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Deals with the diagnosis of cutaneous diseases. Analysis of the different approaches to diagnosing cutaneous diseases; Observations from staining cutaneous T-cell lymphoma lesional skin with monoclonal antibodies to mononuclear cells; Conclusion.

Melanoma, originating through malignant transformation of melanin-producing melanocytes, is a formidable malignancy, characterized by local invasiveness, recurrence, early metastasis, resistance to therapy, and a high mortality rate. This review discusses etiologic and risk factors for melanoma, diagnostic and prognostic tools, including recent advances in molecular biology, omics, and bioinformatics, and provides an overview of its therapy. Since the incidence of melanoma is rising and mortality remains unacceptably high, we discuss its inherent properties, including melanogenesis, that make this disease resilient to treatment and propose to use AI to solve the above complex and multidimensional problems. We provide an overview on vitamin D and its anticancerogenic properties, and report recent advances in this field that can provide solutions for the prevention and/or therapy of melanoma. Experimental papers and clinicopathological studies on the role of vitamin D status and signaling pathways initiated by its active metabolites in melanoma prognosis and therapy are reviewed. We conclude that vitamin D signaling, defined by specific nuclear receptors and selective activation by specific vitamin D hydroxyderivatives, can provide a benefit for new or existing therapeutic approaches. We propose to target vitamin D signaling with the use of computational biology and AI tools to provide a solution to the melanoma problem.

The skin, which is comprised of the epidermis, dermis, and subcutaneous tissue, is the largest organ in the human body and it plays a crucial role in the regulation of the body's homeostasis. These functions are regulated by local neuroendocrine and immune systems with a plethora of signaling molecules produced by resident and immune cells. In addition, neurotransmitters, endocrine factors, neuropeptides, and cytokines released from nerve endings play a central role in the skin's responses to stress. These molecules act on the corresponding receptors in an intra-, juxta-, para-, or autocrine fashion. The epidermis as the outer most component of skin forms a barrier directly protecting against environmental stressors. This protection is assured by an intrinsic keratinocyte differentiation program, pigmentary system, and local nervous, immune, endocrine, and microbiome elements. These constituents communicate cross-functionally among themselves and with corresponding systems in the dermis and hypodermis to secure the basic epidermal functions to maintain local (skin) and global (systemic) homeostasis. The neurohormonal mediators and cytokines used in these communications regulate physiological skin functions separately or in concert. Disturbances in the functions in these systems lead to cutaneous pathology that includes inflammatory (i.e., psoriasis, allergic, or atopic dermatitis, etc.) and keratinocytic hyperproliferative disorders (i.e., seborrheic and solar keratoses), dysfunction of adnexal structure (i.e., hair follicles, eccrine, and sebaceous glands), hypersensitivity reactions, pigmentary disorders (vitiligo, melasma, and hypo- or hyperpigmentary responses), premature aging, and malignancies (melanoma and nonmelanoma skin cancers). These cellular, molecular, and neural components preserve skin integrity and protect against skin pathologies and can act as "messengers of the skin" to the central organs, all to preserve organismal survival.

Hydroxyderivatives of vitamin D3, including classical 1,25(OH) 2 D3 and novel CYP11A1‑derived hydroxyderivatives, exert their biological activity by acting as agonists on the vitamin D receptor (VDR) and inverse agonists on retinoid‑related orphan receptors (ROR)α and γ. The anticancer activities of CYP11A1‑derived hydroxyderivatives were tested using cell biology, tumor biology and molecular biology methods in human A431 and SCC13 squamous (SCC)‑ and murine ASZ001 basal (BCC)‑cell carcinomas, in comparison with classical 1,25(OH) 2 D3. Vitamin D3‑hydroxyderivatives with or without a C1α(OH) inhibited cell proliferation in a dose‑dependent manner. While all the compounds tested had similar effects on spheroid formation by A431 and SCC13 cells, those with a C1α(OH) group were more potent in inhibiting colony and spheroid formation in the BCC line. Potent anti‑tumorigenic activity against the BCC line was exerted by 1,25(OH) 2 D3, 1,20(OH) 2 D3, 1,20,23(OH) 3 D3, 1,20,24(OH) 3 D3, 1,20,25(OH) 3 D3 and 1,20,26(OH) 3 D3, with smaller effects seen for 25(OH)D3, 20(OH)D3 and 20,23(OH) 2 D3. 1,25(OH) 2 D3, 1,20(OH) 2 D3 and 20(OH)D3 inhibited the expression of GLI1 and β‑catenin in ASZ001 cells. In A431 cells, these compounds also decreased the expression of GLI1 and stimulated involucrin expression. VDR, RORγ, RORα and CYP27B1 were detected in A431, SCC13 and ASZ001 lines, however, with different expression patterns. Immunohistochemistry performed on human skin with SCC and BCC showed nuclear expression of all three of these receptors, as well as megalin (transmembrane receptor for vitamin D‑binding protein), the level of which was dependent on the type of cancer and antigen tested in comparison with normal epidermis. Classical and CYP11A1‑derived vitamin D3‑derivatives exhibited anticancer‑activities on skin cancer cell lines and inhibited GLI1 and β‑catenin signaling in a manner that was dependent on the position of hydroxyl groups. The observed expression of VDR, RORγ, RORα and megalin in human SCC and BCC suggested that they might provide targets for endogenously produced or exogenously applied vitamin D hydroxyderivatives and provide excellent candidates for anti‑cancer therapy.

