FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

Breast carcinomas with hyperprolactinemia at the time of diagnosis-clinico-biological association.

AIM: To analyse association between preoperative hyperprolactinemia serum levels and clinical and biological features of breast tumors. METHODS: Serum levels of prolactin were measured in 253 women with invasive breast cancer. Clinical and biological parameters analysed were age, size, lymph node involvement, distant metastasis and immunohistochemical expression of estrogen receptor, progesterone receptor, androgen receptor, bcl-2, p53 and Ki67. RESULTS: In ductal carcinomas hyperprolactinemia were associated with high age (p = 0.017), and with bcl-2 + + + expression (p = 0.017). Furthermore, serum prolactin values were significantly higher in bcl-2 +++ cases vs negative (p = 0.029); the same happened when we considered the positivity threshold of 25 ng/mL (p = 0.015). CONCLUSION: Is possible to detect in 6% of infiltrating ductal breast carcinomas hyperprolactinemia (>25 ng/mL), being associated only with increasing age, but not with other clinical or biological factors; and 2) the most surprising data was the association between prolactinemia (qualitative (>25 ng/mL) and quantitative) and intense bcl-2 tissue expression, which suggests that, probably, this (prolactinemia) is not a sign of worse prognosis and evolution.

Effects of estradiol, calcitriol and both treatments combined on bone histomorphometry in rats with chronic kidney disease and ovariectomy.

BACKGROUND: The aim of this experimental study was to analyze the histomorphometric changes observed when using different doses of estradiol, calcitriol and both treatments combined, in rats with both chronic kidney disease (CKD) and ovariectomy (OVX). METHODS: Six groups of rats with CKD+OVX were treated for 8 weeks with placebo, with different doses of 17beta-estradiol (E2), with calcitriol or with both treatments combined (E2+calcitriol). Histomorphometric studies were carried out at the proximal tibia segment. RESULTS: All groups that received active treatments showed a trabecular bone volume similar to those of rats with normal ovarian function. Treatment with E2 was effective, E2-10 diminished osteoid and eroded surfaces, and E2-30 was able to achieve a bone remodeling similar to that of the normal group. Calcitriol proved to have a positive effect on bone microarchitecture, achieving normal trabecular connectivity. The combined treatment with E2-30+calcitriol was the most effective treatment as it was not only capable of achieving normal trabecular remodeling and connectivity, but also normal trabecular bone volume. CONCLUSIONS: E2 and calcitriol seem to have independent effects on cancellous bone turnover in rats with CKD+OVX. In rats with chronic kidney disease and ovariectomy, these two agents are able to produce additive effects on bone and offer additional advantages as opposed to the use of both drugs independently.

[Effect of strontium on bone metabolism in hemodialysis patients]. / Efecto del estroncio sobre el metabolismo óseo en pacientes en hemodiálisis.

The objective of this study was to assess the relationship between the bone strontium content and bone histomorphometric parameters in bone biopsies from patients with chronic renal failure undergoing hemodialysis. The study was carried out in 74 illiac crest bone biopsies from patients with renal osteodystrophy from different worldwide regions (Argentina, Portugal and Spain). They were underwent to histological and histomorphometric evaluation. The bone strontium/calcium ratio was measured by quadrupole inductively coupled plasma-mass spectrometry. The samples were classified into groups according to histological criteria: hyperparathyroidism (HP), mixed (MX), osteomalacia (OM) and adynamic bone disease (ABD). Serum PTH and alkaline phosphatase before biopsy were available in most of the patients. No correlation was found between the different histomorphometric parameters and the Sr/Ca ratio. The one way ANOVA test showed statistical differences in the Sr/Ca ratio of the different histological forms (HP: 0.58 +/- 0.39; MX: 1.16 +/- 0.74; OM: 1.10 +/- 0.46; ABD: 0.91 +/- 0.40 microgram Sr/mg Ca; p < 0.003). The post-Hoc analysis showed differences between HP and MX. The biopsies having greater or equal values than 1.4 micrograms Sr/mg Ca showed higher levels of bone formation histomorphometric parameters and serum alkaline phosphatase (395 +/- 519 vs 1,022 +/- 989 UI/L, p < 0.05). Although it has been found that the biopsies with higher bone strontium had higher levels of osteoid tissue (characteristic of osteomalacia), the hypothesis of strontium-induced osteomalacia could not be demonstrated.

[Chronic renal insufficiency and secondary hyperparathyroidism in rats. Biochemical and histological evaluation]. / Insuficiencia renal crónica e hiperparatiroidismo secundario en ratas: valoración bioquímica e histológica.

