Several studies have explored the relationship

Several studies have explored the relationship between dental implants and MRONJ development. López-Cedrún JL et al. [13] reported that BRONJ developed after implant treatment in nine patients who were taking bisphosphonates orally. The mean interval between the initiation of treatment and the onset of BRONJ lesions was 60 months. Most of these lesions were located around mandibular implants. The mean interval between placement of dental implants and the onset of BRONJ was 34 months [13]. Kwon et al. [14] reported the development of BRONJ related to implants in 19 patients treated with BPs. Sixteen of those patients had been treated with BPs before implant installation, while 3 patients were treated with BPs after implant installation. The authors suggested that after osseointegration of implants, BRONJ could develop around implants due to BP therapy. In the present case, there were implants in both mandibular posterior area. Implant treatments were completed 6 years prior. There were no symptoms at implant sites until recently. Eight months prior to presentation, the patient was treated with antiangiogenic agents and MRONJ developed around the implants. Treatment strategies for MRONJ are classified according to stage [3]. The present case was stage 3. In stage 3 disease, treatment consists of antiseptic mouthwash, antibiotics, pain control and surgical therapy. Antiseptic mouthwash, BAY 41-8543 and pain control were all administered in the present case. Surgical treatment involved sequestrectomy and removal of implants from both mandibular posterior areas under general anesthesia via an intraoral approach. After sequestrectomy, internal fixation was done using a reconstruction plate for the prevention of pathologic fracture because of the thin basal bone thickness of the left mandible. After antibiotics and surgical treatment, good healing results were observed at MRONJ sites. In conclusion, MRONJ can develop from the use of various medicines, including antiangiogenic agents. Moreover, there are some reports that after implant installation and prosthetic treatment bone necrosis can develop around implants in the presence of MRONJ-inducing agents [9,10]. Therefore when a patient with dental implants requires treatment using MRONJ-inducing agents, informed consent concerning the possibility of MRONJ development is needed, after which periodic follow-up facilitating diagnosis and treatment at an early stage could help improve patient prognosis.
Conflicts of interest
Introduction Angiogenesis inhibition was initially viewed as insurmountable to cancer resistance mechanisms [1]. This concept has been proven wrong over the last decade with clinical and experimental studies showing different resistance patterns in response to antiangiogenic treatment [2], [3], [4]. Especially in glioblastoma (GB) treatment, angiogenesis inhibition did not meet the high expectations as a variety of clinical trials failed to demonstrate a survival benefit for antiangiogenic agents [5], [6]. As individualized treatment strategies are becoming more and more important in glioblastoma treatment with the introduction of molecular markers like O6-methylguanine methyltransferase (MGMT) promoter methylation status and 1p/19q co-deletion [7], also the identification of resistance mechanisms to antiangiogenic agents may promise to identify and select patients who benefit from antiangiogenic treatment.Hypoxia-induced resistance factors are key mediators of vascular resistance to antiangiogenic treatment [2]. N-myc-downstream regulated gene-1 (NDRG1) has been implicated as a hypoxia-regulated gene in GB patients [8]. In untreated patients with WHO grade II gliomas high NDRG1 expression is associated with improved survival [8]. Reduced angiogenesis is thought to represent a potential biological mechanism explaining improved survival in GB patients linking NDRG1 to glioma angiogenesis [8], [9]. In other cancer entities, however, NDRG1 has been shown to impose pro- or antiangiogenic effects inducing either prolonged or reduced survival [10]. Therefore, NDRG1 seems to function in a cell-dependent manner [10]. Moreover, NDRG1 has been shown to be involved in cancer therapy resistance mechanisms. In colon cancer cells, NDRG1 alterations induce sensitivity changes to irinotecan [11]. In GB, NDRG1 was recently described as a mediator of resistance against alkylating agents by stabilizing MGMT [8]. Consequently, the exact role of NDRG1 for GB angiogenesis and its consequences for antiangiogenic treatment remain unknown. It was the aim of this preclinical study to investigate the influence of NDRG1 on glioma angiogenesis and to analyze the efficacy of antiangiogenic treatment under NDRG1 overexpression.