RESUMEN
Acid ceramidase (ASAH1) a key enzyme of sphingolipid metabolism converting pro-apoptotic ceramide to sphingosine has been shown to be overexpressed in various cancers. We previously demonstrated higher expression of ASAH1 in ER positive compared to ER negative breast cancer. In the current study we performed subtype specific analyses of ASAH1 gene expression in invasive and non invasive breast cancer. We show that expression of ASAH1 is mainly associated with luminal A - like cancers which are known to have the best prognosis of all breast cancer subtypes. Moreover tumors with high ASAH1 expression among the other subtypes are also characterized by an improved prognosis. The good prognosis of tumors with high ASAH1 is independent of the type of adjuvant treatment in breast cancer and is also detected in non small cell lung cancer patients. Moreover, even in pre-invasive DCIS of the breast ASAH1 is associated with a luminal phenotype and a reduced frequency of recurrences. Thus, high ASAH1 expression is generally associated with an improved prognosis in invasive breast cancer independent of adjuvant treatment and could also be valuable as prognostic factor for pre-invasive DCIS.
Asunto(s)
Ceramidasa Ácida/biosíntesis , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/mortalidad , Carcinoma Intraductal no Infiltrante/enzimología , Carcinoma Intraductal no Infiltrante/mortalidad , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Intraductal no Infiltrante/tratamiento farmacológico , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Tasa de SupervivenciaRESUMEN
The RANK/RANKL/OPG pathway is well known for bone destruction in skeletal metastases but has also been implicated in osteoclast-independent roles in tumorigenesis and de novo metastasis. Experimental data suggest contribution of progesterone to tumorigenesis may be mediated by RANKL. Importantly, modulation of this pathway became possible through the availability of denosumab, an artificial counterpart of OPG, but significant gaps remain in the translation of preclinical findings on the pathway. We analyzed gene expression of RANK, RANKL and OPG from 40 Affymetrix datasets encompassing 4467 primary breast cancers and focused on ER positive disease. We did not observe a significant prognostic value of RANK and RANKL mRNA expression. In contrast, OPG was associated with a better prognosis among 1941 ER positive cancers (HR 0.64, 95% CI 0.53-0.77; P < 0.0001) using a cutoff from its highly bimodal expression. We detected considerable heterogeneity regarding the prognostic value of OPG between different datasets. This heterogeneity could neither be attributed to technical reasons nor to differences in standard clinical parameters or treatments of the cohorts. Interestingly, the prognostic value of the progesterone receptor and of OPG showed similar cohort specific effects. Still both factors were no surrogates for each other but contributed independent prognostic value in multivariate analyses. Thus, both OPG and PgR are independently associated with good prognosis in ER positive breast cancer. However both markers share common cohort specific differences in contrast to proliferation markers as Ki67 which may be based on the underlying biology.
Asunto(s)
Neoplasias de la Mama/diagnóstico , Mama/patología , Osteoprotegerina/genética , Receptores de Estrógenos/análisis , Receptores de Progesterona/genética , Transcriptoma , Biomarcadores de Tumor/genética , Mama/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Ligando RANK/genética , ARN Mensajero/genética , Receptor Activador del Factor Nuclear kappa-B/genéticaRESUMEN
Acid ceramidase (AC), a key enzyme of sphingolipid metabolism, seems to play an important role in cancer progression. The objective of this study was to explore the expression of AC in ovarian cancer and its impact on prognosis. Expression analysis of AC in n=112 ovarian cancer patients was performed by immunohistochemical analysis of primary paraffin-embedded tumor samples. The results were scored on the basis of the staining intensity and percentage of positive tumor cells, resulting in an immunoreactive score from 0 to 12. These results were correlated to clinical and pathologic characteristics and survival. AC expression correlated significantly only with FIGO stage (0.047). In serous carcinoma, low level of AC was independently associated with reduced progression-free survival and overall survival of 12.0 mo [95% confidence interval (CI), 5.78-18.23] versus 18.1 mo (95% CI, 11.61-24.59; P=0.008) and 35.7 mo (95% CI, 22.24-47.16) versus 58.7 mo (95% CI, 36.48-80.91; P=0.032), respectively. In multivariate analysis, AC presents as an independent prognostic factor for progression-free survival (hazard ratio 1.88; 95% CI, 1.13-3.11; P=0.015). AC is a prognostic factor in epithelial ovarian cancer. Low AC expression can be associated with tumor progression in carcinoma of the ovaries. These results are in contrast to the concept of AC as a promoter for cancer progression. Nevertheless, they are supported by the lately discovered tumor-suppressing function of sphingosine, the enzymatic product of AC.