Background: Long-term safety of topical calcineurin inhibitors is not well understood. APPLES (A Prospective Pediatric Longitudinal Evaluation to Assess the Long-Term Safety of Tacrolimus Ointment for the Treatment of Atopic Dermatitis; NCT00475605) examined incidence of lymphoma and other cancers in a pediatric population with atopic dermatitis., Objective: To quantify incident malignancies during 10 years in children with atopic dermatitis who used topical tacrolimus for ≥6 weeks., Methods: Standardized incidence ratios for cancer events were analyzed relative to sex-, age-, and race-matched control data from national cancer registries., Results: There were 7954 eligible patients enrolled at 314 sites in 9 countries. During 44,629 person-years, 6 confirmed incident cancers occurred (standardized incidence ratio, 1.01; 95% confidence interval, 0.37-2.20). No lymphomas occurred., Limitations: Observational prospective cohort study., Conclusion: The cancer incidence was as expected, given matched background data. This finding provides no support for the hypothesis that topical tacrolimus increases long-term cancer risk in children with atopic dermatitis., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Actinic keratoses (AKs) are common premalignant skin lesions triggered by excessive ultraviolet exposure. The majority of AKs regress or persist, but some progress to squamous cell carcinomas. Biomarkers associated with their persistence, progression and regression have not been characterized., Objectives: We performed skin biopsies in patients with extensive actinic damage to identify biomarkers that correlate with clinical progression and regression of AKs., Methods: This was an observational study of a cohort of patients with extensive actinic damage. AKs were mapped on a clear plastic template in 26 patients at months 3, 6, 9 and 11. Biopsies were taken from randomly selected, predetermined AKs and were evaluated for p53, E-cadherin, Snail, Slug and Twist. The study is registered at Clinicaltrials.gov: NCT00027976., Results: p53 exhibited greater expression in clinically apparent AKs (histological score 2·89 ± 1·45) than in regressed AKs (0·75 ± 0·96); P < 0·01. There was also significantly less membrane E-cadherin, the lack of which is a marker of epithelial-mesenchymal transition, in clinically apparent AKs (1·89 ± 1·81) than in sun-exposed skin (3·07 ± 1·75); P < 0·005. The E-cadherin transcription repressors Snail, Slug and Twist were increased in AKs compared with sun-exposed skin. A limitation of the study is that measurement of histological biomarkers was not a primary end point. In addition, patients were allowed to apply sunscreens., Conclusions: At the molecular level, loss of E-cadherin and an increase in p53 are linked to the dynamic interplay between the persistence, progression and regression of AKs. What's already known about this topic? Actinic keratoses (AKs) are common dysplastic epidermal lesions that result from chronic and excessive ultraviolet exposure. Biomarkers associated with progression and regression of AK have not been characterized. What does this study add? Decreased E-cadherin and increased p53, Snail, Slug and Twist (E-cadherin transcription factors) were associated with progression from AK to nonmelanoma skin cancer. What is the translational message? Strategies targeting these molecules may be effective in reversing rising skin cancer rates. E-cadherin, p53, Snail, Slug and Twist are potential biomarkers that may be used to assess the efficacy of existing chemopreventive agents., (© 2019 British Association of Dermatologists.)

Nonmelanoma skin cancers including basal and squamous cell carcinomas (SCC and BCC) represent a significant clinical problem due to their relatively high incidence, imposing an economic burden to healthcare systems around the world. It is accepted that ultraviolet radiation (UVR: λ = 290-400 nm) plays a crucial role in the initiation and promotion of BCC and SCC with UVB (λ = 290-320 nm) having a central role in this process. On the other hand, UVB is required for vitamin D3 (D3) production in the skin, which supplies >90% of the body's requirement for this prohormone. Prolonged exposure to UVB can also generate tachysterol and lumisterol. Vitamin D3 itself and its canonical (1,25(OH) 2 D3) and noncanonical (CYP11A1-intitated) D3 hydroxyderivatives show photoprotective functions in the skin. These include regulation of keratinocyte proliferation and differentiation, induction of anti-oxidative responses, inhibition of DNA damage and induction of DNA repair mechanisms, and anti-inflammatory activities. Studies in animals have demonstrated that D3 hydroxyderivatives can attenuate UVB or chemically induced epidermal cancerogenesis and inhibit growth of SCC and BCC. Genomic and non-genomic mechanisms of action have been suggested. In addition, vitamin D3 itself inhibits hedgehog signaling pathways which have been implicated in many cancers. Silencing of the vitamin D receptor leads to increased propensity to develop UVB or chemically induced epidermal cancers. Other targets for vitamin D compounds include 1,25D3-MARRS, retinoic orphan receptors α and γ, aryl hydrocarbon receptor, and Wnt signaling. Most recently, photoprotective effects of lumisterol hydroxyderivatives have been identified. Clinical trials demonstrated a beneficial role of vitamin D compounds in the treatment of actinic keratosis. In summary, recent advances in vitamin D biology and pharmacology open new exciting opportunities in chemoprevention and treatment of skin cancers.

Background: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma., Methods: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805., Findings: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related., Interpretation: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma., Funding: Kyowa Kirin., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Melanoma represents a significant clinical problem affecting a large segment of the population with a relatively high incidence and mortality rate. Ultraviolet radiation (UVR) is an important etiological factor in malignant transformation of melanocytes and melanoma development. UVB, while being a full carcinogen in melanomagenesis, is also necessary for the cutaneous production of vitamin D3 (D3). Calcitriol (1,25(OH) 2 D3) and novel CYP11A1-derived hydroxyderivatives of D3 show anti-melanoma activities and protective properties against damage induced by UVB. The former activities include inhibitory effects on proliferation, plating efficiency and anchorage-independent growth of cultured human and rodent melanomas in vitro, as well as the in vivo inhibition of tumor growth by 20(OH)D3 after injection of human melanoma cells into immunodeficient mice. The literature indicates that low levels of 25(OH)D3 are associated with more advanced melanomas and reduced patient survivals, while single nucleotide polymorphisms of the vitamin D receptor or the D3 binding protein gene affect development or progression of melanoma, or disease outcome. An inverse correlation of VDR and CYP27B1 expression with melanoma progression has been found, with low or undetectable levels of these proteins being associated with poor disease outcomes. Unexpectedly, increased expression of CYP24A1 was associated with better melanoma prognosis. In addition, decreased expression of retinoic acid orphan receptors α and γ, which can also bind vitamin D3 hydroxyderivatives, showed positive association with melanoma progression and shorter disease-free and overall survival. Thus, inadequate levels of biologically active forms of D3 and disturbances in expression of the target receptors, or D3 activating or inactivating enzymes, can affect melanomagenesis and disease progression. We therefore propose that inclusion of vitamin D into melanoma management should be beneficial for patients, at least as an adjuvant approach. The presence of multiple hydroxyderivatives of D3 in skin that show anti-melanoma activity in experimental models and which may act on alternative receptors, will be a future consideration when planning which forms of vitamin D to use for melanoma therapy., (Published by Elsevier Ltd.)

The use of Polypodium leucotomos, a species of fern, has been reported to be beneficial in the treatment of atopic dermatitis, vitiligo, and psoriasis, and for prevention of polymorphic light eruption, sunburn, and squamous cell carcinoma. We review the in vivo animal, in vitro human, and human clinical studies performed to help elucidate the actions of and biologic pathways affected by P. leucotomos. These results serve as the scientific rationale and basis for the protection and effectiveness afforded by P. leucotomos in cutaneous diseases., Competing Interests: Relevant Conflicts of Interest: Dr. Berman is and has served on Advisory Boards and as investigator for Ferndale. Dr. Ellis serves as a consultant to Ferndale Healthcare, Inc. and to companies that market products for the treatment or prevention of photoaging, psoriasis, and atopic dermatitis. Dr. Elmets is a consultant for Ferndale Healthcare, Inc.

