Targeting Cutaneous T-Cell Lymphoma Cells by Ingenol Mebutate (PEP005) Correlates with PKCδ Activation, ROS Induction as Well as Downregulation of XIAP and c-FLIP.

New therapeutic strategies are needed for cutaneous T-cell lymphoma (CTCL), and the plant extract ingenol mebutate (PEP005) may be considered. PEP005 has been approved for actinic keratosis, and proapoptotic activities were described in different cancer cells. Here, we aimed to investigate its efficacy in four CTCL cell lines and its mode of action. While HuT-78 and HH responded with induced apoptosis as well as with loss of cell viability and cell proliferation, MyLa and SeAx remained resistant. Interestingly, both sensitive and resistant cells showed caspase-8 activation and enhanced levels of reactive oxygen species (ROS), while final caspase-3 activation was restricted to sensitive cells. Apoptosis induction was prevented by the caspase inhibitor QVD-Oph as well as by the antioxidant vitamin E. Caspase activation by PEP005 may be explained to some extent by the downregulation of the caspase antagonistic proteins c-FLIP and XIAP in sensitive cells, whereas both proteins were strongly expressed in resistant cells. Finally, PEP005 resulted in the activation of proapoptotic PKCδ, and the PKC inhibitor bisindolylmaleimide I reduced apoptosis, caspase-3 processing and ROS production, as well as restored cell viability. In conclusion, PKCδ appeared as a central player in apoptosis regulation in CTCL cells, also suggesting its therapeutic targeting.

Sleep disturbance in adult dermatologic patients: A cross-sectional study on prevalence, burden, and associated factors.

BACKGROUND: Sleep disturbance remains insufficiently characterized in many dermatoses. OBJECTIVE: To investigate the prevalence, burden, and factors associated with sleep disturbance in dermatologic patients. METHODS: We recruited 800 patients and recorded pruritus characteristics and sociodemographic and clinical parameters. Validated questionnaires were used to assess sleep disturbance, psychological distress, health-related quality of life, and work productivity. RESULTS: Two thirds of patients met criteria of poor sleep, which was associated with psychological distress, diminished health-related quality of life, and lost work productivity. Patients with average and maximum pruritus on the visual analog scale exceeding 5 and 6.5 points, respectively, were at high risk of suffering pruritus-related sleep disturbance. Overall pruritus intensity and its nocturnal exacerbation contributed independently to sleep disturbance. Psychological distress was of even higher impact on sleep than pruritus and almost a third of the relationship between pruritus intensity and sleep was mediated by psychological distress. CONCLUSION: Sleep disturbance is prevalent in dermatologic patients and constitutes a considerable burden. CLINICAL IMPLICATION: Dermatologic patients with intense pruritus and psychological distress should be examined for sleep disorders. Adequate antipruritic therapy and complementary psychotherapy in affected patients may help them regain restorative sleep.

The characteristics and impact of pruritus in adult dermatology patients: A prospective, cross-sectional study.

BACKGROUND: Pruritus often accompanies chronic skin diseases, exerting considerable burden on many areas of patient functioning; this burden and the features of pruritus remain insufficiently characterized. OBJECTIVE: To investigate characteristics, including localization patterns, and burden of pruritus in patients with chronic dermatoses. METHODS: We recruited 800 patients with active chronic skin diseases. We assessed pruritus intensity, localization, and further characteristics. We used validated questionnaires to assess quality of life, work productivity and activity impairment, anxiety, depression, and sleep quality. RESULTS: Nine out of every 10 patients had experienced pruritus throughout their disease and 73% in the last 7 days. Pruritus often affected the entire body and was not restricted to skin lesions. Patients with moderate to severe pruritus reported significantly more impairment to their sleep quality and work productivity, and they were more depressed and anxious than control individuals and patients with mild or no pruritus. Suicidal ideations were highly prevalent in patients with chronic pruritus (18.5%) and atopic dermatitis (11.8%). CONCLUSIONS: Pruritus prevalence and intensity are very high across all dermatoses studied; intensity is linked to impairment in many areas of daily functioning. Effective treatment strategies are urgently required to treat pruritus and the underlying skin disease.

Key Role of Reactive Oxygen Species (ROS) in Indirubin Derivative-Induced Cell Death in Cutaneous T-Cell Lymphoma Cells.

Cutaneous T-cell lymphoma (CTCL) may develop a highly malignant phenotype in its late phase, and patients may profit from innovative therapies. The plant extract indirubin and its chemical derivatives represent new and promising antitumor strategies. This first report on the effects of an indirubin derivative in CTCL cells shows a strong decrease of cell proliferation and cell viability as well as an induction of apoptosis, suggesting indirubin derivatives for therapy of CTCL. As concerning the mode of activity, the indirubin derivative DKP-071 activated the extrinsic apoptosis cascade via caspase-8 and caspase-3 through downregulation of the caspase antagonistic proteins c-FLIP and XIAP. Importantly, a strong increase of reactive oxygen species (ROS) was observed as an immediate early effect in response to DKP-071 treatment. The use of antioxidative pre-treatment proved the decisive role of ROS, which turned out upstream of all other proapoptotic effects monitored. Thus, reactive oxygen species appear as a highly active proapoptotic pathway in CTCL, which may be promising for therapeutic intervention. This pathway can be efficiently activated by an indirubin derivative.

