Several studies have been performed by other groups that

Several studies have been performed by other groups that indicate the possibility of discriminating renal cell carcinoma subtypes using texture analysis or single phase corticomedullary contrast-enhanced CT [18–21]. These studies also found that CT order ll-37 enhancement was a valid method of representing tumor vascularity in either hetero- or homogeneously contrast-enhanced lesions. In order to directly assess the relationship between IMP3 expression in primary RCC and tumor vascularity, we first had to develop a quantitative outcome measure of tumor vascularity in vivo (Figs. 2 and 4A). Although several approaches to quantify tumor vascularity have been described, a consensus on the best method has not emerged [27]. As we were restricted to protocols that utilize clinical CT scans, we chose a method similar to that which we have described for other clinical conditions [28,29], but acknowledge that this approach still requires formal prospective studies for validation. Nevertheless, we find our contrast CT approach to be safe, feasible and readily translatable if future studies can validate its sensitivity and specificity. One surprising result from our CT study was the lack of correlation between primary RCC tumor size and its vascularity. While the Low contrast enhancing tumors were 2-fold smaller than the Intermediate enhancing tumors as expected, the High contrast enhancing tumors were also significantly smaller than the Intermediate tumors (Fig. 4). Holding to the theory that RCC tumor vascularity is associated with virulence, our interpretation of this finding is that High contrast enhancing primary RCC tumors greater than 200cm3 are incompatible with human life, and thus none were observed in our study. However, consistent with the central hypothesis of this study, we found a strong association between primary RCC vascularity as measured by CT and IMP3 expression (Fig. 4D). Furthermore, IHC assessment of tissue from 11 patients with confirmed metastatic RCC to bone revealed that all of the metastatic tumors had strong IMP3 staining (Fig. 3). In contrast, we did not see strong IHC staining in poorly vascular metastatic bone-prostate cancer biopsies. Although our conclusions are limited by the small sample size, these findings suggest that IMP3 may play a critical role in tumor vascular development and potential to spread.
Acknowledgments The authors would like to thank Sarah Mack for technical assistance with the histology and IHC. We would also like to acknowledge Dr. Gregory Dieudonne in the Department of Musculoskeletal Radiology, University of Rochester Medical Center for advice and assistance in manuscript writing; Dr. Houjing Huang in the Department of Hygiene and Statistics, Zunyi Medical University for advice and assistance in statistic analysis; Dr. Zhengyuan Xian in the Department of Radiology, First Affiliated Hospital of Zunyi Medical University for advice in CT scan protocol and image analysis. National Nature Science Foundation of China award NSFC81260280/H0606, the Orthopaedic Research and Education Foundation, the National Institutes of Health PHS awards AR061307 and AR54041, and University of Rochester Wilmot Cancer Center in USA. This work was supported by research grants from the National Nature Science Foundation of China award NSFC81260280, the Orthopaedic Research and Education Foundation, the National Institutes of Health PHS awards AR061307 and AR54041, and University of Rochester Wilmot Cancer Center in USA.
Introduction Osteonecrosis of the jaw (ONJ) emerged as a well-known devastating side effect of parenteral bisphosphonate therapy since the widespread use of biphosphonates to reduce skeletal related events (SRE) [1]. Biphosphonates are commonly used every three to four weeks with around 14–48% reduction of SRE occurrence and ONJ occurrence in 1.2–3.8% despite preventive measures [2–5]. Although the positive results of 4 different trials, the use of biyearly biphosphonates regimens to reduce AIBL is NOT approved [6–9]. This spaced interval of six months achieved an increase in median bone mineral density of 2.7–4.3% in the lumbar spine and 1.6–1.7% in the hip when used in post-menopausal women receiving adjuvant hormonal aromatase inhibitor [7,8]. However, the risk of developing ONJ with the bi-annually regimen of zoledronic acid is not well recognized.
Material and methods
Results The upfront biyearly regimen of zoledronic acid significantly increased bone mineral density (BMD) in postmenopausal women receiving aromatase inhibitors for early breast cancer [6–9]. The Z-FAST trial enrolled 602 postmenopausal women with early hormone receptor-positive breast cancer receiving adjuvant letrozole [6]. Patients were randomized equally to receive upfront or delayed zoledronic acid with a 4mg intravenous regimen every 6 months for 5 years. The investigators reported two cases of ONJ in the upfront group during the 60 months follow-up. However, an ONJ adjudication committee deemed one of the cases inconsistent with ONJ and the other one indeterminate because of insufficient information [6].