BACKGROUND: There is a need for improved prognostic markers in melanoma. In this study, the authors tested the prognostic significance and clinicopathologic correlations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations in patients with metastatic melanoma. METHODS: Clinical and pathologic data were collected retrospectively on melanoma patients who were clinically tested for BRAF (exon 15) and NRAS (exons 1 and 2) mutations at The University of Texas M. D. Anderson Cancer Center. Analyses were performed to identify significant associations of mutations with tumor and patient characteristics and with survival from the diagnosis of stage IV disease. RESULTS: The genotypes of the full cohort (n ¼ 677) were 47% BRAF mutation, 20% NRAS mutation, and 32% wild-type for BRAF and NRAS (''WT''). Tumor mutation status was associated (P ¼ .008) with the risk of central nervous system involvement at the diagnosis of stage IV disease, with a higher prevalence observed in BRAF-mutant (24%) and NRAS-mutant (23%) patients than in WT patients (12%). Among patients with nonuveal melanoma who underwent mutation testing within 6 months of stage IV diagnosis (n ¼ 313), patients with NRAS mutations had a median survival of 8.2 months from stage IV diagnosis, which was shorter than the median survival of WT patients (15.1 months; P ¼ .004). Multivariate analysis of this population incorporating age, sex, metastases (M1) category, serum lactate dehydrogenase level, and mutation status confirmed that NRAS mutations are associated independently with decreased overall survival (vs WT; P ¼ .005; hazard ratio, 2.05). CONCLUSIONS: Patients with BRAF or NRAS mutations were more likely than WT patients to have central nervous system involvement at the time they were diagnosed with distant metastatic disease. NRAS mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma. Cancer 2012;118:4014-

BACKGROUND: Hotspot mutations in BRAF and NRAS are the most common somatic events in patients with melanoma. These mutations occur at highly conserved residues, but include several different substitutions. To determine whether specific mutations are clinically important to differentiate, tumor characteristics and clinical outcomes were compared among patients with advanced melanoma with 1) BRAF V600E versus V600K mutations and 2) NRAS exon 1 versus exon 2 mutations. METHODS: Retrospective clinical and pathologic data were collected for patients with advanced melanoma with BRAF or NRAS mutations. The demographics, tumor characteristics, and clinical outcomes of the patients were compared to identify significant mutation-specific associations. RESULTS: Among 302 patients with activating BRAF mutations, 76% had BRAF V600E and 24% had V600K substitutions. Compared with V600E, the presence of a V600K mutation was significantly associated with older age (median, 60.0 years vs 44.7 years; P <.001), male sex (80% vs 59%; P 5.001), head=neck primary tumor location (30% vs 15%; P 5.0026), shorter interval to stage IV disease (0.98 years vs 2.8 years; P 5.015), and a shorter overall survival from the time of diagnosis of stage IV disease (median, 2.44 years vs 1.25 years; hazards ratio, 1.68 [P 5.014]). Comparison of 136 patients with NRAS exon 1 (18%) and exon 2 (82%) mutations found an association with primary tumor histology (P 5.0096) only. CONCLUSIONS: The presence of different substitutions at BRAF V600 correlates with patient demographics, tumor characteristics, and prognosis. These findings demonstrate the presence of mutation-specific clinical differences between different BRAF genotypes in patients with melanoma, and support the incorporation of this information in patient evaluation and clinical trial design. Cancer 2013;119:3821-9.

Purpose Determine the antitumor activity of the epidermal growth factor receptor (EGFR) inhibitor gefitinib in patients with recurrent/metastatic salivary gland cancer. Methods Phase II study in adenoid cystic (ACC) and non-adenoid cystic (non-ACC) carcinomas. Gefitinib was administered 250mg orally daily. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and disease control rates (DCR). EGFR and HER2 expression were evaluated and correlated with outcomes. Results Thirty-seven patients were enrolled, and 36 were evaluable (18 with ACC and 18 with non-ACC). No responses were observed. Median PFS was 4.3 months and 2.1 months, and median OS was 25.9 months and 16 months for patients with ACC and non-ACC respectively. DCR at 8 weeks was higher in ACC patients. No unexpected toxicities occurred. EGFR and HER2 overexpression did not correlate with outcomes. Conclusions We did not observe significant clinical activity of gefitinib in advanced salivary gland cancer. NCT00509002.

DA strain of TMEV induces a chronic, persistent, demyelinating disease in SJL/J weanling mice, while inoculation with GDVII strain of TMEV induces an acute, lethal neurovirulent disease. We show that three amino acids in the DA EF loop-DAV P2 141 Lys, 143 Gly, and 173 Thr-are part of a neutralization site of DA monoclonal antibody (mAb), DAmAb1. DA virus with a mutation of VP2 143 from Gly to Asp, like wild-type virus, persists 6 weeks postinfection (PI) and produces white matter disease. DA virus with a mutation of VP2 141 from Lys to Asn persists but does not induce significant white matter disease. DA virus with a mutation of DA VP2 173 from Thr to Phe fails to persist or to induce significant white matter disease. The diversity and complexity of the mutant virus-induced disease phenotype presumably reflects the varied effects of the mutated amino acid residues on the three-dimensional structure of the viral capsid. The localization of DA VP2 141 and VP2 173 near the putative receptor binding region of the virus suggest that a disruption of interactions between the virus and its receptor is important in the late demyelinating disease and for virus neutralization.