Follicular mucinosis: clinical, histologic, and molecular remission with minocycline.

Follicular mucinosis is an uncommon inflammatory disorder characterized histologically by mucin accumulation in the follicular epithelium. The condition is generally divided into primary and secondary forms, the latter being frequently associated with mycosis fungoides. Lesional skin T-cell clonality has been documented in some patients with follicular mucinosis, even those with no histologic evidence of cutaneous lymphoma. In this report, we describe a patient with clonal idiopathic primary follicular mucinosis who had complete clinical, histologic, and molecular remission with minocycline therapy.

Low-dose acitretin is associated with fewer adverse events than high-dose acitretin in the treatment of psoriasis.

OBJECTIVE: In practice, lower dose acitretin therapy (25 mg/d) seems to be better tolerated and associated with fewer abnormalities found after laboratory testing. Here we revisit the original phase 3 trials for acitretin to evaluate the evidence for low-dose therapy producing fewer adverse effects than the 50 mg/d dosage. DESIGN: We retrospectively analyzed pooled data from 2 large pivotal trials, each including a randomized, placebo-controlled, 8-week double-blind phase followed by a 16-week open-label phase. SETTING: Multicenter pivotal trial of subjects in referral centers and private practice. PARTICIPANTS: Subjects with severe psoriasis requiring systemic therapy were recruited according to inclusion/exclusion criteria. INTERVENTION: During the double-blind phase, subjects received placebo or one of several fixed acitretin doses. Dose adjustment was allowed during the open-label phase, during which high-dose treatment was defined as a mean dosage of 50 mg/d and low-dose treatment was defined as a mean dosage of 25 mg/d. MAIN OUTCOME MEASURES: The frequency of anomalies found after laboratory testing and clinical adverse events were the outcomes of interest. RESULTS: Common adverse effects (dry skin, alopecia, rhinitis, etc) were 2 to 3 times more frequent in subjects receiving 50-mg/d acitretin than in those receiving 25 mg/d. Increases in hepatic enzymes and triglycerides in subjects receiving low-dose therapy were minimal compared with levels in those receiving high-dose therapy. CONCLUSIONS: We have shown low-dose therapy (25 mg/d) to be an effective strategy for substantially reducing acitretin-associated adverse effects. Many adverse effects associated with acitretin therapy are dose dependent and can limit the usefulness of this potentially beneficial therapy.

Efficacy of low-dose acitretin in the treatment of psoriasis.

OBJECTIVES: Clinical experience favors low doses of acitretin to reduce adverse events but still maintain efficacy. We revisited the pivotal acitretin trials to compare the efficacy of high- versus low-dose acitretin. MATERIALS AND METHODS: We analyzed data from two large randomized trials which had an 8-week, double-blinded (DB), placebo-controlled phase followed by a 16-week open-label (OL) phase. During the DB phase, patients received placebo, 10, 25, 50, or 75 mg of acitretin daily. Dose adjustment was allowed during the OL phase, during which high-dose treatment was defined as approximately 50 mg/day and low-dose as approximately 25 mg/day. Primary end points were improvement of psoriasis based on investigator static global assessment (ISGA) and reduction in affected body surface area (BSA). RESULTS: At the end of the OL phase (week 24), treatment success rates were similar among all groups (29%-33%)--with the exception of the group receiving low-dose treatment for both DB and OL phases (47% success). Decrease in BSA was also highest in this group (73% vs. 28% to 54%). CONCLUSION: Individualization of acitretin dosing is crucial to minimize side effects and should lead to improved adherence and efficacy. This analysis supports the utility of low-dose acitretin for psoriasis over extended treatment periods.

Reactive oxygen signaling and MAPK activation distinguish Epstein-Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma.

Burkitt's lymphoma (BL) is an aggressive B cell neoplasm, which is one of the most common neoplasms of childhood. It is highly widespread in East Africa, where it appears in endemic form associated with Epstein-Barr virus (EBV) infection, and around the world in a sporadic form in which EBV infection is much less common. In addition to being the first human neoplasm to be associated with EBV, BL is associated with a characteristic translocation, in which the Ig promoter is translocated to constitutively activate the c-myc oncogene. Although many BLs respond well to chemotherapy, a significant fraction fails to respond to therapy, leading to death. In this article, we demonstrate that EBV-positive BL expresses high levels of activated mitogen-activated protein kinase and reactive oxygen species (ROS), and that ROS directly regulate NF-kappaB activation. EBV-negative BLs exhibit activation of phosphoinositol 3-kinase, but do not have elevated levels of ROS. Elevated reactive oxygen may play a role in diverse forms of viral carcinogenesis in humans, including cancers caused by EBV, hepatitis B, C, and human T cell lymphotropic virus. Our findings imply that inhibition of ROS may be useful in the treatment of EBV-induced neoplasia.

Transgenic expression of dominant negative tuberin through a strong constitutive promoter results in a tissue-specific tuberous sclerosis phenotype in the skin and brain.

Tuberous sclerosis (TS) is a common autosomal dominant disorder caused by loss or malfunction of hamartin (tsc1) or tuberin (tsc2). Many lesions in TS do not demonstrate loss of heterozygosity for these genes, implying that dominant negative forms of these genes may account for some hamartomas and neoplasms in TS. To test this hypothesis, we expressed a dominant negative allele of tuberin (DeltaRG) behind the cytomegalovirus promoter in NIH3T3 cells and transgenic mice. This allele binds hamartin but has a deletion in the C terminus of tuberin, leading to constitutive activation of rap1 and rab5/rabaptin. Expression of DeltaRG in NIH3T3 cells led to a strong induction of reactive oxygen species, induction of vascular endothelial growth factor, and malignant transformation in vivo. Expression of DeltaRG driven by the constitutive cytomegalovirus promoter led to high level expression in all murine tissues examined, including skin, kidney, liver, and brain. Surprisingly, mice expressing the DeltaRG transgene developed a fibrovascular collagenoma in the dermis, which closely resembles the Shagreen patch observed in human patients with TS. In addition, numerous small subpial collections of external granule cells in the cerebellum were observed, which may be the murine equivalent of subependymal giant cell astrocytomas or tubers commonly seen in TS patients. Thus, expression of a dominant negative tuberin in multiple tissues can lead to a tissue-specific phenotype resembling some of the findings in human TS. Our data are the first to demonstrate that specific signaling abnormalities underlie specific hamartomas in a model of a human genetic disorder.

Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo.

Natural products comprise a major source of small molecular weight angiogenesis inhibitors. We have used the transformed endothelial cell line SVR as an effective screen of natural product extracts to isolate anti-angiogenesis and anti-tumor compounds. Aqueous extracts of Magnolia grandiflora exhibit potent activity in our SVR proliferation assays. We found that the small molecular weight compound honokiol is the active principle of magnolia extract. Honokiol exhibited potent anti-proliferative activity against SVR cells in vitro. In addition, honokiol demonstrated preferential inhibition of primary human endothelial cells compared with fibroblasts and this inhibition was antagonized by antibodies against TNF alpha-related apoptosis-inducing ligand. In vivo, honokiol was highly effective against angiosarcoma in nude mice. Our preclinical data suggests that honokiol is a systemically available and non-toxic inhibitor of angiogenesis and should be further evaluated as a potential chemotherapeutic agent.