FGFR2 overexpression predicts survival outcome in patients with metastatic papillary renal cell carcinoma

Background. Up to date, there are no data about FGFR2 expression and its predictive role in papillary RCC (pRCC) patients. The aim of the present study was to test FGFR2 expression and mutations for association with survival outcome in patients with pRCC. Methods. Specimens of removed primary tumors from 214 untreated metastatic pRCC patients were evaluated by immunohistochemistry with FGFR2 antibody. FGFR2 mutations were assessed by PCR and direct sequencing, with DNA obtained from 62 paraffin-embedded pRCC samples. FGFR2 expression was tested for associations with progression-free survival (PFS), overall survival (OS) and best objective response. Results. Expression of FGFR2 was observed in 23 % (49/214) of primary pRCC, mostly in cytoplasm of tumor cells. Expression of FGFR2 was significant lower in normal tissue of kidney (1 %, P = 0.001). FGFR2 S252W mutation was found in one patient (1.6 %), and no N549K mutation was detected. FGFR2 expression was strongly associated with a number of metastatic sites, type 2 of pRCC, lower nucleolar grade (P < 0.001). FGFR2-positive patients had significantly shorter OS and PFS (P < 0.05). On multivariate analysis, FGFR2 expression, MSKCC risk group and type of pRCC were found to be independent predictors of survival. Conclusions. In this study, we described immunohistochemical expression of FGFR2 in a large series of pRCC specimens. FGFR2 expression was found to be prognostic factor for survival in patients with metastatic pRCC. FGFR2 mutations are rare across papillary types of RCC (AU)

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Osteomalacia en un adulto joven / Osteomalacia in a young adult

Los cuadros de osteomalacia hipofosfatémica responden a diversas causas genéticas y adquiridas. Algunas variantes de tumores mesenquimales producen cantidades inapropiadas de factor de crecimiento fibroblástico 23 (FGF-23), un mediador que induce una pérdida renal de fosfatos. El cuadro bioquímico se caracteriza por hipofosfatemia, disminución de la reabsorción tubular de fosfatos, niveles bajos o inapropiadamente normales de calcitriol sérico y niveles altos o inapropiadamente normales de FGF-23 plasmático. Este síndrome paraneoplásico es denominado osteomalacia tumoral u oncogénica. Existen limitadas series de casos publicadas, pero su reconocimiento es creciente en los últimos años. El diagnóstico puede ser complejo por su baja incidencia, la dificultosa localización de los tumores y la heterogeneidad en la interpretación histopatológica. La exéresis quirúrgica completa es curativa, pero puede haber recidivas y los suplementos orales de fósforo y calcitriol son alternativas de tratamiento médico (AU)

Cases of hypophosphatemic osteomalacia respond to various causes, both genetic and acquired. Some variants of mesenchymal tumors produce inappropriate amounts of fibroblast growth factor 23 (FGF-23), a mediator which induces renal phosphate loss. The biochemical picture is characterized by hypophosphatemia, decreased tubular reabsorption of phosphates, low or inappropriately normal serum calcitriol and high or unusually normal levels of FGF-23 plasma. This paraneoplastic syndrome is called tumorinduced or oncogenic osteomalacia. There are a limited series of published cases, although it has been increasingly accepted in recent years. Diagnosis may be complex given its low incidence, the difficulties in localizing the tumors and heterogeneity in histopathologic interpretation. Complete surgical removal has healed, but there may be recurrences whereas phosphorus and calcitriol oral supplements offer alternative medical treatment (AU)

Therapeutic effect of nanogel-based delivery of soluble FGFR2 with S252W mutation on craniosynostosis.

