Clinical significance of epithelial-mesenchymal transition-related markers expression in the micrometastatic sentinel lymph node of NSCLC.

OBJECTIVES: Metastatic lymph node affectation is the main prognostic factor in localised lung cancer. However, the pathological study of lymph nodes reveals tumour relapse for 20% of patients after oncological curative surgery. Recently, EMT (epithelial-mesenchymal transition) has been established as one of the main factors related to lymphatic dissemination and metastasis. This study evaluated the prognostic value of EMT-related gene expression in micrometastatic sentinel lymph nodes (SLN) of non-small cell lung cancer (NSCLC) patients. METHODS: The presence of genes CDH1, CDH2, VIM, TWIST1, SNAI1, SNAI2, ZEB1, and ZEB2 in mRNA was analysed in tumours and in the SLN of NSCLC patients for whom surgery was planned for treatment. The significant association between the expression level of EMT-related markers and patients' clinicopathological characteristics and relapse was assessed. RESULTS: Of the 96 patients, 56 (58.33%) presented molecular micrometastasis in SLN, which showed higher CDH1, CDH2, and VIM expressions than non-micrometastatic ones. An association linking a low CDH1/CDH2 ratio in SLN with molecular micrometastasis, adenocarcinoma, and non-smoking patients was found. The multivariate Cox regression analysis proved the prognostic accuracy of the CDH1/CDH2 ratio in SLN. CONCLUSIONS: The molecular EMT status of SLN could be used as an independent prognosis predictor in early stage NSLCL patients, and as a new tool to better stratify and predict patient outcomes.

Topography of the sentinel node according to the affected lobe in lung cancer

Purpose. The objective of this study is to describe the anatomic location of the sentinel lymph node (SLN) of patients with lung carcinoma and to analyze its relationship with the characteristics of the tumor. Patients and methods. 98 Stage I lung cancer patients were included in the study. SLN was marked just after performing the thoracotomy by injecting peritumorally 0.25 mCi of nanocolloid of albumin (Nanocol1) labeled with Tc-99 m in 0.3 ml, and later, it was resected. For SLN micrometastasis analysis, CEACAM5, BPIFA1, and CK7 gene expression at mRNA level was studied. Possible relation between tumor characteristics and SLN location was analyzed. Results. While most of the SLN were located in hilar area, we find a significantly higher number of SLN located in mediastinal stations when the lesion is in the left upper lobe (LUL). This difference disappears in the group of SLN with a positive result in the micrometastasis study. Regarding tumor size, squamous tumors and tumors located in the left lower lobe (LLL) were found significantly larger. Conclusion. The location of the SLN in patients with stage I lung cancer is predominantly hilar, being less consistent in the left hemithorax. The tumor size or histological type is not variables that affect this distribution. The distribution of SLNs with a positive result in the analysis of micrometastasis suggests further spread to the hilar areas when the lesion is in the LUL and to the mediastinal zones when it is in the LLL (AU)

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Topography of the sentinel node according to the affected lobe in lung cancer.

PURPOSE: The objective of this study is to describe the anatomic location of the sentinel lymph node (SLN) of patients with lung carcinoma and to analyze its relationship with the characteristics of the tumor. PATIENTS AND METHODS: 98 Stage I lung cancer patients were included in the study. SLN was marked just after performing the thoracotomy by injecting peritumorally 0.25 mCi of nanocolloid of albumin (Nanocol1) labeled with Tc-99 m in 0.3 ml, and later, it was resected. For SLN micrometastasis analysis, CEACAM5, BPIFA1, and CK7 gene expression at mRNA level was studied. Possible relation between tumor characteristics and SLN location was analyzed. RESULTS: While most of the SLN were located in hilar area, we find a significantly higher number of SLN located in mediastinal stations when the lesion is in the left upper lobe (LUL). This difference disappears in the group of SLN with a positive result in the micrometastasis study. Regarding tumor size, squamous tumors and tumors located in the left lower lobe (LLL) were found significantly larger. CONCLUSION: The location of the SLN in patients with stage I lung cancer is predominantly hilar, being less consistent in the left hemithorax. The tumor size or histological type is not variables that affect this distribution. The distribution of SLNs with a positive result in the analysis of micrometastasis suggests further spread to the hilar areas when the lesion is in the LUL and to the mediastinal zones when it is in the LLL.