Secukinumab (also known as AIN-457) is a human monoclonal antibody targeting IL-17A, which has been recently FDA-approved for the treatment of moderate to severe psoriasis and psoriatic arthritis with coexistent moderate to severe plaque psoriasis based on clinical trials demonstrating excellent efficacy. This review will address the rationale for targeting the IL-23/Th17/IL-17 axis, the role of IL-17 and Th17 cells in psoriasis and other chronic inflammatory diseases, and will examine pre-clinical studies, pharmacologic properties, clinical efficacy, and the safety profile of secukinumab.

Background: Osteopontin (OPN) is a matricellular glycoprotein that is markedly expressed in cutaneous squamous cell carcinomas (cSCCs) and in actinic keratoses implicating its role in photocarcinogenesis., Objective: To determine whether OPN facilitates the development of cSCC and its function., Methods: cSCCs development was compared between wild-type (WT) and OPN-null mice subjected to UVB irradiation for 43 weeks. UVB-induced OPN expression was determined by Western blot, immunoprecipitation, ELISA, and semi-quantitative RT-PCR. Epidermal layer and TUNEL analyses assessed if OPN mediates UVB-induced epidermal hyperplasia or suppresses UVB-induced apoptosis of basal keratinocytes, respectively. In vitro experiments determined whether OPN enhances cell survival of UVB-induced apoptosis and its potential mechanisms. Immunohistochemical analyses of epidermis assessed the expression of CD44 and focal adhesion kinase (FAK), molecules that mediate OPN survival function., Results: Compared to female WT mice, OPN-null mice did not develop cSCCs. UVB irradiation stimulated OPN protein expression in the dorsal skin by 11h and remains high at 24-48h. OPN did not mediate UVB-induced epidermal hyperplasia; instead, it protected basal keratinocytes from undergoing apoptosis upon UVB exposure. Likewise, the addition of OPN suppressed UVB-induced OPN-null cSCC cell apoptosis, the activation of caspase-9 activity, and increased phosphorylation of FAK at Y397. Furthermore, the expression of CD44 and FAK in WT mice epidermis was greater than that of OPN-null mice prior to and during early acute UVB exposure., Conclusion: These data support the hypothesis that chronic UVB-induced OPN expression protects the survival of initiated basal keratinocytes and, consequently, facilitates cSCC develop., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The matricellular protein osteopontin (OPN), expressed in various cancer types and elevated in the blood of cancer patients, is thought to have different functions when derived from host versus cancer cells. To assess the effect of host-derived OPN on growth of cancers of epithelial origin, we established a line of cutaneous squamous cell carcinoma (SCC) cells, named ONSC, which lacks the OPN gene and develops SCC in syngeneic wild-type (WT) and OPN-null mice. At 8 and/or 10 week after subcutaneous injection of ONSC cells in mice, however, there was a lower tumor incidence in WT mice, suggesting that host-derived OPN is associated with suppression of early growth of extrinsic cancer cells. Histological, immunohistochemical, biochemical and hematological analyses were performed on the tumor microenvironment and blood from tumor-bearing mice during the first week after implantation. Host-derived OPN suppression of extrinsic ONSC cell progression is likely mediated through elicitation of an early innate inflammatory response, through its function as a chemoattractant and/or by enhancing survival of inflammatory cells. Further, consistent with a previous report, the serum levels of host-derived OPN, which are elevated during the early phase of tumor growth in mice implanted with ONSC, appear to reflect an anti-tumor progression effect., (Copyright © 2011 UICC.)

Background: Studies of noncutaneous and cutaneous malignancies support the hypothesis that poor risk-perception status contributes to health disparity., Objective: We evaluated skin cancer (SC) risk perceptions across race and other demographic markers using the Health Information National Trends Survey (HINTS) and compared them to discover differences in perception that may contribute to the disparities in SC diagnosis and treatment., Methods: Respondents with no history of SC were randomly selected to answer questions assessing perceived risk and knowledge of preventive strategies of SC. Logistic regression was performed to identify associations between perceptions of SC and demographic variables including self-described race, age, sex, education, income, and health insurance status., Results: Blacks, the elderly, and people with less education perceived themselves as at lower risk of developing SC. They, along with Hispanics, were also more likely to believe that one cannot lower their SC risk and that there are so many different recommendations on how to prevent SC that it makes it difficult to know which ones to follow. Lower education also correlated with greater reluctance to have a skin examination., Limitations: HINTS is a cross-sectional instrument, thus it only provides a snapshot of SC perceptions., Conclusion: Uncertainty and altered perceptions are more common in the SC risk perceptions of ethnic minorities, the elderly, and those with less education. These are the same groups that are subject to disparities in SC outcomes. Educational programs directed at these demographic groups may help to reduce the SC-related health disparities., (Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Introduction: Hand and foot psoriasis may be more disabling than psoriasis at other body locations because of its interference with daily functional activities. Most treatment options have limited efficacy, short duration of response, toxicity, intolerability, or inconvenience., Objective: To investigate whether efalizumab (Raptiva) is efficacious and safe for the treatment of patients with hand and foot psoriasis., Method: Adult patients with moderate-to-severe hand and/or foot psoriasis received a conditioning dose of efalizumab 0.7 mg/kg at week 0 with subsequent doses of efalizumab 1 mg/kg given weekly for 11 additional weeks (total of 12 doses). Patients were followed until week 24 (12 weeks after the last treatment) to monitor safety and efficacy. Static Physician's Global Assessment (PGA) scores were used to measure efficacy. The primary efficacy endpoint was the number of patients achieving a 50% reduction in the global evaluation by static PGA from baseline at week 12., Results: Ten patients enrolled, six of whom completed the study. Of these six patients, four patients showed overall improvement at 12 weeks, including two patients that achieved 50% improvement overall. At 12 weeks, the hands of two patients and the feet of two patients showed at least 50% improvement from baseline. Efalizumab was well tolerated and there were no serious adverse events., Conclusion: Continuous treatment with efalizumab for 12 weeks was safe and efficacious in this open-label study of patients with hand and foot psoriasis.

Background: The efficacy and safety of UVA1 (340-400 nm) phototherapy were established by studies from European countries., Purpose: Evaluate experience with UVA1 phototherapy for patients with cutaneous diseases in the United States., Methods: A retrospective analysis of 92 cases of UVA1-treated cutaneous conditions from four medical centers in the United States was performed., Results: Two-third of the patients showed a fair to good response (26-100% improvement) and one-third of the patients showed a poor response (0-25% improvement). Diseases with a moderate to good response (51-100% improvement) included scleredema adultorum, hand or foot dermatitis, atopic dermatitis, morphea (medium or medium- to high-dose UVA1), systemic sclerosis, and urticaria pigmentosa. Besides tanning, other adverse effects were found in 15% of patients, which include pruritus, erythema, tenderness, and burning sensation. Patients with skin types I-III responded better that those with a darker skin type., Conclusion: UVA1 phototherapy is a useful and well-tolerated treatment option for a variety of skin conditions.

