Mecanismos de tumorogénesis hipofisaria: Estudio de factores angiogénicos y de proliferación / Mechanisms of Pituitary Tumorigenesis: Study of Angiogenic and Proliferation factors

Introducción y Objetivos: La angiogénesis es un proceso fundamental en el desarrollo tumoral. Sin embargo, se han encontrado discrepancias en el patrón angiogénico de los tumores hipofisarios. Nos propusimos estudiar la expresión de VEGF y FGF2 y su importancia en la vascularización de los adenomas hipofisarios, cuantificar los vasos con los marcadores CD31 y CD34 y determinar el índice de proliferación con PCNA y Ki67. Materiales y Métodos: Se estudiaron 76 macroadenomas hipofisarios que fueron intervenidos quirúrgicamente. Los adenomas se clasificaron según su secreción hormonal. A partir de cortes histológicos se realizó inmunohistoquímica para los marcadores de endotelio CD31 y CD34; y Ki-67 para estudio de proliferación celular. Por western blot se midieron VEGF, CD31 y PCNA. Se efectuaron comparaciones con glándulas normales. Resultados: El nivel de expresión de VEGF, hallado en todas las muestras analizadas, resultó mayor en los prolactinomas resistentes respecto a los demás tipos de adenomas hipofisarios. Esta proteína localizó en las células endoteliales de los vasos como así también en citoplasmas y núcleos de células tumorales. El 56 % de las muestras resultaron positivas para FGF2, mostrando localización citoplasmática y en matriz extracelular. Obtuvimos una fuerte correlación positiva entre VEGF y CD31 en las muestras tumorales, sin encontrar correlación lineal entre PCNA y VEGF, ni Ki-67 y VEGF en las muestras estudiadas. El área vascular resultó mayor en los tejidos normales que en los tumores utilizando CD34 como marcador de vasos. Conclusión: La importancia del estudio de la angiogénesis en los adenomas hipofisarios radica en la necesidad de hallar marcadores moleculares que predigan el comportamiento tumoral. Pudimos demostrar la expresión de los factores angiogénicos VEGF y FGF2 en estos adenomas, y la existencia de correlación lineal entre VEGF y CD31. Nuestros resultados son indicativos de existencia de angiogénesis en los adenomas hipofisarios por lo que su bloqueo podría plantearse como una estrategia alternativa para los casos resistentes a las terapias convencionales.(AU)

Introduction and objectives: Angiogenesis is an essential process in tumor development. Nevertheless, discrepancies in the angiogenic pattern of pituitary tumors, in terms of hormonal phenotype, size or invasiveness have been found. Our aim was to study the expression of VEGF and FGF2 growth factors, and their importance in the vascularization of pituitary adenomas. We also quantified blood vessels with the endothelial cell markers CD31 and CD34 determining the vascular area, and the proliferation rate through PCNA and Ki67 index. Materials and Methods: We studied 76 pituitary macroadenomas that were surgically resected in the period between 2006 and 2010 from a total of 276 patients with this pathology. Adenomas were classified into prolactinomas (PRL), somatotropinomas (GH), corticotropinomas (ACTH), non-functioning (NF) and plurihormonal (Ph) according to their hormonal secretion. Samples were collected in formalin, embedded in paraffin, and immunohistochemistry was performed from histological sections for endothelial markers CD31 and CD34; and for Ki-67 to study cell proliferation. VEGF, CD31 and PCNA were measured by Western blot. We compared results with normal glands (N=6). Results: VEGF expression levels, found in all of the samples analyzed, were higher in resistant prolactinomas than in other pituitary adenomas. This protein was detected in endothelial cells of blood vessels and in tumor cells cytoplasms and nuclei. Fifty-six percent of samples were positive for FGF2, the other potent angiogenic factor studied, showing cytoplasmatic and extracellular matrix localization. We obtained a strong positive correlation between VEGF and CD31 in tumor samples, but we did not find lineal correlation between PCNA and VEGF, or between Ki-67 and VEGF in the samples studied. The vascular area was higher in normal tissues than in tumors when CD34 was used as endothelial cell marker. Conclussion: The importance of studying angiogenesis in pituitary adenomas lies in the need to find molecular markers that can predict tumor behavior. We could demonstrate the expression of VEGF and FGF2, two potent angiogenic factors, and the existence of linear correlation between VEGF and CD31. Our results are indicative of the existence of angiogenesis in pituitary adenomas; therefore the blockage of angiogenesis might be proposed as an alternative strategy for cases of resistance to standard therapy.(AU)

Mecanismos de tumorogénesis hipofisaria: Estudio de factores angiogénicos y de proliferación / Mechanisms of Pituitary Tumorigenesis: Study of Angiogenic and Proliferation factors

