Complete resolution of mycosis fungoides tumors with imiquimod 5% cream: a case series.

OBJECTIVE: To demonstrate the clinical efficacy of topical 5% imiquimod for mycosis fungoides (MF) tumors. BACKGROUND: Treatment of tumor-stage MF represents a therapeutic challenge because of a limited number of effective topical therapies. Single tumors can be treated with localized radiation but may recur. Systemic therapies are also an option but are associated with serious adverse effects. Imiquimod is a topical agent whose efficacy has been documented in treating MF patches and plaques as well as one case of tumor-stage disease. METHODS: We present two stage IIB MF patients, including one with large cell transformation, whose tumors were treated with imiquimod 5% cream after failing prior therapies. RESULTS: The MF tumors in both patients demonstrated a complete response to imiquimod 5% cream without recurrence over 8 years and 2 years of follow-up, respectively. One patient experienced application site irritation and flu-like symptoms as adverse effects. CONCLUSIONS: Our case series is only the second report in the literature demonstrating complete resolution of MF tumors with topical imiquimod. An additional therapeutic option for tumor-stage MF, imiquimod may represent an effective alternative to localized radiation for isolated MF tumors and warrants further investigation in the treatment of various stages of MF.

Liver kinase B1 (LKB1) in the pathogenesis of UVB-induced murine basal cell carcinoma.

LKB1, a known tumor suppressor, is mutated in Peutz-Jeghers Syndrome (PJS). It is responsible for the enhanced cancer risk in patients with PJS. Dysregulation of LKB1-dependent signaling also occurs in various epithelial cancers. UVB alters the expression of LKB1, though its role in the pathogenesis of skin cancer is unknown. Here we describe upregulation of LKB1 expression in UVB-induced murine basal cell carcinoma (BCC) and in human skin tumor keratinocytes. AMP-kinase and acetyl Co-A carboxylase, the downstream LKB1 targets, are also enhanced in this neoplasm. In addition, p-Akt, a kinase which inactivates GSK3ß by its phosphorylation, is enhanced in BCCs. Consistently, an accumulation of p-GSK3ß and an increase in activated nuclear ß-catenin are found. mTOR signaling, which is also inhibited by LKB1, remains upregulated in BCCs. However, a marked decrease in the expression of sestrins, which function as potent negative regulators of mTOR is observed. Metformin, a known chemical inducer of this pathway, was found effective in immortalized HaCaT keratinocytes, but failed to activate the LKB1-dependent signaling in human carcinoma A431 cells. Thus, our data show that the LKB1/AMPK axis fails to regulate mTOR pathway, and a complex regulatory mechanism exists for the persistent mTOR activation in murine BCCs.

Localization of phosphatidylinositol (3,4,5)-trisphosphate to phagosomes in entamoeba histolytica achieved using glutathione S-transferase- and green fluorescent protein-tagged lipid biosensors.

Entamoeba histolytica is an intestinal protozoan parasite that causes amoebic dysentery and liver abscess. Phagocytosis by the parasite is a critical virulence process, since it is a prerequisite for tissue invasion and establishment of chronic infection. While the roles of many of the proteins that regulate phagocytosis-related signaling events in E. histolytica have been characterized, the functions of lipids in this cellular process remain largely unknown in this parasite. In other systems, phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)), a major product of phosphoinositide 3 kinase (PI3-kinase) activity, is essential for phagocytosis. Pleckstrin homology (PH) domains are protein domains that specifically bind to PIP(3). In this study, we utilized glutathione S-transferase (GST)- and green fluorescent protein (GFP)-labeled PH domains as lipid biosensors to characterize the spatiotemporal aspects of PIP(3) distribution during various endocytic processes in E. histolytica. PIP(3)-specific biosensors accumulated at extending pseudopodia and in phagosomal cups in trophozoites exposed to erythrocytes but did not localize to pinocytic compartments during the uptake of a fluid-phase marker, dextran. Our results suggest that PIP(3) is involved in the early stages of phagosome formation in E. histolytica. In addition, we demonstrated that PIP(3) exists at high steady-state levels in the plasma membrane of E. histolytica and that these levels, unlike those in mammalian cells, are not abolished by serum withdrawal. Finally, expression of a PH domain in trophozoites inhibited erythrophagocytosis and enhanced motility, providing genetic evidence supporting the role of PI3-kinase signaling in these processes in E. histolytica.