The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.

BACKGROUNDAlterations of BRAF have been implicated in the carcinogenesis of colorectal tumors with microsatellite instability (MSI). These alterations were attributed to defective DNA mismatch repair, which underlies MSI. It was the objective of this study to clarify the role of BRAF in colorectal carcinoma with MSI.METHODSAfter sequencing for BRAF and KRAS in 82 colorectal tumor samples with or without MSI, mismatch repair protein expression was analyzed by immunohistochemistry, and promoter methylation of hMLH1 was analyzed with a methylation‐specific polymerase chain reaction. Results were correlated with the germline status of hMLH1 or hMSH2 and clinical characteristics.RESULTSBRAF was mutated more often in tumors with MSI than in tumors without MSI (27% vs. 5%; P = 0.016). The most prevalent BRAF alteration, V599E, occurred only in tumors with MSI. BRAF V599E was associated with more frequent hMLH1 promoter methylation (P = 0.07) and loss of hMLH1 (P = 0.02). The median age of patients with BRAF V599E was older compared with the median age of patients without this mutation (P = 0.001; 78 vs. 49 yrs). No BRAF alterations occurred in patients with germline mutations of mismatch repair genes. Five novel BRAF mutations were identified.CONCLUSIONSAlthough BRAF V599E was common in colorectal carcinomas with MSI, it was not a consequence of deficient mismatch repair. The current data showed instead that the BRAF V599E mutation was associated only with a subgroup of colorectal carcinomas with MSI that were obtained from older patients without hereditary nonpolyposis colorectal carcinoma and showed epigenetic silencing of hMLH1. These results indicated that tumors with MSI caused by epigenetic MLH1 silencing have a distinct mutational background from that of tumors with genetic loss of mismatch repair, suggesting that there are two genetically distinct entities of microsatellite‐instable tumors. Cancer 2005. © 2005 American Cancer Society.

The INK4a/ARF locus on chromosome 9p21 is one of the important defenses against tumor development and engages both the Rb and the p53 tumor suppressor pathways through its capacity to encode two distinct proteins, p16(INK4a) and p14(ARF). Despite controversial reports, the body of present data suggests that tumor suppressors p16(INK4a) and p14(ARF) are targets of in-activation in GEP-NETs. Moreover, tumor type-specific aberrant p16(INK4a) silencing appears to be associated with advanced tumor stage and may function as a predictor of patients' outcome after surgical resection. Since conventional histological and biochemical assessment are limited with respect to predicting GEP-NET behavior or outcome, methylation profiles including INK4a/ARF might offer a tool to refine future diagnosis and therapeutic management of GEP-NET patients.

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Sorafenib has recently been shown to be effective for the treatment of advanced hepatocellular carcinoma in randomized controlled trials. Here, we report the experience with sorafenib in 25 patients with advanced HCC under daily practice conditions. Tolerance to sorafenib was acceptable and side effects were manageable, although the ECOG performance status was reduced in all patients. The most prevalent grade 2/3 side effects were fatigue (40%) and diarrhea (24%), and withdrawal from therapy occurred in 29% of patients. Disease stabilization was documented in 60% of patients. The median treatment time was 2.7 months and overall survival was 11.0 months. No significant serum alpha-fetoprotein decline was noted at the time of the first radiological control in a subgroup of patients with baseline levels >50 ng/ml who achieved stable disease. In conclusion, in daily practice sorafenib is safe and disease stabilization can be achieved in the majority of patients. However, intolerance to sorafenib can affect treatment adherence substantially.