Osteopontin is a secreted, adhesive glycoprotein, whose expression is markedly elevated in several types of cancer and premalignant lesions, implicating its association with carcinogenesis. To test the hypothesis that induced osteopontin is involved in tumor promotion in vivo, osteopontin-null and wild-type (WT) mice were subjected to a two-stage skin chemical carcinogenesis protocol. Mice were initiated with 7,12-dimethylbenz(a)anthracene (DMBA) applied on to the dorsal skin followed by twice weekly application of 12-O-tetradecanoylphorbol-13-acetate (TPA) for 27 weeks. Osteopontin-null mice showed a marked decrease both in tumor/papilloma incidence and multiplicity compared with WT mice. Osteopontin is minimally expressed in normal epidermis, but on treatment with TPA its expression is highly induced. To determine the possible mechanism(s) by which osteopontin regulates tumor development, we examined cell proliferation and cell survival. Epidermis from osteopontin-null and WT mice treated with TPA thrice or with DMBA followed by TPA for 11 weeks showed a similar increase in epidermal hyperplasia, suggesting that osteopontin does not mediate TPA-induced cell proliferation. Bromodeoxyuridine staining of papillomas and adjacent epidermis showed no difference in cell proliferation between groups. However, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analyses indicated a greater number of apoptotic cells in DMBA-treated skin and papillomas from osteopontin-null versus WT mice. These studies are the first to show that induction of the matricellular protein osteopontin facilitates DMBA/TPA-induced cutaneous carcinogenesis most likely through prevention of apoptosis.

A body of evidence indicates that expression of the programmed cell death 1 (PD-1) receptor by activated T cells plays an important role in the down-regulation of immune responses; however, the functions of its known ligands, B7-H1 (PD-L1) and B7-dendritic cell (DC; PD-L2), at the effector phase of immune responses are less clear. In the current study, we investigated the roles of B7-H1 in DC-mediated regulation of hapten-activated T cells and the delayed-type contact hypersensitivity response in primed animals. We found that the expression of B7-H1 and B7-DC was induced on activation of DC by hapten stimulation. Blockade of B7-H1, but not B7-DC, enhanced the activity of hapten-specific T cells. Interaction with a DC line that expresses high cell-surface levels of B7-H1 (B7-H1/DC) suppressed the proliferation of, and cytokine production by, activated T cells. In vivo administration of hapten-carrying B7-H1/DC desensitized the response of sensitized animals to hapten challenge, and this desensitization was hapten-specific. These data indicate that B7-H1 expressed by DC mediates inhibitory signals for activated T cells and suppresses the elicitation of immune responses. The ability of B7-H1/DC to inhibit the function of preactivated T cells in vivo suggests novel strategies for the treatment of immune response-mediated disorders.

Objective: To determine whether atopic dermatitis (AD) patients treated with tacrolimus ointment experienced an increased risk of non-melanoma skin cancer (NMSC)., Methods: Data were collected from 9813 adult and paediatric patients with AD who applied 0.03% or 0.1% tacrolimus ointment twice daily and were examined every 3 months during the tacrolimus ointment development programme., Results: Thirteen adult patients were diagnosed with NMSC during the follow-up period. All patients with NMSC were white adults and 12 were over 40 years of age. Based on 1718 patient-years of tacrolimus ointment exposure in patients 40 years of age, the calculated incidence of NMSC did not suggest an increased risk of first NMSC over that of a similarly aged US cohort., Conclusion: This study does not indicate an increased risk for the development of NMSC in patients with AD treated with tacrolimus ointment for a mean duration of 208 days with a maximum observation period of 1479 days.

Background: Efficient treatment of patients with multiple synchronous nonmelanoma skin cancers represents a therapeutic challenge., Objective: To study the safety and efficacy of photodynamic therapy (PDT) with verteporfin and red light in the treatment of multiple nonmelanoma skin cancers., Design: Open-label, randomized, multicenter, dose-ranging phase 2 study conducted at 4 North American university-based dermatology clinics., Patients: Fifty-four patients with 421 multiple nonmelanoma skin cancers including superficial and nodular basal cell carcinoma and squamous cell carcinoma in situ (Bowen disease)., Methods: A single intravenous infusion of 14 mg/m(2) of verteporfin followed 1 to 3 hours later by exposure of tumors to 60, 120, or 180 J/cm(2) of red light (688 +/- 10 nm) from a light-emitting diode panel., Main Outcome Measures: Pathologic response of treated sites was assessed at 6 months. Clinical and cosmetic responses were assessed and graded at 6 weeks, 3 months, and 6 months after verteporfin PDT, with optional follow-up visits at 12, 18, and 24 months., Results: The histopathologic response, defined as absence of tumor on biopsy specimens 6 months after verteporfin PDT, ranged from 69% at 60 J/cm(2) to 93% at 180 J/cm(2). At 24 months of follow-up (276 tumors in 31 patients), the clinical complete response rate ranged from 51% at 60 J/cm(2) to 95% at 180 J/cm(2). No significant systemic adverse events were observed; most events occurred at the treated tumor sites and included events such as pain. Overall, 65% (95% confidence interval, 58%-71%) of tumors were judged to have good to excellent cosmesis at 24 months., Conclusion: A single course of verteporfin PDT showed treatment benefit for patients with multiple nonmelanoma skin cancers.

One of the essential functions of dendritic cells is to take up Ags in peripheral tissues and migrate into secondary lymphoid organs to present Ags to lymphocytes for the induction of immune responses. Although many studies have demonstrated that the migration of dendritic cells is closely associated with the development of immune responses, little is known about factors that inhibit dendritic cell migration and control the extent of immune responses to Ag stimulation. We show that Slit2, a neuronal repellent factor, is up-regulated in the skin by allergen sensitization and down-regulates the migration of Langerhans cells. The effect is mediated by direct interaction of Slit2 with cells that express a Slit-specific receptor, Robo1. Slit2-mediated inhibition of Langerhans cell migration results in suppression of contact hypersensitivity responses. These findings provide insights into a novel mechanism by which Slit2 functions as an anti-inflammatory factor for the initiation of immune responses.