Treatment of localized mycosis fungoides with digital UV photochemotherapy.

BACKGROUND/PURPOSE: Photochemochemotherapy with 8-methoxypsoralen and UV-A light (PUVA) is a well-established treatment for mycosis fungoides (MF), although evidence for this therapy by means of prospective studies is scarce. However, long-term risks of PUVA are premature skin aging and development of nonmelanoma skin cancer. We therefore evaluated a device for targeted UV therapy, which reduces irradiation of unaffected skin in MF patients. METHODS: Ten patients with patch- or plaque-type MF affecting less than 10% body surface area were included in a prospective study. A total of 14 lesions were treated with cream PUVA using the digital phototherapy device skintrek(®) PT3. RESULTS: Seven of ten patients showed response to treatment. Complete clinical remission was achieved in four of ten patients (complete remission of seven of fourteen treated lesions) after an average of 13.4 weeks and an average cumulative UV dose of 42.6 J/cm(2) in a mean of 31.2 treatment sessions. Adverse events were rare and of mild severity. CONCLUSIONS: This study is the first prospective trial demonstrating efficacy and safety of cream PUVA in MF patients. As healthy adjacent skin remains unaffected, the potential to reduce the carcinogenic risk of PUVA treatment makes this new method a promising therapeutic option for localized MF.

Seroprevalence of 34 human papillomavirus types in the German general population.

The natural history of infections with many human papillomavirus (HPV) types is poorly understood. Here, we describe for the first time the age- and sex-dependent antibody prevalence for 29 cutaneous and five mucosal HPV types from 15 species within five phylogenetic genera (alpha, beta, gamma, mu, nu) in a general population. Sera from 1,797 German adults and children (758 males and 1,039 females) between 1 and 82 years (median 37 years) were analysed for antibodies to the major capsid protein L1 by Luminex-based multiplex serology. The first substantial HPV antibody reactions observed already in children and young adults are those to cutaneous types of the genera nu (HPV 41) and mu (HPV 1, 63). The antibody prevalence to mucosal high-risk types, most prominently HPV 16, was elevated after puberty in women but not in men and peaked between 25 and 34 years. Antibodies to beta and gamma papillomaviruses (PV) were rare in children and increased homogeneously with age, with prevalence peaks at 40 and 60 years in women and 50 and 70 years in men. Antibodies to cutaneous alpha PV showed a heterogeneous age distribution. In summary, these data suggest three major seroprevalence patterns for HPV of phylogenetically distinct genera: antibodies to mu and nu skin PV appear early in life, those to mucosal alpha PV in women after puberty, and antibodies to beta as well as to gamma skin PV accumulate later in life.

Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study.

BACKGROUND: Human papillomavirus (HPV), the causal agent of cervical cancer, appears to be involved in the etiology of cancer of the oral cavity and oropharynx. To investigate these associations, we conducted a multicenter case-control study of cancer of the oral cavity and oropharynx in nine countries. METHODS: We recruited 1670 case patients (1415 with cancer of the oral cavity and 255 with cancer of the oropharynx) and 1732 control subjects and obtained an interview, oral exfoliated cells, and blood from all participants and fresh biopsy specimens from case patients. HPV DNA was detected by polymerase chain reaction (PCR). Antibodies against HPV16 L1, E6, and E7 proteins in plasma were detected with enzyme-linked immunosorbent assays. Multivariable models were used for case-control and case-case comparisons. RESULTS: HPV DNA was detected in biopsy specimens of 3.9% (95% confidence interval [CI] = 2.5% to 5.3%) of 766 cancers of the oral cavity with valid PCR results and 18.3% (95% CI = 12.0% to 24.7%) of 142 cancers of the oropharynx (oropharynx and tonsil combined) with valid PCR results. HPV DNA in cancer biopsy specimens was detected less frequently among tobacco smokers and paan chewers and more frequently among subjects who reported more than one sexual partner or who practiced oral sex. HPV16 DNA was found in 94.7% of HPV DNA-positive case patients. HPV DNA in exfoliated cells was not associated with cancer risk or with HPV DNA detection in biopsy specimens. Antibodies against HPV16 L1 were associated with risk for cancers of the oral cavity (odds ratio [OR] = 1.5, 95% CI = 1.1 to 2.1) and the oropharynx (OR = 3.5, 95% CI = 2.1 to 5.9). Antibodies against HPV16 E6 or E7 were also associated with risk for cancers of the oral cavity (OR = 2.9, 95% CI = 1.7 to 4.8) and the oropharynx (OR = 9.2, 95% CI = 4.8 to 17.7). CONCLUSIONS: HPV appears to play an etiologic role in many cancers of the oropharynx and possibly a small subgroup of cancers of the oral cavity. The most common HPV type in genital cancers (HPV16) was also the most common in these tumors. The mechanism of transmission of HPV to the oral cavity warrants further investigation.