis subjects. Providing the evidence for local mucosal IgE production in allergic rhinitis is a pre-requisite to reviewing its existence in non-allergic rhinitis. In addition, practical and theoretical approaches useful in the detection of allergy in non-allergic rhinitis will be discussed. Furthermore, successful therapeutic regimens used in the treatment of non-allergic rhinitis will be examined as these could provide an insight into the underlying pathophysiology of this common but poorly understood disease.
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Inmunoglobulina E/inmunología , Mucosa Nasal/inmunología , Rinitis/inmunología , Alérgenos/inmunología , Humanos , Pruebas Inmunológicas/métodos , Mediadores de Inflamación/inmunología , Rinitis Alérgica Perenne/inmunologíaRESUMEN
The aim of this study was to assess the morphological characteristics and immunohistochemical profile of breast carcinomas with basal and myoepithelial phenotypes to obtain a better understanding of their biological behaviour and nature. One thousand nine hundred and forty-four invasive breast carcinomas were examined, using tissue microarray (TMA) technology and immunohistochemistry, to identify those tumours that showed basal and myoepithelial phenotypes, and their immunophenotype profile was characterized using a variety of markers. In addition, haematoxylin and eosin-stained sections of these tumours were studied for several morphological parameters. The findings were correlated with patient and tumour characteristics and outcome data. Tumours were classified into two groups: (1) tumours with basal phenotype [expressing one or both basal markers (CK5/6 and/or CK14)] and (2) tumours with myoepithelial phenotype (expressing SMA and/or p63). Group 1 was further subdivided into two subgroups: (A) dominant basal pattern (more than 50% of cells positive) and (B) basal characteristics (10-50% of cells positive). Group 1 tumours constituted 18.6% (8.6% and 10% for groups 1A and 1B, respectively) and group 2 constituted 13.7% of the cases. In both groups, the most common histological types were ductal/no specific type, tubular mixed and medullary-like carcinomas; the majority of these tumours were grade 3. There were positive associations with adenoid cystic growth pattern, loss of tubule formation, marked cellular pleomorphism, poorer Nottingham prognostic index, and development of distant metastasis. In addition, associations were found with loss of expression of steroid hormone receptors and FHIT proteins and positive expression of p53 and EGFR. The most common characteristics in group 1 were larger size, high-grade comedo-type necrosis, development of tumour recurrence, and absence of lymph node disease. Group 2 tumours were more common in younger patients and were associated with central acellular zones, basaloid change, and positive E-cadherin protein expression. Group 1 characteristics were associated with both reduced overall survival (OS) [log rank (LR) = 22.5, p < 0.001] and reduced disease-free interval (DFI) (LR = 30.1, p < 0.001), while group 2 characteristics showed an association with OS (LR = 5, p = 0.02) but not with DFI. Multivariate analysis showed that basal, but not myoepithelial, phenotype has an independent value in predicting outcome. Breast cancers with basal and myoepithelial phenotypes are distinct groups of tumours that share some common morphological features and an association with poor prognosis. The basal rather than the myoepithelial phenotype has the strongest relationship with patient outcome.
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Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Mioepitelioma/patología , Neoplasias Basocelulares/patología , Actinas/genética , Adulto , Factores de Edad , Anciano , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Cadherinas/análisis , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidad , Diferenciación Celular , Supervivencia sin Enfermedad , Receptores ErbB/análisis , Femenino , Genes p53 , Humanos , Inmunohistoquímica , Queratinas/genética , Persona de Mediana Edad , Análisis Multivariante , Mioepitelioma/metabolismo , Mioepitelioma/mortalidad , Necrosis , Neoplasias Basocelulares/inmunología , Neoplasias Basocelulares/mortalidad , Receptores Androgénicos/análisis , Coloración y Etiquetado , Tasa de SupervivenciaRESUMEN
BACKGROUND: Allergic rhinitis is characterized by selective expansion of T cell subsets with a CD4+ phenotype. Recently, we identified a subpopulation of nonallergic rhinitis subjects with increased epithelial mast cell and eosinophil populations, suggestive of local mucosal allergy. Previously, T cell subsets have not been characterized in this subselection of nonallergic subjects and furthermore, their relationship to mast cell and basophil effector cells remain unidentified. OBJECTIVE: To determine if a subpopulation of nonallergic subjects with idiopathic rhinitis (IR) have localized allergy confined to their nasal mucosa by comparing the T cell subsets and major histocompatibility complex (MHC) II expressing cells to persistent allergic rhinitis (PAR). Furthermore, the relationship between T cell subsets and mast cells/basophils was investigated. METHODS: None of the symptomatic patients in this study were