It has been reported that gammadeltaT cells are required for transfer of contact hypersensitivity responses by hapten-primed T cells. The mechanism by which they do so, however, remains to be elucidated. To specifically investigate the role of gammadeltaT cells in the development of contact hypersensitivity, this study employed Tdelta gene knockout mice that are deficient in gammadeltaT cells but are normal in the development of alphabetaT cells. The result indicates that contact hypersensitivity responses were significantly greater in gammadeltaT cell deficient mice than in wild-type mice. Similar results were obtained when wild-type mice were depleted of gammadeltaT cells with antibody treatment before hapten sensitization. Depletion of CD4+ T cells did not affect the increased contact hypersensitivity response in gammadeltaT cell deficient mice, suggesting that the effect of gammadeltaT cells is on CD8+ T cells and does not require CD4+ T cells. Further experiments demonstrated that primed CD8+ T cells from the deficient mice exhibited significantly higher CTL activity. The cytokine profile of CD4+ T cells was not significantly altered. Transfer of primed lymph node cells from hapten-primed gammadeltaT cell deficient mice elicited a similar level of contact hypersensitivity in naive wild-type and the deficient recipient mice, indicating that gammadeltaT cells have little effect on the elicitation of primed T cells and contact hypersensitivity responses. We conclude that gammadeltaT cells downregulate contact hypersensitivity responses to hapten sensitization by limiting the development of hapten-specific CD8+ effector T cells during sensitization and that this effect is independent of CD4+ T cells.

The effectiveness of vaccination programs would be enhanced greatly through the availability of vaccines that can be administered simply and, preferably, painlessly without the need for timed booster injections. Tetanus is a prime example of a disease that is readily preventable by vaccination but remains a major threat to public health due to the problems associated with administration of the present vaccine. Here we show that a protective immune response against live Clostridium tetani infection in mice can be elicited by an adenovirus vector encoding the tetanus toxin C fragment when administered as a nasal or epicutaneous vaccine. The results suggest that these vaccination modalities would be effective needle-free alternatives. This is the first demonstration that absorption of a small number of vectored vaccines into the skin following topical application of a patch can provide protection against live bacteria in a disease setting.

Polyaromatic hydrocarbons (PAHs) are chemicals that are widely employed to examine the complex mechanisms by which chemicals cause cancer. While it is clear that the tumors that carcinogenic PAHs produce elicit an immune response, the interplay between host immune defense mechanisms and earlier stages in the cutaneous carcinogenesis pathway has received little attention. Studies from our laboratories have shown that topical application of several different PAHs to mice results in the development of an antigen-specific cell-mediated immune response to them. The response is genetically determined and is mediated by CD8+ T cells. Development of a cell-mediated immune response is associated with resistance to dimethylbenz(a)anthracene tumorigenesis. These findings are consistent with the hypothesis that host defense mechanisms against PAHs help to protect individuals from the carcinogenic actions of these agents. This may form the basis for novel immunopreventive strategies for individuals at high risk for development of tumors produced by PAHs., (Copyright 2001 S. Karger AG, Basel)

ICAM-1 (CD54) plays an important role in the cell-cell interaction and migration of leukocytes. Previous studies have shown that ICAM-1 is involved in inflammatory reactions and that a defect in ICAM-1 gene inhibits allergic contact hypersensitivity. This study indicates that the migration of hapten presenting Langerhans cells into the regional lymph nodes was significantly reduced in ICAM-1-deficient mice compared to wild-type C57BL/6 mice. The reduced number of dendritic cells in regional lymph nodes did not result from abnormal migration of Langerhans cells into the skin of ICAM-1-deficient mice. The concentration and distribution of Langerhans cells in the naïve skin of ICAM-1-deficient mice was equal to that of wild-type mice. Following hapten sensitization, Langerhans cell migration out of the skin and recruitment of fresh Langerhans cells back to the epidermis was not affected in ICAM-1-deficient mice. Further experiments demonstrated that ICAM-1 deficiency on lymphatic endothelium rather than on dendritic cells was responsible for the reduced migration of Langerhans cells into draining lymph nodes. This study indicates that ICAM-1 regulates the migration of dendritic cells into regional lymph nodes but not into or out of the skin.

Background: The purine nucleoside phosphorylase inhibitor peldesine is a new agent being evaluated as a T-cell inhibitor., Objective: We attempted to determine the efficacy of peldesine (BCX-34) in a 1% dermal cream formulation as a treatment for cutaneous T-cell lymphoma (CTCL)., Methods: Ninety patients with patch and plaque phase CTCL, histologically confirmed by a referee dermatopathologist, were enrolled in a randomized, double-blind, placebo-controlled study. BCX-34 dermal cream 1% or the vehicle cream (as a placebo control) was applied twice daily to the entire skin surface for up to 24 weeks. Efficacy of the topical therapy was assessed in terms of complete or partial (> or = 50%) clearing of patches and plaques., Results: Of the 89 patients able to be examined, 43 received BCX-34 and 46 received the placebo vehicle cream. One patient withdrew early and was not analyzed. The two groups were well balanced for potential prognostic factors. A total of 28% (12/43) of the patients treated with BCX-34 showed a response, but 24% (11/46) of patients who received vehicle also responded (P =.677)., Conclusion: Although BCX-34 dermal cream 1% was not significantly better than the control as therapy for patch and plaque-phase CTCL, this appears to be the first published placebo-controlled trial evaluating treatment for CTCL. Whether the vehicle cream has more than a placebo therapeutic effect is unclear. The relatively high (24%) placebo response rate should be kept in mind in assessing other treatments for early-stage CTCL.

Green tea is consumed as a popular beverage worldwide particularly in Asian countries like China, Korea, Japan and India. It contains polyphenolic compounds also known as epicatechins, which are antioxidant in nature. Many laboratories have shown that topical treatment or oral consumption of green tea polyphenols inhibits chemical carcinogen- or ultraviolet radiation-induced skin tumorigenesis in different animal models. Studies have shown that green tea extract also possesses anti-inflammatory activity. These anti-inflammatory and anti-carcinogenic properties of green tea are due to their polyphenolic constituents present therein. The major and most chemopreventive constituent in green tea responsible for these biochemical or pharmacological effects is (-)-epigallocatechin-3-gallate (EGCG). Understanding the molecular mechanisms of these effects of green tea is a subject of investigation in many laboratories. Treatment of green tea polyphenols to skin has been shown to modulate the biochemical pathways involved in inflammatory responses, cell proliferation and responses of chemical tumor promoters as well as ultraviolet (UV) light-induced inflammatory markers of skin inflammation. Topical treatment with EGCG on mouse skin also results in prevention of UVB-induced immunosuppression, and oxidative stress. The protective effects of green tea treatment on human skin either topically or consumed orally against UV light-induced inflammatory or carcinogenic responses are not well understood. Based on documented extensive beneficial effects of green tea on mouse skin models and very little in human skin, many pharmaceutical and cosmetic companies are supplementing their skin care products with green tea extracts. Therefore, the focus of this communication is to review and analyze the photoprotective effects of green tea polyphenols to skin.