Chronic renal failure (CRF) in rats (surgical nephrectomy, 5/6) as well as its derived bone lesions have been studied. Eighty-five male Wistar rats were used, to which chronic renal failure was induced in 1 or 2 surgical times, the parameters of renal function in basal conditions and at different times after surgery being determined. With the method used chronic renal failure is induced with values of creatinine clearance 2/3 times lower than the initial ones (p < 0.05), which stabilize at the 7th week. On the other hand the parathyroid hormone levels (PTH) in serum triple (from 125 +/- 49 to 395 +/- 191, p < 0.05), and a decrease in the tubular phosphate reabsorption is produced (p < 0.001). In bone histology an increase in resorption and bone formation is observed as well as paratrabecular fibrosis, all of which is compatible with the histological diagnosis of hyperparathyroidism. The model of surgical renal insufficiency with ablation of 5/6 of the renal mass, reduces renal function to 1/3 of the initial values after 7 weeks, this procedure having a 20% global mortality without differences being observed between the carrying out of nephrectomies in 1 or 2 surgical times. This degree of CRF was accompanied by secondary hyperparathyroidism both at the biochemical and histological levels, findings which are of great usefulness for future experimental studies.

Aluminum-induced osteogenesis in osteopenic rats with normal renal function.

Previous studies have shown a different effect of aluminum (Al) on bone metabolism in animals with chronic renal failure and conversely, positive osteogenic effects in animals with normal renal function. The aim of this study was to evaluate the effect of aluminum on bone metabolism in osteopenic rats. We studied male Wistar rats with severe osteopenia induced by adding NH4Cl (2%) to the drinking water over a 6-month period. The rats were divided into two groups and followed for 4 months. The Aluminum group (G1) received AlC13 intraperitoneally (10 mg/kg/5 days/week) (n = 8); the Control group (G2) did not receive any treatment after stopping the administration of NH4Cl (n = 5). In all animals we measured biochemical markers (serum Ca, P, Cr, Al, osteocalcin, hydroxyproline) as well as bone mineral density and bone histomorphometry (BV/TV, CTh, ObS/BS, OTh, and NOc/TV). Bone aluminum content, measured by atomic absorption spectrometry, was 101.6 +/- 13 microg/g in the Al overloaded group and 1.31 +/- 0.14 in controls. Bone mineral density, evaluated by dual X-ray absorptiometry (DXA) at the proximal extremity of the tibia was significantly higher in G1 (0.292 +/- 0.01 g/cm2 versus 0. 267 +/- 0.02 g/cm2). No significant differences were found between the biochemical markers. In the histomorphometric parameters we observed significant differences in G1 compared with G2: an increase in BV/TV (18.59 +/- 5.6 versus 7.69 +/- 3.08%) and in CTh (0.52 +/- 0.06 versus 0.36 +/- 0.07 mm) with a moderate increment of the osteoid thickness (14.05 +/- 4.72 versus 5.25 +/- 0.9 microm) (P < 0. 05). Changes in others parameters and the relationship between biochemical parameters of bone remodeling, Al, and histology were analyzed. These findings indicate that in rats with normal renal function, Al is able to induce bone formation even when osteopenia is present.

Utilización de la capacidad de calcificación y osificación de la pared arterial para conseguir regeneración ósea completa en defectos de huesos largos / Use of the calcification and ossification capacity of arterial walls to achieve bone regeneration in complete defects of long bones

Objetivo. Evaluar el uso de aloinjertos arteriales criopreservados como membranas de regeneración ósea guiada en defectos de hueso largo. Material y método. Estudio experimental, prospectivo, aleatorizado y ciego. Se crearon defectos osteoperiósticos de 10 mm de longitud en el tercio medio de la diáfisis del radio de conejos de raza blanca de Nueva Zelanda. En los casos experimentales el defecto se aisló de los tejidos circundantes con un aloinjerto aórtico criopreservado, conforme a las técnicas de regeneración tisular guiada. En los controles no se colocó ningún tipo de membrana. Resultados. No se obtuvo curación del defecto en ningún control. En 9 de los 10 defectos experimentales se observó una regeneración ósea completa, con un patrón similar al del hueso sano en los estudios con técnicas de diagnóstico por imagen, de cuantificación morfodensitométrica y de microscopía óptica y electrónica. Además, los estudios morfológicos y ultraestructurales han mostrado imágenes sugerentes de que los propios aloinjertos aórticos criopreservados pueden haber contribuido a la regeneración ósea en el defecto, por diferenciación osteoblástica de las «células calcificantes vasculares» de la pared arterial (una subpoblación de musculares lisas de la pared arterial que algunos autores consideran células madre adultas) y/o por calcificación u osificación inducida por alteraciones en las proteínas de la matriz extracelular arterial. Conclusiones. Es posible utilizar aloinjertos arteriales criopreservados como membranas de osteopromoción para conseguir regeneración ósea completa en defectos diafisarios de hueso largo, siendo una alternativa al uso de membranas sintéticas

