Mutational analysis of KRAS codons 12 and 13 is standard for patients with metastatic colorectal cancer since mutations in these codons predict lack of response to anti-EGFR therapies. However, even among patients whose tumors are wildtype for KRAS codons 12 and 13, only a subset respond to therapy. Since additional activating mutations downstream of EGFR may also play a role in treatment resistance, we sought to establish the frequency of these mutations. We evaluated 2121 colorectal tumors for mutations in codons 12 and 13 of the KRAS gene. A subset of these samples, comprised of 513 samples wildtype for KRAS codons 12 and 13, were tested for mutations in codons 61 and 146 of KRAS, codon 600 of BRAF, and codons 12, 13, and 61 of NRAS. Mutation status was determined by targeted pyrosequencing. Mutations in KRAS codon 12 or 13 were identified in 900/2121 (42.4%) samples. Of the 513 wildtype samples tested for additional mutations, 78 samples were mutant for BRAF, 19 for KRAS codon 61, 17 for KRAS codon 146, and 26 for NRAS. In total, 140/513 (27.3%) tumors wildtype for KRAS codons 12 and 13 harbored a mutation in another of the RAS pathway genes. While further study is needed to determine the full therapeutic implications of mutations in these codons, mutational testing of these codons may be useful for identifying a significant proportion of patients who may also be resistant to anti-EGFR therapies.

No abstract

Varenicline, a recently approved therapy for smoking cessation, is likely to be a cost-effective alternative compared with currently available options.

Varenicline significantly reduces craving and the rewarding effects of smoking after the TQD to a greater extent than bupropion, which may contribute to varenicline's greater efficacy for smoking cessation. Varenicline's lack of effect in reducing insomnia, restlessness and increased appetite in this analysis suggests that receptors other than the alpha4-beta2 nAChR subtype may be implicated in these withdrawal symptoms.

A total of 12 weeks of varenicline followed by a further 12-week course for successful quitters is a highly cost-effective alternative compared with currently available smoking cessation options.