KIT and BRAF heterogeneous mutations in gastrointestinal stromal tumors after secondary imatinib resistance.

BACKGROUND AND AIMS: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the digestive tract and characterized by expression of KIT protein. Imatinib is the frontline therapy for metastatic and unresectable GIST patients showing clinical responses in 80 % of cases. Despite the often long-lasting clinical benefit seen in most patients treated with imatinib, many will eventually suffer disease progression. The most frequent mechanism of imatinib resistance in GIST is the acquisition of secondary mutations in either KIT or PDGFRA. There are also some imatinib-resistant GIST patients lacking an identifiable mechanism of treatment failure. Recently, activating BRAF mutation was detected in a small percentage of GISTs. In this study, we report a case of GIST with acquired resistance to imatinib during therapy. METHODS: Histological, immunohistochemical, Western blot and mutational analyses were performed on GIST tissues before and after imatinib resistance. RESULTS: The imatinib-resistant tumor showed not only heterogeneous mutations of KIT and BRAF besides the primary mutation, but also transdifferentiation into a rhabdomyosarcoma phenotype. According to Western blot analysis, in imatinib-resistant GIST with both KIT V559D and BRAF V600E mutations, the inhibition of KIT V559D by imatinib caused a strong decrease of AKT phosphorylation, while ERK1/2 phosphorylation was not affected. CONCLUSIONS: This finding, in combination with the loss of KIT expression, suggests the possibility of activation of RAS-RAF-MEK-ERK pathways driven by a KIT-independent oncogenic mechanism. Understanding the genetic aberrations beyond KIT and PDGFRA may lead to the identification of additional therapeutic targets for GISTs.

Low-dose-rate californium-252 neutron intracavitary afterloading radiotherapy combined with conformal radiotherapy for treatment of cervical cancer.

PURPOSE: To study the efficacy of low-dose-rate californium-252 ((252)Cf) neutron intracavitary afterloading radiotherapy (RT) combined with external pelvic RT for treatment of cervical cancer. METHODS AND MATERIALS: The records of 96 patients treated for cervical cancer from 2006 to 2010 were retrospectively reviewed. For patients with tumors ≤4 cm in diameter, external beam radiation was performed (1.8 Gy/day, five times/week) until the dose reached 20 Gy, and then (252)Cf neutron intracavitary afterloading RT (once/week) was begun, and the frequency of external beam radiation was changed to four times/week. For patients with tumors >4 cm, (252)Cf RT was performed one to two times before whole-pelvis external beam radiation. The tumor-eliminating dose was determined by using the depth limit of 5 mm below the mucosa as the reference point. In all patients, the total dose of the external beam radiation ranged from 46.8 to 50 Gy. For (252)Cf RT, the dose delivered to point A was 6 Gy/fraction, once per week, for a total of seven times, and the total dose was 42 Gy. RESULTS: The mean ± SD patient age was 54.7 ± 13.7 years. Six patients had disease assessed at stage IB, 13 patients had stage IIA, 49 patients had stage IIB, 3 patients had stage IIIA, 24 patients had stage IIIB, and 1 patient had stage IVA. All patients obtained complete tumor regression (CR). The mean ± SD time to CR was 23.5 ± 3.4 days. Vaginal bleeding was fully controlled in 80 patients within 1 to 8 days. The mean ± SD follow-up period was 27.6 ± 12.7 months (range, 6-48 months). Five patients died due to recurrence or metastasis. The 3-year survival and disease-free recurrence rates were 89.6% and 87.5 %, respectively. Nine patients experienced mild radiation proctitis, and 4 patients developed radiocystitis. CONCLUSIONS: Low-dose-rate (252)Cf neutron RT combined with external pelvic RT is effective for treating cervical cancer, with a low incidence of complications.