Introducción y Objetivos: La angiogénesis es un proceso fundamental en el desarrollo tumoral. Sin embargo, se han encontrado discrepancias en el patrón angiogénico de los tumores hipofisarios. Nos propusimos estudiar la expresión de VEGF y FGF2 y su importancia en la vascularización de los adenomas hipofisarios, cuantificar los vasos con los marcadores CD31 y CD34 y determinar el índice de proliferación con PCNA y Ki67. Materiales y Métodos: Se estudiaron 76 macroadenomas hipofisarios que fueron intervenidos quirúrgicamente. Los adenomas se clasificaron según su secreción hormonal. A partir de cortes histológicos se realizó inmunohistoquímica para los marcadores de endotelio CD31 y CD34; y Ki-67 para estudio de proliferación celular. Por western blot se midieron VEGF, CD31 y PCNA. Se efectuaron comparaciones con glándulas normales. Resultados: El nivel de expresión de VEGF, hallado en todas las muestras analizadas, resultó mayor en los prolactinomas resistentes respecto a los demás tipos de adenomas hipofisarios. Esta proteína localizó en las células endoteliales de los vasos como así también en citoplasmas y núcleos de células tumorales. El 56 % de las muestras resultaron positivas para FGF2, mostrando localización citoplasmática y en matriz extracelular. Obtuvimos una fuerte correlación positiva entre VEGF y CD31 en las muestras tumorales, sin encontrar correlación lineal entre PCNA y VEGF, ni Ki-67 y VEGF en las muestras estudiadas. El área vascular resultó mayor en los tejidos normales que en los tumores utilizando CD34 como marcador de vasos. Conclusión: La importancia del estudio de la angiogénesis en los adenomas hipofisarios radica en la necesidad de hallar marcadores moleculares que predigan el comportamiento tumoral. Pudimos demostrar la expresión de los factores angiogénicos VEGF y FGF2 en estos adenomas, y la existencia de correlación lineal entre VEGF y CD31. Nuestros resultados son indicativos de existencia de angiogénesis en los adenomas hipofisarios por lo que su bloqueo podría plantearse como una estrategia alternativa para los casos resistentes a las terapias convencionales.

Introduction and objectives: Angiogenesis is an essential process in tumor development. Nevertheless, discrepancies in the angiogenic pattern of pituitary tumors, in terms of hormonal phenotype, size or invasiveness have been found. Our aim was to study the expression of VEGF and FGF2 growth factors, and their importance in the vascularization of pituitary adenomas. We also quantified blood vessels with the endothelial cell markers CD31 and CD34 determining the vascular area, and the proliferation rate through PCNA and Ki67 index. Materials and Methods: We studied 76 pituitary macroadenomas that were surgically resected in the period between 2006 and 2010 from a total of 276 patients with this pathology. Adenomas were classified into prolactinomas (PRL), somatotropinomas (GH), corticotropinomas (ACTH), non-functioning (NF) and plurihormonal (Ph) according to their hormonal secretion. Samples were collected in formalin, embedded in paraffin, and immunohistochemistry was performed from histological sections for endothelial markers CD31 and CD34; and for Ki-67 to study cell proliferation. VEGF, CD31 and PCNA were measured by Western blot. We compared results with normal glands (N=6). Results: VEGF expression levels, found in all of the samples analyzed, were higher in resistant prolactinomas than in other pituitary adenomas. This protein was detected in endothelial cells of blood vessels and in tumor cells cytoplasms and nuclei. Fifty-six percent of samples were positive for FGF2, the other potent angiogenic factor studied, showing cytoplasmatic and extracellular matrix localization. We obtained a strong positive correlation between VEGF and CD31 in tumor samples, but we did not find lineal correlation between PCNA and VEGF, or between Ki-67 and VEGF in the samples studied. The vascular area was higher in normal tissues than in tumors when CD34 was used as endothelial cell marker. Conclussion: The importance of studying angiogenesis in pituitary adenomas lies in the need to find molecular markers that can predict tumor behavior. We could demonstrate the expression of VEGF and FGF2, two potent angiogenic factors, and the existence of linear correlation between VEGF and CD31. Our results are indicative of the existence of angiogenesis in pituitary adenomas; therefore the blockage of angiogenesis might be proposed as an alternative strategy for cases of resistance to standard therapy.

The subscapular artery and the thoracodorsal branch: an anatomical study.