clinically allergen-challenged. Nasal turbinate mucosa was removed from patients with PAR, IR and normal controls. Morphometry was performed on immunostained sections for T cell subset populations including CD3+, CD4+, CD8+, CD25+, CD45RA+, CD45RO+, human leucocyte antigen (HLA)-DRalpha (MHC class II), mast cell tryptase and for basophils. RESULTS: Subjects with persistent allergic rhinitis differed to normal controls in showing significantly increased numbers of total (CD3+), activated (CD25+) and allergen-naïve (CD45RA+) T lymphocytes in their nasal mucosa (P < 0.025). The naïve CD45RA+ memory T cells correlated to mucosal mast cells in PAR (P = 0.03). IR patients differ to allergic subjects in showing significantly reduced numbers of epithelial HLA-DRalpha+ cells (P = 0.007), but increased numbers of CD8+ lymphocytes (P = 0.02). The CD8+ T cells correlated with mucosal mast cell numbers (P = 0.02). In both rhinitis groups, basophils were present in very low numbers obviating the need for statistical analysis. CONCLUSION: PAR is characterized by increased numbers of CD3+, CD25+ and CD45RA+ T lymphocytes compared with normal mucosa. Allergic and nonallergic rhinitis groups can be separated by significant differences in the number of epithelial antigen presenting cells (APCs) (HLA-DRalpha+) and sub-epithelial activated (CD25+) T cells. Moreover, IR patients do not significantly differ to their allergic counterparts with respect to total (CD3+) and naïve (CD45RA+) T cell numbers, or numbers of epithelial activated (CD25+) lymphocytes. IR subjects show significantly increased numbers of CD8+ lymphocytes compared with control mucosa and although our findings suggest that the initiating inflammatory events may differ, both rhinitis groups show a similarity in pathology involving mucosal mast cells with an association to infiltrating T cells.
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Mastocitos/patología , Mucosa Nasal/inmunología , Rinitis Alérgica Perenne/inmunología , Rinitis/inmunología , Subgrupos de Linfocitos T , Adolescente , Adulto , Células Presentadoras de Antígenos/patología , Basófilos/patología , Recuento de Células , Epitelio/inmunología , Antígenos HLA-DR/análisis , Humanos , Inmunofenotipificación , Complejo Mayor de Histocompatibilidad , Persona de Mediana Edad , Mucosa Nasal/patología , Rinitis/patología , Rinitis Alérgica Perenne/patologíaRESUMEN
BACKGROUND: The Th2 immune response in the nasal mucosa of subjects with allergic rhinitis is mediated by allergen-specific IgE. Moreover, these subjects show positive responses for markers of systemic atopy, including allergen-specific skin sensitivity and raised serum IgE titres. In contrast, idiopathic rhinitis (IR) subjects with similar histological nasal mucosal features differ in being defined as non-allergic because they have negative atopic responses. OBJECTIVE: We hypothesized that it is possible to have an allergic Th2 disease pathway localized in the nasal mucosa of 'non-allergic' rhinitis subjects despite an absence of atopic responses. METHODS: The presence of house dust mite and grass pollen-specific IgE antibodies was investigated in non-atopic (n=10) and atopic (n=11) subjects with persistent rhinitis and compared to normal (n=12) control subjects. Biotin-labelled allergen was used to localize specific allergen-binding antibodies in situ in sections of nasal mucosa. RESULTS: Grass pollen allergen binding was detected in the nasal mucosa of 3/10 non-atopic IR subjects but, in contrast, dust mite-specific antibodies were not detected. Specific antibodies were present in a total of 8/11 mucosal samples from the allergic group, but none was detected in normal control tissues. CONCLUSION: These findings support the concept of localized nasal allergy in 'non-atopic' rhinitis subjects. We propose the term 'entopy' to define this phenomenon and believe that this concept has a wider implication for localized allergic responses in other mucosal sites.
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Mucosa Nasal/inmunología , Rinitis/inmunología , Adolescente , Adulto , Alérgenos/inmunología , Animales , Linfocitos B/inmunología , Femenino , Humanos , Inmunoglobulina E/sangre , Masculino , Mastocitos/inmunología , Persona de Mediana Edad , Ácaros/inmunología , Mucosa Nasal/patología , Células Plasmáticas/inmunología , Polen/inmunología , Rinitis/patología , Rinitis Alérgica Perenne/inmunología , Rinitis Alérgica Perenne/patologíaRESUMEN
Keratinocytes in middle ear cholesteatoma have hyperproliferative properties. There is controversy regarding the role of p53 and its effect on cellular proliferation in cholesteatoma. This study was instituted to examine this. Cholesteatoma and deep meatal skin control specimens were analysed for MIB-1 (n = 7, controls = 7), a marker of cellular proliferation, and p53 (n = 17, controls = 17) expression by immunocytochemistry. Expression of p53 was minimal or absent in both cholesteatoma and controls (P = 0.2). MIB-1 expression was higher, but not significantly so, in cholesteatoma than in controls (P = 0.09). Our study has shown no significant p53 expression in cholesteatoma epithelium. This suggests that there is no dysfunction in the p53-mediated cell cycle control mechanisms in cholesteatoma.