Síndrome de Phelan-McDermid: un caso clínico con una deleción de 1, 7 Mb en 22q13.3 / Phelan-McDermid syndrome: a case with a 1.7 Mb deletion in 22q13.3

Introducción: El síndrome de Phelan-McDermid está producido por una microdeleción en la región 22q13.3. Esta microdeleción se ve asociada a una gran variabilidad fenotípica, y recientemente se ha sugerido una correlación entre el tamaño de la deleción y la gravedad de la sintomatología. Caso clínico: En el presente trabajo describimos el caso clínico de un niño atendido en nuestro hospital con un importante retraso en el área del lenguaje y el aprendizaje, en el que se realizó un análisis genético mediante MLPA (multiplex ligation-dependent probe amplification) y microarray. Resultados: Se detectó en el paciente una deleción terminal de 1,7 Mb en el cromosoma 22 con una pérdida de los genes ARSA-1, SHANK3 y RABL2B. Conclusión: El análisis de las microdeleciones en el cromosoma 22q13.3 mediante la técnica de microarray permite determinar qué genes están afectados en los casos de síndrome de Phelan-McDermid, y establecer una mejor correlación genotipo-fenotipo para predecir la evolución de cada paciente de una forma más precisa (AU)

Introduction: Phelan-McDermid syndrome is caused by a microdeletion in the 22q13.3 region that has been related to high phenotypic variability. Recently, it has been suggested a correlation between the size of the deletion and the severity of the symptoms presented by patients. Case report: We report the case of a child treated at our Hospital with a significant delay in the area of language and learning, and the results of the genetic analysis performed using multiplex ligation-dependent probe amplification (MLPA) and microarray techniques. Results: A 1.7 Mb terminal deletion was detected on chromosome 22 with a loss of ARSA-1, SHANK3 and RABL2B genes. Conclusion: Microdeletion analysis of 22q13.3 region should be performed by microarray technique in order to detect which genes are involved in Phelan-McDermid syndrome, finding a better phenotype-genotype correlation that will allow predicting patient’s prognosis more accurately (AU)

Prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 in early stage of non-small cell lung cancer

Introduction: Nowadays, 40 % of early-stage NSCLC patients relapse in the 2 years following resection, suggesting a mis-staging in this group of patients who are not receiving adjuvant chemotherapy. Although different biomarkers, such as ERCC1, RRM1 and BRCA1 have been found to present prognostic value in advanced NSCLC patients, in early-stage NSCLC patients its relevance remains unclear. Moreover, SETDB1 has been recently proposed as a bona fide oncogene in lung tumourigenesis and related with metastasis. The aim of the present study was to analyze the prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 expression levels in NSCLC patients at stage I. Patients and methods: ERCC1, RRM1, BRCA1 and SETDB1 expression at mRNA level was analyzed by realtime quantitative RT-PCR in fresh-frozen tumor and normal adjacent lung tissue samples from 64 stage I NSCLC patients. Later, significant association between gene expression levels, clinicopathological characteristics and patient’s disease-free survival was assessed. Results: We did not find any statistically significant correlation between gene expression and gender, age, histological type or smoking status. Univariate followed by multivariate Cox analysis showed that higher levels of BRCA1 and SETDB1 expression were significantly associated with shorter disease-free survival in stage I NSCLC patients. Conclusion: Our study finds that ERCC1 and RRM1 are not independent prognostic factors of recurrence in stage I NSCLC patients. By contrast, BRCA1 and SETDB1 stand out as the most significant prognostic markers in this group of patients, appearing as promising tools to predict tumor recurrence in early-stage NSCLC patients (AU)

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Prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 in early stage of non-small cell lung cancer.

INTRODUCTION: Nowadays, 40 % of early-stage NSCLC patients relapse in the 2 years following resection, suggesting a mis-staging in this group of patients who are not receiving adjuvant chemotherapy. Although different biomarkers, such as ERCC1, RRM1 and BRCA1 have been found to present prognostic value in advanced NSCLC patients, in early-stage NSCLC patients its relevance remains unclear. Moreover, SETDB1 has been recently proposed as a bona fide oncogene in lung tumourigenesis and related with metastasis. The aim of the present study was to analyze the prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 expression levels in NSCLC patients at stage I. PATIENTS AND METHODS: ERCC1, RRM1, BRCA1 and SETDB1 expression at mRNA level was analyzed by real-time quantitative RT-PCR in fresh-frozen tumor and normal adjacent lung tissue samples from 64 stage I NSCLC patients. Later, significant association between gene expression levels, clinicopathological characteristics and patient's disease-free survival was assessed. RESULTS: We did not find any statistically significant correlation between gene expression and gender, age, histological type or smoking status. Univariate followed by multivariate Cox analysis showed that higher levels of BRCA1 and SETDB1 expression were significantly associated with shorter disease-free survival in stage I NSCLC patients. CONCLUSION: Our study finds that ERCC1 and RRM1 are not independent prognostic factors of recurrence in stage I NSCLC patients. By contrast, BRCA1 and SETDB1 stand out as the most significant prognostic markers in this group of patients, appearing as promising tools to predict tumor recurrence in early-stage NSCLC patients.