Aim. To assess the use of cryopreserved arterial allograft membranes in guided bone regeneration (GBR) in bone defects of long bones. Materials and methods. Prospective randomized blind study using white New Zealand rabbits as an animal model. Bone and periosteum defects 10 mm in length were created in the middle third of the shaft of the radius of white New Zealand rabbits. In the rabbits in the study group the bone defect was isolated from surrounding tissues with a membrane of cryopreserved aortic allograft according to guided tissue regeneration (GTR) techniques. In the rabbits in the control group no membrane was used. Results. The defect did not heal in any of the rabbits in the control group. In 9 out of 10 of the rabbits in the study group there was complete bone regeneration. The regenerated bone had a similar pattern to that of healthy bone in diagnostic images, in morpho-densitometric quantification studies and when seen using light and electron microscopes. Morphological and microscopic images suggest that cryopreserved aortic allografts may have contributed to bone regeneration in the defect area by osteoblastic differentiation of calcifying vascular cells (CVC) of the arterial walls and/or by calcification or ossification induced by alterations of proteins of the arterial extracellular matrix. Calcifying vascular cells are a sub-population of smooth muscle cells of the arterial walls that are considered to be adult stem cells by some authors. Conclusions. It is possible to use cryopreserved arterial allografts as membranes to promote bone growth and achieve complete bone regeneration in long bone shaft defects. These membranes can be used as an alternative to synthetic membranes

Efecto del estroncio sobre el metabolismo óseo en pacientes en hemodiálisis / Effect of strontium on bone histomorphometric parameters in haemodialysis patients

El objetivo de este estudio fue investigar la relación que existe entre el contenido de estroncio en el hueso y parámetros histomorfométricos óseos en biopsias de pacientes con insuficiencia renal crónica sometidos a hemodiálisis. El estudio se realizó sobre 74 biopsias óseas de cresta ilíaca de enfermos con osteodistrofia renal de distintas procedencias (Argentina, Portugal y España) que fueron sometidas a análisis histológico e histomorfométrico. Además se cuantificó estroncio y calcio en un fragmento de la biopsia mediante espectrometría de masas con fuente de plasma acoplado por inducción (ICP-MS). Las biopsias fueron clasificadas en cuatro grupos según criterios histológicos: hiperparatiroidismo (HP), enfermedad mixta (MX), osteomalacia (OM) y enfermedad ósea adinámica (EOA). También fueron medidos los niveles séricos de fosfatasa alcalina y de PTH intacta. No se encontró correlación entre los distintos parámetros histomorfométricos y la relación Sr/Ca. El análisis de varianza mostró diferencias significativas de Sr/Ca entre las distintas formas histológicas (HP: 0,58 ± 0,39; MX: 1,16 ± 0,74; OM: 1,10 ± 0,46; AD: 0,91 ± 0,40; p < 0,003), habiendo diferencias entre HP y MX (p < 0,005). Cuando se dividieron las biopsias en dos grupos de acuerdo al nivel de la relación Sr/Ca (estroncio bajo < 1,4 μg Sr/mg Ca, estroncio alto _ 1,4 μg Sr/mg Ca), se encontró que aquellas con estroncio elevado mostraron niveles más altos en parámetros de formación ósea. De los parámetros séricos analizados, solo la fosfatasa alcalina mostró valores incrementados en los pacientes con Sr elevado en el hueso (395 ± 519 vs 1.022 ± 989 UI/L). Si bien se ha encontrado que aquellas biopsias con estroncio elevado muestran niveles más altos de osteoide (compatible con osteomalacia), el grado de causalidad del mismo no ha quedado claramente establecido (AU)

The objective of this study was to assess the relationship between the bone strontium content and bone histomorphometric parameters in bone biopsies from patients with chronic renal failure undergoing hemodialysis. The study was carried out in 74 illiac crest bone biopsies from patients with renal osteodystrophy from different worldwide regions (Argentina, Portugal and Spain). They were underwent to histological and histomorphometric evaluation. The bone strontium/calcium ratio was measured by quadrupole inductively coupled plasma-mass spectrometry. The samples were classified into groups according to histological criteria: hyperparathyroidism (HP), mixed (MX), osteomalacia (OM) and adynamic bone disease (ABD). Serum PTH and alkaline phosphatase before biopsy were available in most of the patients. No correlation was found between the different histomorphometric parameters and the Sr/Ca ratio. The one way ANOVA test showed statistical differences in the Sr/Ca ratio of the different histological forms (HP: 0.58 ± 0.39; MX: 1.16 ± 0.74; OM: 1.10 ± 0.46; ABD: 0.91 ± 0.40 μg Sr/ mg Ca; p < 0.003). The post-Hoc analysis showed differences between HP and MX. The biopsies having greater or equal values than 1.4 μg Sr/mg Ca showed higher levels of bone formation histomorphometric parameters and serum alkaline phosphatase (395 ± 519 vs 1,022 ± 989 UI/L, p < 0.05) Although it has been found that the biopsies with higher bone strontium had higher levels of osteoid tissue (characteristic of osteomalacia), the hypothesis of strontium-induced osteomalacia could not be demonstrated (AU)