Activating oncogenic mutations of BRAF have been described in patients with gastrointestinal stromal tumor (GIST), but treatment of GIST with BRAF inhibitors and mechanisms of mediating the emergence of resistance in GIST have not been reported. Dabrafenib is a potent ATP-competitive inhibitor of BRAF kinase and is highly selective for mutant BRAF in kinase panel screening, cell lines, and xenografts. We report prolonged antitumor activity in the first patient with V600E BRAF-mutated GIST who was treated with a BRAF inhibitor. Whole exome sequencing performed in tumor tissue obtained at the time of progressive disease demonstrated a somatic gain-of-function PIK3CA mutation (H1047R) as well as a CDKN2A aberration, which may have contributed to eventual resistance to treatment.
Background
Salivary ductal carcinoma is a rare cancer with poor prognosis and limited treatment options. HER2-directed treatment has been attempted in HER2-amplified or overexpressed salivary gland malignancies with limited success.
Methods
We report resolution of measurable disease and minimal residual disease in a patient with salivary duct cancer treated with trastuzumab, lapatinib, and bevacizumab, with treatment ongoing for more than two years.
Results
This treatment has been tolerated well except for grade 2 diarrhea and mucositis, which required a dose reduction of lapatinib to 1000 mg daily. The response observed was achieved in spite of receiving extensive prior therapy, including trastuzumab and/or chemotherapy for 20 months on which his tumors progressed.
Conclusions
The combination of trastuzumab, lapatinib, and bevacizumab may warrant investigation as a non-cytotoxic alternative for treatment of HER2-amplified or overexpressed salivary duct carcinoma and other HER2-amplified or overexpressed salivary gland tumors, particularly those not responsive to trastuzumab monotherapy.
In male golden hamsters (Mesocricetus auratus), attack frequency decreases during puberty. As serotonin inhibits offensive responses in adult hamsters, it is hypothesized that the serotonin system becomes upregulated in the hypothalamus during puberty. This hypothesis was tested through acute treatment with fluoxetine, a serotonin reuptake inhibitor, as well as through analysis of serotonin innervation in specific brain areas. In adults, fluoxetine treatment inhibited aggressive behavior. In juveniles, high doses of fluoxetine only reduced offensive responses (i.e., frequency and repetition of attacks), whereas low doses enhanced them. Juveniles also showed a dose-specific maturation of attack targets. In addition, the density of serotonin innervation of the hypothalamus was 20% higher in adult hamsters compared with juveniles. On the basis of these data, it is proposed that the developing serotonergic system shapes the development of offensive behaviors in male golden hamsters.
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