The motive for this research was the use of the muscles of the scapular region in transposition, transplantation and reparative surgery and the need for more detailed knowledge of the blood supply to these muscles. In addition, the subscapular arterial tree may be used as a source of microvascular grafts to replace damaged or diseased portions of arteries, particularly in the hand and forearm. The research was conducted on 60 sides of corpses of adults of both sexes. It was noticed that the subscapular artery was present in 96.7% of cases and originated laterally to the pectoralis minor muscle in 76.7% of cases. The average calibre was 5.0 mm, and in 73.2% of cases it measured between 4.0 and 5.9 mm. The average length was 18.0 mm, ranging from 10.0 to 29.9 mm (76.7%). It presented in its course important relations with the axillary nerve (69%) and with the radial nerve (82.8%). Its branches were collateral (subscapular muscle - 61.3%) and terminal (except for the circumflex scapular artery), leading to the following muscles: serratus anterior (43.9%), latissimus dorsi (27.6%), and subscapular (23.3%). The thoracodorsal artery, one of the terminal branches, most frequently showed a calibre of between 2.0 and 3.9 mm (70.3%), collateral branches in 85.0%, was mainly distributed to the subscapular muscle (36.7%) and to the serratus anterior muscle (29.0%) and had terminal branches to the following muscles: latissimus dorsi (44.1%), serratus anterior (40.5%) and the subscapular (12.5%). The serratus anterior muscle received one branch in 39.5% and two branches in 41.9%, while the latissimus dorsi muscle received one branch in 66.7% and two branches in 23.1%.

Resynchronization of mitral valve annular segments reduces functional mitral regurgitation in cardiac resynchronization therapy.

AIM: Cardiac resynchronization therapy (CRT) reduces the severity of functional mitral regurgitation (FMR) in patients with heart failure and left bundle branch block. Our hypothesis was that the induction of a more synchronous mitral valve anulus contraction can be a mechanism of FMR reduction in CRT patients. METHODS: An echo tissue Doppler imaging (TDI) examination was performed at baseline and 6 months after biventricular pacing system implant in 30 patients (4 females and 26 males, 74.1+/-6.1 years) with dilatative or ischemic chronic heart failure, NYHA class = or >III, ejection fraction (EF) = or <35% and QRS = or >140 ms. EF, Myocardial Performance Index (MPI), left end-diastolic and systolic volumes (LVEDV, LVESV), mitral regurgitation jet area/left atrial area (JA/LAA), effective regurgitant orifice area (EROA), mitral anulus contraction (MAC) were evaluated. Using TDI, at the 6 left ventricle (LV) basal segments the time to the peak myocardial sustained systolic velocity (Ts) and the standard deviation (SD) of TS were evaluated. RESULTS: At 6 months follow-up NYHA class, EF, MPI were significantly improved, LV volumes were reduced. FMR degree, evaluated both as JA/LAA and EROA, was significantly reduced. This effect was associated with the 6 basal segments resynchronization and with a more effective annular contraction. CONCLUSIONS: Our data show that CRT by resynchronizing left ventricular basal segments produces a more effective mitral valve annulus contraction and contributes to FMR improvement. Further studies need to evaluate if this could be taken into account as new therapeutic perspective of functional mitral valve regurgitation.

Atrioventricular interval optimization in the right atrial appendage and interatrial septum pacing: a comparison between echo and peak endocardial acceleration measurements.

Interatrial septum pacing (IASP) reduces interatrial conduction time and consequently may interfere with atrioventricular delay (AVD) optimization. We studied 14 patients with an implanted BEST Living system device able to measure peak endocardial acceleration (PEA) signal. The aims of our study were to compare the (1) optimal AVD (OAVD) in right atrial appendage pacing (RAAP) and IASP, and (2) OAVD derived by the PEA signal versus OAVD derived by Echo/Doppler evaluation of the left ventricular filling time (LVFT) and cardiac output (CO). Measurements were performed in DDD VDD modes Eight patients (group A) had RAAP and six patients (group B) had IASP. In group A, OAVD measured by LVFT, CO, and PEA was 185 +/- 23 ms, 177 +/- 19 ms, and 192 +/- 23 ms in DDD and 147 +/- 19 ms, 135 +/- 27 ms, and 146 +/- 20 ms in VDD, respectively. OAVD measured by LVFT, CO, and PEA was significantly longer in DDD mode than in VDD (P < 0.01, P < 0.01, P < 0.001). In group B, OAVD measured by LVFT, CO, and PEA was 116 +/- 19 ms, 113 +/- 10 ms, and 130 +/- 30 ms in DDD and 106 +/- 16 ms, 96 +/- 15 ms, and 108 +/- 26 ms in VDD, respectively. No statistical differences were observed between DDD and VDD. Significant correlations between OAVDs PEA derived and OAVDs LVFT and CO derived were observed (r = 0.71, r = 0.69, respectively). When new techniques of atrial stimulation, as IASP, are used an OAVD shorter and similar in VDD and DDD has to be considered. The BEST Living system could provide a valid method to ensure, in every moment, the exact required OAVD to maximize atrial contribution to CO.

Vaginal discharge: an approach to diagnosis and management.

Vaginal discharge is a frequent presenting complaint in an office practice. The authors of this article review the most common causes of this condition, namely Candidiasis, Trichimoniasis, and Bacterial Vaginosis (Gardnerella), as well as the more serious causes, namely gonorrhea, chlamydia, and Herpes simplex. Symptoms and physical signs are generally insufficient to distinguish specific etiologic agents and, as treatment for each is different, diagnostic examination of smears in the office is critical to the management of these patients. A clinical approach and method of office diagnosis is described.