Changes in nerve- and endothelium-mediated contractile tone of the corpus cavernosum in a mouse model of pre-mature ageing.

Erectile dysfunction (ED) is very prevalent in the older population, although the ageing-related mechanisms involved in the development of ED are poorly understood. We propose that age-induced differences in nerve- and endothelium-mediated smooth muscle contractility in the corpus cavernosum (CC) could be found between a senescent-accelerated mouse prone (SAMP8) and senescent-accelerated mouse resistant (SAMR1) strains. We analysed the changes in muscle tension induced by electrical field stimulation (EFS) or agonist addition 'in vitro', assessing nerve density (adrenergic, cholinergic and nitrergic), the expression of endothelial nitric oxide synthase (eNOS), cGMP accumulation and the distribution of interstitial cells (ICs) by immunofluorescence. We observed no change in both the nerve-dependent adrenergic excitatory contractility at physiological levels of stimulation and in the nitrergic inhibitory response in SAMP8 animals. Unlike cholinergic innervation, the density of adrenergic and nitrergic nerves increased in SAMP8 mice. In contrast, smooth muscle sensitivity to exogenous noradrenaline (NA) was slightly reduced, whereas cGMP accumulation in response to EFS and DEA/NO, and relaxations to DEA/NO and sildenafil, were not modified. No changes in the expression of eNOS and in the distribution of vimentin-positive ICs were detected in the aged animals. The ACh induced atropine-sensitive biphasic endothelium-dependent responses involved relaxation at low concentrations that turned into contractions at the highest doses. CC relaxation was mainly because of the production of NO together with some relaxant prostanoid, which did not change in SAMP8 animals. In contrast, the contractile component was considerably higher in the aged animals and it was completely inhibited by indomethacin. In conclusion, a clear imbalance towards enhanced production of contractile prostanoids from the endothelium may contribute to ED in the elderly. On the basis of these data, we propose the senescence-accelerated mouse model as a reliable tool to analyse the basic ageing mechanisms of the CC.

Changes in nerve-mediated contractility of the lower urinary tract in a mouse model of premature ageing.

BACKGROUND AND PURPOSE: A high incidence of lower urinary tract disorders is associated with ageing. In the senescent-accelerated prone (SAMP8) mouse strain and the senescent-accelerated resistant (SAMR1) strain, we compared smooth muscle contractility in responses to intrinsic neurotransmitters, both in the bladder and urethra. EXPERIMENTAL APPROACH: We analysed micturition frequency, the changes in muscle tension induced by electrical field stimulation or agonist administration, the density of nerves (adrenergic, cholinergic and nitrergic) and interstitial cells (ICs), as well as cGMP accumulation in bladder and urethral preparations. KEY RESULTS: Senescent mice of the SAMP8 strain displayed increased micturition frequency and excitatory contractility of neurogenic origin in the bladder. While cholinergic nerve density remained unchanged, there was a mild sensitization to ACh in male mice. Potentiation in the detrusor may be also provoked by the stronger contribution of ATP, together with reduced adrenergic innervation in males and COX-derived prostanoid production in females. The greater excitatory contractility in the urethra was probably due to the sensitization to noradrenaline, in conjunction with attenuated nitrergic relaxation. There were also fewer neuronal NOS immunoreactive (ir) nerves and vimentin-positive ICs, although the sildenafil- and diethylamine-NONOate-induced relaxations and cGMP-ir remained unchanged. CONCLUSIONS AND IMPLICATIONS: Premature senescent mice exhibit bladder and urethral hyperexcitability, coupled with reduced urethral relaxation of neurogenic origin, which could model the impaired urinary function in elderly humans. We propose that senescence-accelerated mice provide a useful tool to analyse the basic mechanisms of age-related changes in bladder and urethral function.