A central challenge to advancing

A central challenge to advancing therapy for progressive PTC is to improve the responses to tyrosine kinase receptor therapy, while minimizing toxicity. So far, the response rates are typically 20% (range 0–45%) and there was substantial toxicity documented from trials using tyrosine kinase receptor inhibitors such as sorafenib, selumetinib, and lenvatinib (Gild et al., 2011; Klein Hesselink et al., 2015). The mechanism of action of these drugs is complex, possibly reflecting an impact on PDGFRα (in the mM range) as well as other downstream pathways including ERK that may influence differentiation. Targeted therapies such as sorafenib clearly inhibit multiple signaling pathways in thyroid carcinoma and can induce cell cycle arrest and initiation of apoptosis. No previous study has documented changes in TTF1 or Pax8 expression or transcription. Here we establish a link between the tyrosine kinase receptor PDGFRα, TTF1 expression, dedifferentiation, and radioactive iodine transport in PTC. We are exploring if focused disruption of PDGFRα by small molecules or monoclonal antibody therapy could be sufficient to induce clinically relevant responses in tumor growth, differentiation, and iodide transport. While it is clear that BRAF and RAS mutations may have a role in tumorigenesis, the subset of thyroid cancers most likely to generate metastases and poor outcomes are dedifferentiated tumors. We believe that targeted therapy of PDGFRα may decrease tumor progression while also inducing differentiation without the side-effects that limit the use of multi-kinase agents to only patients with the most advanced disease.
Funding Sources The authors would like to acknowledge the funding support of the Canadian Institutes of Health Research (61710), the Edmonton Civic Employees Charitable Fund (16263), and Alberta Innovates Health Solutions (201311) (TPWM).
Author Contributions
Acknowledgements
Introduction Bladder cancer is the fourth most common malignancy in the West (Jemal et al., 2010). In Asia, the incidence of ibmx cancer is three to four times less than Western countries (Ferlay et al., 2015). However, population-based cancer registries covering 21% of the world\'s population only included 8% of patients in these registries are from Asia (Parkin, 2006). At initial diagnosis, about 85% of patients have non-muscle-invasive bladder cancer (NMIBC), which is managed by transurethral resection of the bladder (TUR-Bt) with or without intravesical therapy (Babjuk et al., 2013). Although the prognosis of NMIBC is generally favourable (survival rates at 5years are above 80%), 50–80% of patients have intravesical recurrence following TUR-Bt (Sylvester et al., 2006; Fernandez-Gomez et al., 2009). Adequate risk classification allows clinicians to not only estimate the clinical behaviour of the tumour, but also the magnitude of benefit and the need for adjuvant therapy. Accordingly, some risk classifications that combine various parameters to estimate the prognosis of NMIBC patients have been reported. There are disadvantages in using these classifications in the clinical setting. For instance, the EORTC(European Organization for Research and Treatment of Cancer) risk table involve complex calculations and imbalance of prevalence of individual risk groups (Sylvester et al., 2006). Furthermore, risk group stratification which takes into account the risk without Bacillus Calmette-Guerin (BCG) instillation or intravesical instillation of chemotherapy has not been reported.
Methods
Results
Discussion Although EAU guideline on NMIBC appears to be a useful decision-making clinical tool,(Ehdaie et al., 2013) one of the issues in the EORTC risk table is the disproportion in prevalence. In this study, 87.8% of all patients (751 patients) were classified into the intermediate risk group according to EORTC recurrence risk classification in the JT cohort. Xu et al. (2013) and Sakano et al. (2011) showed similar results with 78.0% and 92.5% of patients classified as intermediate risk, respectively. The low frequency of low risk patients could possibly depend in part to the lower rate of G1 tumours in the present study (18.5%) compared with the EORTC trials (43.2%) (Sylvester et al., 2006; Sakano et al., 2011). Because other Asian studies have also reported lower rates of G1 tumours (Sakano et al., 2011; Kikuchi et al., 2009; Hong et al., 2008), there might be racial difference in grade distribution of bladder cancer between Asian and Caucasian populations, similar to the difference between Caucasians and African-Americans (Underwood et al., 2006).