Asunto(s)
Ceramidasa Ácida/biosíntesis , Biomarcadores de Tumor/análisis , Neoplasias Glandulares y Epiteliales/enzimología , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/mortalidad , Ceramidasa Ácida/análisis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Esfingolípidos/metabolismo , Adulto JovenRESUMEN
OBJECTIVE/AIMS: To investigate the presence of signal ambiguity of intrapartum fetal heart rate (FHR) monitoring during delivery by comparing simultaneous cardiotocogram (CTG), abdominal fetal electrocardiogram (ECG) with continuous maternal ECG. METHODS: A total of 144 simultaneous CTG (Corometrics 250 series), abdominal fetal ECG (Monica -AN24™) and maternal ECG (Monica AN24™) recordings were evaluated. MAIN OUTCOME MEASURES: When the FHR is within 5 bpm of the maternal heart rate (MHR) acquired from the ECG, it is classified as 'MHR/FHR ambiguity'. Statistical analyses were performed with Fisher's exact test and the Wilcoxon signed-rank test. RESULTS: Comparison of abdominal fetal ECG against CTG demonstrates significantly less 'MHR/FHR ambiguity' in both the first stage (mean 0.70 vs. 1.22%, p < 0.001) and second stage of labour (mean 3.30 vs. 6.20%, p < 0.001). CONCLUSION: Intrapartum FHR monitoring in daily practice via the CTG modality provides significantly more 'MHR/FHR ambiguity' than abdominal fetal ECG, which also provides additional information on the MHR.
Asunto(s)
Cardiotocografía/normas , Electrocardiografía/normas , Frecuencia Cardíaca Fetal/fisiología , Femenino , Monitoreo Fetal/métodos , Frecuencia Cardíaca/fisiología , Humanos , Trabajo de Parto/fisiología , Embarazo , Reproducibilidad de los ResultadosRESUMEN
We recently reported that a ratio of high B cell and low IL-8 metagene expression identified 32 % of triple negative breast cancers (TNBC) with good prognosis and was the only significant predictor in multivariate analysis including routine clinicopathological variables. However, the clinical relevance of this signature in other breast cancer subtypes remains unclear. We compiled Affymetrix gene expression datasets from 4,467 primary breast cancer samples and excluded 329 triple negative samples which were used as discovery cohort in our previous study. Molecular classification of the remaining 4,138 samples was performed by two methods, including single genes (ER, PgR, HER2, and Ki67) and a centroid-based method using the intrinsic gene list. The prognostic value within the respective subtypes was assessed by analyzing the event-free survival of patients as a function of the B cell/IL-8 metagene ratio using previously published cutoff. ER-negative subtypes had the highest expression of the B cell and the IL-8 metagenes. The IL-8/B cell signature assigned a considerable fraction of samples (range 20.7-42.0 %) into the "good prognosis" group. However, a significant prognostic value was only observed in the subgroup of triple negative breast cancer (P = 0.035). The prognostic value of the B cell/IL-8 ratio is mainly confined to the basal-like and TNBC subtypes of breast cancer. This result underlines the importance of subtype-specific analyses and suggests a sequential multistep approach to developing and applying outcome predictors in the clinic.
Asunto(s)
Linfocitos B/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Interleucina-8/genética , Neoplasias de la Mama/metabolismo , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
Three to four percent of full-term singleton pregnancies present themselves as breech deliveries. External cephalic version (ECV) is a procedure to try to turn a breech fetus to cephalic by externally maneuvering the fetus through the maternal abdomen. This trial examines a clinical hypnosis intervention against standard medical care of women before ECV. A total of 78 women, who received a hypnosis intervention prior to ECV, had a 41.6% (n = 32) successful ECV, whereas the control group of 122, who had similar baseline characteristics, had a 27.3% (n = 33) successful ECV procedure (p < 0.05). This trial found that a relaxation technique with the help of clinical hypnosis was successful at increasing the likelihood of a successful ECV procedure.
Asunto(s)
Presentación de Nalgas/terapia , Hipnosis/métodos , Versión Fetal/métodos , Adulto , Terapia Combinada , Femenino , Edad Gestacional , Humanos , Embarazo , Resultado del Tratamiento , Versión Fetal/efectos adversosRESUMEN
OBJECTIVE: The objective of this study was to assess the fetal heart rate (FHR) signal quality of non-invasive abdominal fetal electrocardiogram (fECG) in comparison to the Doppler ultrasound cardiotocogram (CTG) during the first and second stage of labour. STUDY DESIGN: This was a prospective observational study of non-invasive fECG using five abdominally sited electrodes against the traditional Doppler ultrasound CTG probe on 144 patients. Data were analysed for signal quality before and after outlier removal. RESULTS: Abdominal fECG signal quality was significantly better during the first stage of labour in comparison to Doppler CTG (median fECG reliability of 95.7 % vs. median 87.3 % for Doppler, p < 0.001), whereas during second stage of labour, equivalence was demonstrated (p > 0.05). For the first and second stage of labour, fECG showed 106/135 (78.5 %) and 46/98 (46.9 %) women having fetal signal loss below 20 %, respectively. Similarly, Doppler ultrasound demonstrated 104/135 (77.0 %) and 51/98 (52.0 %) women having fetal signal loss below 20 % during first and second stage of labour, respectively. CONCLUSION: The non-invasive abdominal fECG presents an improved FHR signal quality during the first stage of labour and an equivalent signal quality during the second stage.