Apert syndrome is an autosomal dominantly inherited disorder caused by missense mutations in fibroblast growth factor receptor 2 (FGFR2). Surgical procedures are frequently required to reduce morphological and functional defects in patients with Apert syndrome; therefore, the development of noninvasive procedures to treat Apert syndrome is critical. Here we aimed to clarify the etiological mechanisms of craniosynostosis in mouse models of Apert syndrome and verify the effects of purified soluble FGFR2 harboring the S252W mutation (sFGFR2IIIcS252W) on calvarial sutures in Apert syndrome mice in vitro. We observed increased expression of Fgf10, Esrp1, and Fgfr2IIIb, which are indispensable for epidermal development, in coronal sutures in Apert syndrome mice. Purified sFGFR2IIIcS252W exhibited binding affinity for fibroblast growth factor (Fgf) 2 but also formed heterodimers with FGFR2IIIc, FGFR2IIIcS252W, and FGFR2IIIbS252W. Administration of sFGFR2IIIcS252W also inhibited Fgf2-dependent proliferation, phosphorylation of intracellular signaling molecules, and mineralization of FGFR2S252W-overexpressing MC3T3-E1 osteoblasts. sFGFR2IIIcS252W complexed with nanogels maintained the patency of coronal sutures, whereas synostosis was observed where the nanogel without sFGFR2S252W was applied. Thus, based on our current data, we suggest that increased Fgf10 and Fgfr2IIIb expression may induce the onset of craniosynostosis in patients with Apert syndrome and that the appropriate delivery of purified sFGFR2IIIcS252W could be effective for treating this disorder.

Application of FGF-2 to modulate herpetic stromal keratitis.

PURPOSE: Herpetic stromal keratitis (SK) is a tissue destructive eye lesion caused by infection of herpes simplex virus-1 (HSV-1). One step by which HSV-1 enters the cell is through binding to surface heparan sulfate proteoglycans (HSPG), a process that can be inhibited by fibroblast growth factor 2 (FGF-2). The current study examined the effect of FGF-2 application on the outcome of ocular HSV infection. METHODS: Vero cells were infected with HSV-1 after preincubation with FGF-2 protein, and viral infectivity was determined by plaque reduction assay. In an in vivo study, mice were ocularly treated with FGF-2 before (plasmid DNA) or after (recombinant protein) HSV-1 infection, and SK lesion severity was observed. RESULTS: Whereas FGF-2 had excellent antiviral effects in vitro, it was without significant inhibitory effects when given as plasmid DNA encoding FGF-2 (100 microg/application) onto the cornea of the susceptible mouse (BALB/c) before virus infection. Only minor antiviral effects of FGF-2 in vivo were initially observed. Interestingly, topical treatment of recombinant FGF-2 protein (50 ng, two times daily until day 10 postinfection) into HSV-1-infected corneas significantly reduced SK lesion severity and incidence, presumably by promoting epithelial ulcer healing. CONCLUSIONS: These results suggest that treatment of FGF-2 has therapeutic effects on herpetic SK progression via its role in wound healing.

Mitogenic and chondrogenic effects of fibroblast growth factor-2 in adipose-derived mesenchymal cells.

Adipose-derived mesenchymal cells (AMCs) have demonstrated a great capacity for differentiating into bone, cartilage, and fat. Studies using bone marrow-derived mesenchymal cells (BMSCs) have shown that fibroblast growth factor (FGF)-2, a potent mitogenic factor, plays an important role in tissue engineering due to its effects in proliferation and differentiation for mesenchymal cells. The aim of this study was to investigate the function of FGF-2 in AMC chondrogenic differentiation and its possible contributions to cell-based therapeutics in skeletal tissue regeneration. Data demonstrated that FGF-2 significantly promoted the proliferation of AMCs and enhanced chondrogenesis in three-dimensional micromass culture. Moreover, priming AMCs with treatment of FGF-2 at 10 ng/ml demonstrated that cells underwent chondrogenic phenotypic differentiation, possibly by inducing N-Cadherin, FGF-receptor 2, and transcription factor Sox9. Our results indicated that FGF-2 potentiates chondrogenesis in AMCs, similar to its functions in BMSCs, suggesting the versatile potential applications of FGF-2 in skeletal regeneration and cartilage repair.