Regarding PDGFRA-mutated

GISTs, PDGFRA exon 18 mutations have better response to imatinib therapy but not with PDFGRA exon 18 D842V-mutation (71). According to the NCCN guidelines, patients with progressive disease after imatinib treatment are allowed to be re-assessed for surgery. Surgical resection has been achieved in those cases (166-168). However, the timing of the surgical intervention is very important and was recommended as the time at which patients reached maximum benefit from imatinib Inhibitors,research,lifescience,medical but before tumor progression occurs (139,169). In addition, neoadjuvant therapy with TKI should be PRT062607 manufacturer considered to facilitate complete resection and allow for a less morbid operation, especially in duodenal GIST which can be sometimes hardly resected completely (170,171). With a short neoadjuvant imatinib therapy, tumor blood flow was decreased and apoptosis was increased Inhibitors,research,lifescience,medical within 3-7 days of starting therapy compared with pre-imatinib tumor tissue, although minimal size reduction

was observed (171). Assessment of treatment response According to the NCCN guidelines, imaging study of contrast-enhanced CT scan is the technique of choice to detect recurrence or progression of GISTs (138,139,172). In rectal GIST, MRI should be used or additional PET or PET-CT/MRI Inhibitors,research,lifescience,medical may be useful for early detection of tumor response to neoadjuvant therapy (172). Inhibitors,research,lifescience,medical Choi and colleagues (173) proposed modified response evaluation criteria which is considered to predict response more accurately than previously proposed Response Evaluation Criteria in Solid Tumor (RECIST) (174) and has a better correlation with time to progression (175). Resistant disease and alterative treatments Although TKIs, especially imatinib, have resulted in disease-free survival Inhibitors,research,lifescience,medical for patients following surgical resection of their primary tumors and increased response rates and survival for patients with metastatic disease, some patients will eventually develop resistance to imatinib (176). Several potential

mechanisms of resistance were proposed and include specific types of mutations (KIT exon 9, KIT wild-type or PDGFRA exon 18) (31,135), acquisition of secondary mutations within the KIT gene, KIT gene amplification, loss of the wild-type allele, or inadequate either imatinib plasma levels (176-179). Sunitinib is the only second-line TKI approved for use after imatinib failure due to its inhibitory function on multi-kinases receptors (136). It has also been shown to be effective against secondary mutations in vitro and in vivo studies (136,161). However, as with imatinib, resistance has recently been documented in patients with prolonged exposure to sunitinib (180,181). In addition, it has been shown that sunitinib can cause serious, life-threatening adverse effects, including hypertension, cardiotoxicity, and hypothyroidism (30,182,183).