Background: In animal models, extracts from green tea have been shown to be remarkably effective at reducing the severity of adverse human health effects of overexposure to ultraviolet (UV) radiation. Although sunscreens and other photoprotective measures have traditionally been used for this purpose, there is a need for additional measures and natural products are increasingly being explored for that purpose., Objective: Our purpose was to evaluate the effect of polyphenols from green tea on parameters associated with acute UV injury., Methods: Areas of skin of normal volunteers were treated with an extract of green tea or one of its constituents. Thirty minutes later, the treated sites were exposed to a 2 minimal erythema dose solar simulated radiation. UV-treated skin was examined clinically for UV-induced erythema, histologically for the presence of sunburn cells or Langerhans cell distributions, or biochemically for UV-induced DNA damage., Results: Application of green tea extracts resulted in a dose-dependent inhibition of the erythema response evoked by UV radiation. The (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) polyphenolic fractions were most efficient at inhibiting erythema, whereas (-)-epigallocatechin (EGC) and (-)-epicatechin (EC) had little effect. On histologic examination, skin treated with green tea extracts reduced the number of sunburn cells and protected epidermal Langerhans cells from UV damage. Green tea extracts also reduced the DNA damage that formed after UV radiation., Conclusion: Polyphenolic extracts of green tea are effective chemopreventive agents for many of the adverse effects of sunlight on human health and may thus serve as natural alternatives for photoprotection.

TNFalpha is a primary cytokine responsible for inflammatory and immunosuppressive responses in skin. After UV-B irradiation of cultured human keratinocytes, we found that TNFalpha was released into the media, as monitored by ELISA, and was bound to cells, as observed by immunofluorescence microscopy. The release of TNFalpha into cell culture supernatant during the 24 h after UV-B irradiation was augmented by the addition of IL-1alpha to the cells. Further, we found this secretion was unaffected by rapamycin, and therefore independent of FRAP DNA-protein kinase mediated signal transduction. However, UV-B also induced expression of membrane-bound TNFalpha, and this was dependent on FRAP signaling. In wild type mice, TNFalpha bound to skin increased immediately after irradiation, declined at 6 h, and then rose again at 12 h before falling by 24 h. This pattern of induction was confirmed by RT-PCR of TNFalpha mRNA message in cultured epidermal cells. Induction of membrane-bound TNFalpha was also found in c-fos gene knockout mice deficient in the AP-1 transcription factor, suggesting that, although AP-1 containing c-fos signaling is required for some UV responses, AP-1 containing c-fos is not required for this TNFalpha activation. However, in homozygous p53 knockout mice the basal level of TNFalpha bound to the epidermis was greatly elevated without UV irradiation. This level declined and remained constant following irradiation. This implies that p53 directly or indirectly represses TNFalpha gene expression and that modification of p53 mRNA stability or phosphorylation of p53 protein after UV may be responsible for TNFalpha induction in the membrane. Overexpression of the immunosuppressive cytokine TNFalpha in this locale may contribute to the carcinogen-susceptibility of p53 knockout mice.

The induction and elicitation phases of allergic contact dermatitis are very complicated processes that differ in many respects. Many issues remain to be investigated, especially in the elicitation phase of this disease. Several key molecules involved in the development and maintenance of allergic contact dermatitis have already been defined, including a number of different cytokines and adhesion molecules. Attempts are being made to develop new, more specific pharmacologic and immunologic inhibitors of their activity. Because patients who see a doctor are already sensitized, further elucidation of the factors affecting the elicitation of allergic contact dermatitis will greatly contribute to the prevention and treatment of the disease., (Copyright 2000 by W.B. Saunders Company)

The purpose of this study was to determine if silicon phthalocyanine 4 (Pc 4), a second-generation photosensitizer being evaluated for the photodynamic therapy (PDT) of solid tumors, was immunosuppressive. Mice treated with Pc 4 PDT 3 days before dinitrofluorobenzene sensitization showed significant suppression of their cell-mediated immune response when compared to mice that were not exposed to PDT. The response was dose dependent, required both Pc 4 and light and occurred at a skin site remote from that exposed to the laser. The immunosuppression could not be reversed by in vivo pre-treatment of mice with antibodies to tumor necrosis factor-alpha or interleukin-10. These results provide evidence that induction of cell-mediated immunity is suppressed after Pc 4 PDT. Strategies that prevent PDT-mediated immunosuppression may therefore enhance the efficacy of this therapeutic modality.

Photodynamic therapy (PDT) is a cancer treatment modality utilizing a photosensitizer, light and oxygen. Photodynamic therapy with Photofrin has been approved by the U.S. Food and Drug Administration for treatment of advanced esophageal and early lung cancer. Because of certain drawbacks associated with the use of Photofrin, there is a need to identify new photosensitizers for human use. The photosensitizer Pc 4 (HOSiPc-OSi[CH3]2[CH2]3N[CH3]2) has yielded promising PDT effects in many in vitro and in vivo systems. The aim of this study was to assess the usefulness of Pc 4 as a PDT photosensitizer for a human tumor grown as a xenograft in athymic nude mice. The ovarian epithelial carcinoma (OVCAR-3) was heterotransplanted subcutaneously in athymic nude mice. Sixty mice bearing OVCAR-3 tumors (approximately 80-130 mm3) were divided into six groups of 10 animals each, three for controls and three for treatment. The Pc 4 was given by tail vein injection, and 48 h later a 1 cm area encompassing the tumor was irradiated with light from a diode laser coupled to a fiberoptic terminating in a microlens (lambda = 672 nm, 150 J/cm2, 150 mW/cm2). Tumors of control animals receiving no treatment, light alone or Pc 4 alone continued to grow. Of animals receiving 0.4 mg/kg Pc 4 and light, one (10%) had a complete response and was cured (no regrowth up to 90 days post-PDT), while all others (90%) had a partial response and were delayed in regrowth. Of animals receiving 0.6 mg/kg Pc 4 and light, eight (80%) had a complete response, and two of these were cured. Of animals receiving 1.0 mg/kg Pc 4 and light, six (60%) had a complete response, and two of these were cured. In additional experiments, tumors from animals treated with Pc 4 (1 mg/kg) and light were removed 15, 30, 60 and 180 min post-PDT, and from these tumors DNA and protein were extracted. Agarose gel electrophoresis revealed the presence of apoptotic DNA fragmentation as early as 15 min post-PDT. Western blotting showed the cleavage of the 116 kDa native poly(ADP-ribose) polymerase (PARP) into fragments of approximately 90 kDa, another indication of apoptosis, and the presence of p21/WAF1/CIP1 (p21) in all PDT-treated tumors. These changes did not occur in control tumors. Pc 4 appears to be an effective photosensitizer for PDT of human tumors grown as xenografts in nude mice. Early apoptosis, as revealed by PARP cleavage, DNA fragmentation and p21 overexpression, may be responsible for the excellent Pc 4-PDT response. Clinical trials of Pc 4-PDT are warranted.

