SLNB identifies micrometastasis in one-third of early-stage patients. Negative SLNB may predict for improved but not necessarily favorable outcome. Initial tumor size and clinical nodal disease predict for poor outcome. High recurrence rates warrant the development of more effective adjuvant therapies, and better markers of recurrence and treatment response for MCC are needed.

Purpose Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor, often metastatic at presentation, for which current chemotherapeutic regimens are largely ineffective. As its pathogenesis is still unknown, we hypothesized that deregulation of signaling pathways commonly activated in cancer may contribute to MCC tumorigenesis and may provide insights into targeted therapy approaches for this malignancy. Experimental Design We retrospectively profiled 60 primary MCC samples using a SNaPshot-based tumor genotyping assay to screen for common mutations in 13 cancer genes. Results We identified mutations in 9 (15%) MCC primary tumors, including mutations in TP53 (3/60) and activating mutations in the PIK3CA gene (6/60). Sanger sequencing of the primary MCC tumors detected one additional PIK3CA mutation (R19K) that had not been previously described in cancer. Merkel cell polyoma virus (MCPyV) was detected in 38 (66%) MCC cases and patients with MCPyV-positive cancers showed a trend toward better survival. With one exception, the presence of MCPyV and of activating mutations in PIK3CA appeared mutually exclusive. We observed that signaling through the PI3K/pAKT pathway was active in one MCPyV-positive and in all MCPyV-negative MCC cell lines, as evidenced by AKT phosphorylation. Importantly, the presence of a PIK3CA activating mutation was associated with sensitivity to treatment with ZST474, a specific PI3K inhibitor and to NVP-BEZ235, a dual PI3K-mTOR inhibitor, targeted agents under active clinical development. Conclusions PI3K pathway activation may drive tumorigenesis in a subset of MCC and screening these tumors for PIK3CA mutations could help identify patients who may respond to treatment with PI3K pathway inhibitors.

Objective To compare outcomes for patients with hepatocellular carcinoma (HCC) treated with either liver resection or transplantation. Methods A retrospective, single institution analysis of 413 HCC patients from 1999–2009. Results 413 patients with HCC underwent surgical resection (n=106), transplantation (n=270), or were listed without receiving transplantation (n=37). Excluding transplanted patients with incidental tumors (n=50), 257 patients with suspected HCC were listed with the intent to transplant (ITT). The median diameter of the largest tumor by radiography was 6.0 cm in resected, 3.0 cm in transplanted, and 3.4 cm in the listed-but-not-transplanted patients. Median time to transplant was 48 days. Recurrence rates were 19.8% for resection and 12.1% for all ITT patients. Overall, patient survival for resection vs. ITT patients was similar (5-year survival of 53.0% vs. 52.0%, NS). However, for HCC patients with MELD scores <10 and who radiologically met Milan or UCSF criteria, 1-year and 5-year survival rates were significantly improved in resected patients. For patients with MELD <10 and who met Milan criteria, 1-year and 5-year survival were 92.0% and 63.0% for resection (n=26) vs. 83.0% and 41.0% for ITT (n=73, p=0.036). For those with MELD <10 and met UCSF criteria, 1-year and 5-year survival was 94.0% and 62.0% for resection (n=33) vs. 81.0% and 40.0% for ITT (n=78, p=0.027). Conclusions Among known HCC patients with preserved liver function, resection was associated with superior patient survival versus transplantation. These results suggest surgical resection should remain the first line therapy for patients with HCC and compensated liver function who are candidates for resection.