Actinic cheilitis: a systematic review of treatment options.

Actinic cheilitis is a premalignant condition that can progress to squamous cell carcinoma with a higher propensity for metastasis than cutaneous squamous cell carcinoma. Optimal treatment for actinic cheilitis has not been established, and evidence-based estimates of clinical cure in the dermatology literature are limited. Here, we review and synthesize outcome data published for patients with actinic cheilitis after treatment with various modalities. A systematic review was conducted in MEDLINE, Embase and the Cochrane library for English, French and German-language studies and references of included articles from inception to 20 January 2020. Studies were included if they reported on at least six patients with biopsy-proven actinic cheilitis. After quality appraisal, results of studies with the strongest methodology criteria were synthesized. 18 studies of 411 patients (published 1985 to 2016) were included. The majority of the studies were case series. Carbon dioxide laser ablation and vermilionectomy were associated with the most favourable outcomes with fewest recurrences. Chemical peel and photodynamic therapy were associated with higher recurrence. Adverse effects generally resolved in the weeks following treatment and cosmetic outcomes were favourable overall. In conclusion, there is a lack of high-quality comparative studies evaluating different treatment options for actinic cheilitis. The included publications used various outcome measures; however, the majority reported on the recently defined core outcome sets. These results suggest that both carbon dioxide laser ablation and vermilionectomy are effective treatments for actinic cheilitis. Prospective head-to-head studies are needed to compare these treatment modalities and to assess patient preferences.

Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sézary syndrome.

BACKGROUND: Quisinostat is a hydroxamate, second-generation, orally available pan-histone deacetylase inhibitor. OBJECTIVES: To evaluate the efficacy and safety of oral quisinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL). METHODS: Patients received quisinostat 8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles. Primary efficacy end point was cutaneous response rate (RR) based on the modified Severity Weighted Assessment Tool (mSWAT). Secondary end points included global RR, duration of response (DOR) in skin, progression-free survival (PFS), pruritus relief, safety and pharmacodynamic markers. RESULTS: Eight of 26 (25 evaluable) patients achieved ≥ 50% reduction in mSWAT score at least once, with confirmed cutaneous response in six (RR 24%). There was a low global RR of 8%. DOR in skin ranged from 2·8 to 6·9 months. Median PFS was 5·1 months. Pruritus relief was more frequent in cutaneous responders (67%) than nonresponders (32%). Serial tumour biopsies revealed an increase in acetylated tubulin, indicating a target effect of histone deacetylase 6. Twenty-one of 26 (81%) patients were withdrawn from the study before or at clinical cut-off; five (19%) continued to receive treatment with quisinostat. The most common drug-related adverse events were nausea, diarrhoea, asthenia, hypertension, thrombocytopenia and vomiting. Grade 3 drug-related adverse events included hypertension, lethargy, pruritus, chills, hyperkalaemia and pyrexia. CONCLUSIONS: Quisinostat 12 mg three times weekly is active in the treatment of patients with relapsed or refractory CTCL, with an acceptable safety profile. Combination therapy with other drugs active in CTCL may be appropriate.

Lessons learned from gene expression profiling of cutaneous T-cell lymphoma.

Gene expression studies of cutaneous T-cell lymphoma (CTCL) span a decade, yet the pathogenesis is poorly understood and diagnosis remains a challenge. This review examines the varied approaches to gene expression analysis of CTCL, with emphasis on cell populations, control selection and expression data collection. Despite discordant results, several dysregulated genes have been identified across multiple studies, including PLS3, KIR3DL2, TWIST1 and STAT4. Here, we provide an overview of the most consistently expressed genes across different studies and bring them together through common pathways biologically relevant to CTCL. Four pathways - evasion of activation-induced cell death, T helper 2 lymphocyte differentiation, transforming growth factor-ß receptor expression, and tumour necrosis factor receptor ligands - appear to encompass the most frequently affected genes, hypothetically providing insight into the disease pathogenesis.

Low-dose electron beam radiation and romidepsin therapy for symptomatic cutaneous T-cell lymphoma lesions.

BACKGROUND: Romidepsin is a structurally unique histone deacetylase inhibitor approved by the U.S. Food and Drug Administration for therapy of relapsed or refractory cutaneous T-cell lymphoma (CTCL). Localized electron beam radiation therapy (LEBT) is standard practice in the care of patients with chronically traumatized and painful lesions. Combination therapy of those two modalities may be beneficial for the therapy of CTCL. OBJECTIVES: To report observations on supportive LEBT utilized for isolated refractory lesions in patients on romidepsin. METHODS: Observations were made during a phase II clinical trial sponsored by the National Cancer Institute (NCI-1312) examining the efficacy of romidepsin for patients with relapsed, refractory or advanced CTCL, stage IB-IVA mycosis fungoides (MF) or Sézary syndrome. Skin responses were assessed by evaluation of five target lesions only. Patients with objective clinical responses in target lesions who had symptomatic nontarget lesions were allowed limited LEBT to isolated lesions for symptomatic relief. Patients who received localized radiation were not considered complete responders at any point. RESULTS: Five patients with advanced MF (three stage IIB and two stage IVA2) received LEBT to symptomatic nontarget lesions while on a protocol with romidepsin. None of these patients experienced additional or unexpected toxicity. Four of the five patients demonstrated fast and durable responses. We noted that significantly lower than standard doses of LEBT effectively treated symptomatic lesions in these patients. CONCLUSIONS: LEBT demonstrated significant responses at very low doses without additional toxicity in patients on protocol treatment with the histone deacetylase inhibitor romidepsin. This merits formal investigation in a clinical trial for potential synergy in patients with CTCL.

Novel approach to gene expression profiling in Sézary syndrome.

BACKGROUND: Microarray hybridization studies in Sézary syndrome (SS) have compared T lymphocytes from patients with cutaneous T-cell lymphoma with those of normal controls; a major limitation of this design is that significant inherent genetic variability of lymphocyte populations between individuals may produce differences in gene expression unrelated to disease state. OBJECTIVE: The objective of this study was to minimize the heterogeneity of information derived from whole-genome expression analysis and to identify specific genetic differences between highly purified malignant and nonmalignant (control) T cells from the same patient with SS. METHODS: Peripheral blood mononuclear cells were obtained from a patient with SS, stained with anti-T-cell receptor Vb (TCR-Vb) antibodies, and sorted by multiparameter flow cytometry. Malignant cells expressed the dominant TCR-Vb; control T cells lacked the dominant TCR-Vb but were otherwise phenotypically identical (CD3+CD4+CD45RO+). These cell populations were compared using the Illumina Inc. Sentrix Human-6 expression BeadChip system. RESULTS: Transcriptome analysis using the J5 test, which was selected for data analysis based on an efficiency analysis of competing statistical methods, showed differential expression of 44 genes between the malignant and nonmalignant cell subsets. Promyelocytic leukaemia zinc finger protein (ZBTB16) was the most profoundly upregulated gene in the malignant cell population, while interferon regulatory factor 3 (IRF3) and interferon-induced protein 35 (IFI35), which are important elements of the cellular response to viral infection, were significantly downregulated. CONCLUSIONS: The results of this study suggest the feasibility of this novel comparative approach to genomic profiling in SS. Using this method, we identified several differentially expressed genes and pathways not previously described in SS. While these findings require validation in larger studies, they may be important in SS pathogenesis.