Identification of natural products capable of affording protection against UVB radiation-induced inflammatory responses and generation of oxidative stress may have important human health implications. The UVB exposure-induced skin injury and oxidative stress has been associated with a variety of skin disease conditions including photoaging, inflammation and cancer. Tea is a popular beverage consumed worldwide. In several mouse skin models, topical application as well as oral consumption of green tea has been shown to afford protection against chemical and UVB-induced carcinogenesis and inflammatory responses. In the present study, we investigated in human skin, whether topical application of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent in green tea, inhibits UVB-induced infiltration of leukocytes (macrophage/neutrophils), a potential source of generation of reactive oxygen species (ROS), and generation of prostaglandin (PG) metabolites. Human subjects were UVB irradiated on sun-protected skin to four times their minimal erythema dosage (MED) and skin biopsies or keratomes were obtained either 24 h or 48 h later. We found that topical application of EGCG (3 mg/2.5 cm2) before UVB (4 MED) exposure to human skin significantly blocked UVB-induced infiltration of leukocytes and reduced myeloperoxidase activity. These infiltrating leukocytes are considered to be the major source of generation of ROS. In the same set of experiments we found that topical application of EGCG before UVB exposure decreased UVB-induced erythema. In additional experiments, we found that microsomes from EGCG pretreated human skin and exposed to UVB, compared to UVB exposure alone, produced significantly reduced PG metabolites, particularly PGE2. The PG metabolites play a critical role in free radical generation and skin tumor promotion in multistage skin carcinogenesis. Careful microscopic examination of skin sections, stained with hematoxylin and eosin, under higher magnification (x400) also revealed that EGCG pretreated and UVB-exposed human skin contained fewer dead cells in the epidermis with comparison to nonpretreated UVB-exposed skin. Taken together, our data demonstrate that EGCG has the potential to block the UVB-induced infiltration of leukocytes and the subsequent generation of ROS in human skin. This may explain the possible mechanism involved in anti-inflammatory effects of green tea. We suggest that EGCG may be useful as a topical agent for protection against UVB-induced ROS-associated inflammatory dermatoses, photoaging and photocarcinogenesis. Further studies are warranted in this direction.

Polyaromatic hydrocarbons are ubiquitous environmental chemicals that are important mutagens and carcinogens. The purpose of this study was to determine whether genes within the major histocompatibility complex (MHC) influence their biological activities. Cell-mediated immunity to dimethylbenz(a)anthracene (DMBA) was investigated in congenic strains of mice. On three different backgrounds, H-2(k) and H-2(a) haplotype mice developed significantly greater contact-hypersensitivity responses to DMBA than H-2(b), H-2(d), and H-2(s) mice. In B10.A(R1) mice, which are Kk and Id, a vigorous contact-hypersensitivity response was present, indicating that the response was governed by class I, rather than class II, MHC genes. C3H/HeN (H-2(k)) and C3H.SW (H-2(s)) strains were also compared for the development of skin tumors and the persistence of DMBA-DNA adducts. When subjected to a DMBA initiation, phorbol 12-tetradecanoate 13-acetate (TPA)-promotion skin-tumorigenesis protocol, C3H/HeN mice, (which develop cell-mediated immunity to DMBA) were found to have significantly fewer tumors than C3H.SW mice (a strain that failed to develop a cell-mediated immune response to DMBA). DMBA-DNA adducts were removed more rapidly in C3H/HeN than in C3H.SW mice. The results indicate that genes within the MHC play an important role in several of the biological activities of carcinogenic polyaromatic hydrocarbons. The observations are consistent with the hypothesis that cell-mediated immunity to chemical carcinogens serves to protect individuals by removing mutant cells before they can evolve into clinically apparent neoplasms.

Photofrin photodynamic therapy (PDT) has recently received FDA approval for the palliative treatment of totally and partially obstructing esophageal malignancies. However, there is a need for new PDT photosensitizers because Photofrin has a number of undesirable features. The purpose of this study was to evaluate the efficacy of four amine-bearing silicon phthalocyanines--Pc4, Pc10, Pc12 and Pc18--as potential PDT photosensitizers. Equimolar concentrations of these Pc were found to be highly effective at causing the regression of RIF-1 tumors transplanted to C3H/HeN mice. The amount of Pc4 necessary to cause an equivalent amount of tumor regression in this model system was substantially less than the amount of Photofrin. The cutaneous phototoxicity of the silicon Pc photosensitizer was assessed by the utilization of the murine ear-swelling model. When C3H mice were exposed to 167 J/cm2 of polychromatic visible light from a UVB-filtered solar simulator, which emitted UV radiation and visible light above 320 nm, the Pc produced little, if any, cutaneous photosensitivity. These results indicate that Pc4, Pc10, Pc12 and Pc18 are at least as effective as Photofrin in PDT protocols, while at the same time addressing many of the drawbacks of Photofrin.

Polyaromatic hydrocarbons are ubiquitous environmental contaminants that are known primarily for their mutagenic and carcinogenic properties. In mice, when applied to the skin, they also act as antigenic substances, capable of initiating a cell-mediated immune response (contact hypersensitivity). Using dimethylbenz(a)anthracene (DMBA) as a prototype, studies from this laboratory have found that genetic polymorphisms, at the Ah receptor locus, the major histocompatibility complex and the Lps locus, control the magnitude of the cell-mediated immune response to these carcinogenic compounds. Strains of mice that metabolize polyaromatic hydrocarbons well and can be immunized to them are less likely to develop cutaneous tumors when subjected to a polyaromatic hydrocarbon-initiation, TPA-promotion cutaneous carcinogenesis protocol. It may thus be possible to assess individual susceptibility to polyaromatic hydrocarbon-induced tumors by characterizing one's ability to metabolize polyaromatic hydrocarbons and his or her immune response to these agents.

Two of the major cutaneous consequences of ultraviolet (UV) radiation exposure are immunosuppression and the development of skin cancer. This study examined whether these effects are genetically determined. Suppression of contact hypersensitivity by local, low-dose UV radiation was examined in what have been termed "UV-susceptible" and "UV-resistant" strains of mice. C3H/HeJ mice ("UV resistant") were resistant to the adverse effects of low-dose UV radiation when normal doses of hapten were applied to UV-irradiated skin; however, they were sensitive when the amount of hapten used for sensitization was reduced. A similar effect was observed in BALB/c mice ("UV resistant") and when the hapten was dimethylbenz(a)anthracene, thus indicating that the genetic variation was not strain or hapten specific. Despite the fact that some strains were sensitive and some were resistant to low-dose UV radiation when high doses of hapten were employed, all strains initially sensitized to hapten through UV-irradiated skin were found to be unresponsive when rechallenged on normal skin, no matter what the initial sensitizing dose of hapten was. To determine whether other biologic effects of UV also exhibited genetic variation, C3H/HeN and C3H/HeJ mice were compared for susceptibility to UVB-induced skin cancer formation. C3H/HeJ mice developed significantly more tumors than C3H/HeN mice when subjected to a single dose of UV radiation followed by repeated exposure to the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. These studies provide strong evidence that genetic factors influence individual susceptibility to the biologic effects of UV radiation.

