Response of Merkel cell polyomavirus-positive Merkel cell carcinoma xenografts to a survivin inhibitor

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer associated with high mortality. Merkel cell polyomavirus (MCV), discovered in 2008, is associated with ∼80% of MCC. The MCV large tumor (LT) oncoprotein upregulates the cellular oncoprotein survivin through its conserved retinoblastoma protein-binding motif. We confirm here that YM155, a survivin suppressor, is cytotoxic to MCV-positive MCC cells in vitro at nanomolar levels. Mouse survival was significantly improved for NOD-Scid-Gamma mice treated with YM155 in a dose and duration dependent manner for 3 of 4 MCV-positive MCC xenografts. One MCV-positive MCC xenograft (MS-1) failed to significantly respond to YM155, which corresponds with in vitro dose-response activity. Combination treatment of YM155 with other chemotherapeutics resulted in additive but not synergistic cell killing of MCC cell lines in vitro. These results suggest that survivin targeting is a promising therapeutic approach for most but not all MCV-positive MCCs. © 2013 Dresang et al

Merkel cell carcinoma: Critical review with guidelines for multidisciplinary management

Merkel cell carcinoma (MCC) is a relatively rare cutaneous malignancy that occurs predominantly in the older white population. The incidence of MCC appears to have tripled during the past 20 years; an increase that is likely to continue because of the growing number of older Americans. The pathogenesis of MCC remains largely unknown. However, ultraviolet radiation and immunosuppression are likely to play a significant pathogenetic role. Many questions currently remain unanswered regarding the biologic behavior and optimal treatment of MCC. Large, prospective, randomized studies are not available and are unlikely to be performed because of the rarity of the disease. The objective of this review was to provide a comprehensive reference for MCC based on a critical evaluation of the current data. The authors investigated the importance of sentinel lymph node biopsy as a staging tool for MCC to assess the status of the regional lymph node basin and to determine the need for additional therapy to the lymph node basin. In an attempt to standardize prospective data collection with the intention to define prognostic indicators, the authors also present histopathologic profiles for primary MCC and sentinel lymph nodes. The controversies regarding the appropriate surgical approach to primary MCC, the use of adjuvant radiation therapy, and the effectiveness of adjuvant chemotherapy were examined critically. Finally, the authors have provided treatment guidelines based on the available evidence and their multidisciplinary experience. Cancer 2007. © 2007 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56047/1/22765_ftp.pd

Supply-Demand Mismatch Transients in Susceptible Peri-infarct Hot Zones Explain the Origins of Spreading Injury Depolarizations

Peri-infarct depolarizations (PIDs) are seemingly spontaneous spreading depression-like waves that negatively impact tissue outcome in both experimental and human stroke. Factors triggering PIDs are unknown. Here, we show that somatosensory activation of peri-infarct cortex triggers PIDs when the activated cortex is within a critical range of ischemia. We show that the mechanism involves increased oxygen utilization within the activated cortex, worsening the supply-demand mismatch. We support the concept by clinical data showing that mismatch predisposes stroke patients to PIDs as well. Conversely, transient worsening of mismatch by episodic hypoxemia or hypotension also reproducibly triggers PIDs. Therefore, PIDs are triggered upon supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. Based on the data, we propose that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke and brain injury would reduce PID incidence and their adverse impact on outcome