Objective: To characterize tumor-infiltrating lymphocytes (TILs) within lesions of cutaneous squamous cell carcinoma (SCC) and related disorders., Design: Case series with 1- and 2-color immunohistologic, molecular biological analysis of T-cell clonality and in vitro cytotoxicity assays., Setting: Academic medical center., Patients: Twenty-one patients, including 6 with actinic keratoses, 4 with SCC in situ, and 11 with invasive SCC., Results: CD8+ TILs were present within lesions of cutaneous SCC and AK. These cells constituted a variable minority of the total T-cell infiltrate, and many expressed a phenotype consistent with major histocompatibility complex-restricted cytotoxic T lymphocytes: CD3+, TIA1+, CD16-, CD56-, CD57-. They also expressed HLA-DR, suggesting their activation in vivo. Virtually all T cells were T-cell receptor (TCR)-beta + delta, indicating that they expressed the TCR-alpha beta protein heterodimer. Molecular biological analysis of TCR-gamma gene rearrangements by the polymerase chain reaction and denaturing gradient gel electrophoresis technique indicated that the TILs were polyclonal. Functional studies suggested that TILs derived from SCC lesions were cytotoxic for autologous tumor cell targets., Conclusion: Tumor-infiltrating lymphocytes within cutaneous SCC lesions contain a subpopulation of polyclonal, major histocompatibility complex-restricted cytotoxic T lymphocytes expressing the TCR-alpha beta heterodimer.

The phthalocyanines are promising second-generation photosensitizers that are being evaluated for the photodynamic therapy (PDT) of malignant tumors. In vivo studies with the silicon phthalocyanine Pc 4 have shown that it is highly effective at causing regression of RIF-1 tumors in C3H/HeN mice in PDT protocols. Because cutaneous photosensitivity is the major complication of photosensitizers used for PDT, experiments were performed to evaluate the effect of inhibitors of the inflammatory response (cyproheptadine, dexamethasone, pentoxifylline, and tumor necrosis factor alpha [TNF-alpha] antibodies) on Pc 4-induced cutaneous photosensitivity and tumor regression. The C3H/HeN mice were injected with either Pc 4 or Photofrin and were exposed to 86 J/cm2 of filtered radiation emitted from a solar simulator. Animals were irradiated at 1, 3, 7, 10, 14 and 28 days postinjection. Cutaneous photosensitivity was assessed using the murine ear-swelling response. Cyproheptadine, dexamethasone, pentoxifylline and TNF-alpha antibodies were administered prior to illumination to assess their ability to block Pc 4-induced cutaneous photosensitivity and to evaluate whether such treatment adversely influenced Pc 4 PDT-induced tumor regression. Compared to Photofrin, Pc 4 produced cutaneous photosensitivity that was transient, resolving within 24 h, and that could be elicited for only 10 days after administration. In contrast, Photofrin caused photosensitivity that required 4 days to resolve and could be elicited for at least 1 month after it was administered. The Pc 4-induced cutaneous photosensitivity could be blocked by corticosteroids and an inhibitor of vasoactive amines (cyproheptadine). The TNF-alpha gene transcription was found to increase in keratinocytes following treatment with Pc 4 and light. The anti-TNF-alpha antibodies and pentoxifylline, an inhibitor of cytokine transcription, also prevented cutaneous photosensitivity, implicating TNF-alpha in the pathogenesis of Pc 4-induced cutaneous photosensitivity. None of these agents had any effect on Pc 4 PDT-induced tumor regression. Cyproheptadine, dexamethasone, pentoxifylline and TNF-alpha antibodies may be valuable pharmacologic agents in the management of cutaneous photosensitivity associated with PDT without altering the efficacy of this new therapeutic modality. The findings suggest that it should be possible to devise PDT protocols that block cutaneous photosensitivity without impairing the anti-tumor response to the agents.

With the advent of AIDS, Kaposi's sarcoma (KS) has become one of the leading malignancies in sub-Saharan Africa. Recently, DNA sequences from a new human herpesvirus called KS-associated herpesvirus (KSHV) or human herpesvirus type 8 have been found in KS tumor lesions in high frequency. Analyses of tumor lesions from 38 Ugandan KS patients indicated a uniform presence of KSHV in KS tumor lesions as revealed by polymerase chain reaction and Southern hybridization. In contrast, only 31% (11/36) of the normal skin biopsies from the same patient population were positive. The frequency of KSHV DNA detection in peripheral blood mononuclear cells (PBMC) of KS patients was also high (84%, 31/37). Similar analyses revealed the presence of cytomegalovirus (21% in KS lesions) to be discordant with KS development. A large number of KS lesions (87%, 33/38) and KS PBMC (70%, 26/37) were, however, positive for Epstein-Barr virus sequences. In addition, KSHV DNA was not found in the PBMC of Ugandans without KS.

Abstract: Epidermal keratinocytes in culture have been shown to produce many cytokines, and their proteins have been identified in skin tissue samples. It has therefore been assumed that these cytokines are transcribed in vivo by the epidermis in response to contact allergens. In this report, in situ hybridization was used to detect the messenger RNAs for interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) in samples of human skin prior to and at various times after application of urushiol, the immunogenic component of poison ivy/oak. In sensitive subjects, IL-1 alpha and TNF-alpha mRNAs showed a progressive increase in transcript levels that paralleled the clinical and histological features of the inflammatory process. The time-course of the IL-1 beta response differed from that of IL-1 alpha and TNF-alpha, in that there was an early (by 6 h after urushiol administration) elevation in IL-1 beta mRNA that occurred before there was evidence of inflammation and had returned to background levels by 72 h when the reaction had reached its peak. In contrast to urushiol-sensitive subjects, urushiol-anergic individuals did not exhibit an increase in IL-1 alpha, IL-1 beta or TNF-alpha mRNA levels. The data provide evidence for an in vivo role for epidermal IL-1 alpha, IL-1 beta and TNF-alpha transcription in the regulation of IL-1 beta and TNF-alpha polypeptide levels in the epidermis in response to this common contact allergen.