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Objectives: Skin cancer is highly preventable through primary prevention activities such as avoiding ultraviolet radiation exposure during peak times and regular use of sun protection. General practitioners (GPs) and primary care nurses have key responsibilities in promoting sustained primary prevention behaviour. We aimed to review the evidence on skin cancer primary prevention activities in primary care settings, including evidence on feasibility, effectiveness, barriers and enablers., Study Type: Rapid review and narrative synthesis., Methods: We searched published literature from January 2011 to October 2022 in Embase, Medline, PsychInfo, Scopus, Cochrane Central and CINAHL. The search was limited to skin cancer primary prevention activities within primary care settings, for studies or programs conducted in Australia or countries with comparable health systems. Analysis of barriers and enablers was informed by an implementation science framework., Results: A total of 31 peer-reviewed journal articles were included in the review. We identified four main primary prevention activities: education and training programs for GPs; behavioural counselling on prevention; the use of novel risk assessment tools and provision of risk-tailored prevention strategies; and new technologies to support early detection that have accompanying primary prevention advice. Enablers to delivering skin cancer primary prevention in primary care included pairing preventive activities with early detection activities, and access to patient resources and programs that fit with existing workflows and systems. Barriers included unclear requirements for skin cancer prevention counselling, competing demands within the consultation and limited access to primary care services, especially in regional and remote areas., Conclusions: These findings highlight potential opportunities for improving skin cancer prevention activities in primary care. Ensuring ease of program delivery, integration with early detection and availability of resources such as risk assessment tools are enablers to encourage and increase uptake of primary prevention behaviours in primary care, for both practitioners and patients., Competing Interests: None declared.

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy that is associated with an increased risk of developing cutaneous malignancies. Clinical outcomes for these malignancies, including melanoma and keratinocyte cancers (KC), are worse for patients with CLL. Individuals with CLL develop an immunodeficiency of both the adaptive and innate immune system, which plays a role in the increased prevalence of skin cancers. This review focuses on the complex interplay between genetics, immunity, and pathogens that influence the cellular composition and biology of skin tumors and their microenvironment in CLL patients, and in comparison with other chronic hematological malignancies. It is paramount for dermatologists to be aware of the association between CLL (and chronic hematological malignancies more broadly) and cutaneous malignancies. This is a high-risk population who require regular and vigorous dermatologic follow-up., (© 2024 Japanese Dermatological Association.)

The immune system plays a key role in the suppression and progression of basal cell carcinoma (BCC). The primary aetiological factor for BCC development is exposure to ultraviolet radiation (UVR) which, particularly in lighter Fitzpatrick skin types, leads to the accumulation of DNA damage. UVR has roles in the generation of an immunosuppressive environment, facilitating cancer progression. Rates of BCC are elevated in immunosuppressed patients, and BCC may undergo spontaneous immune-mediated regression. Histologic and immunohistochemical profiling of BCCs consistently demonstrates the presence of an immune infiltrate and associated immune proteins. Early studies of immune checkpoint inhibitors reveal promising results in BCC. Therefore, the host immune system and tumor responses to it are important in BCC pathogenesis. Understanding these interactions will be beneficial for disease prognostication and therapeutic decisions., Competing Interests: The authors have nothing to disclose., (Copyright © The Korean Dermatological Association and The Korean Society for Investigative Dermatology.)

Cutaneous squamous cell carcinoma (cSCC) is the most common malignancy in immune-suppressed organ transplant recipients (OTRs). Whilst rates of other malignancies (both cutaneous and non-cutaneous) are elevated in this population, the increase is far less striking. This suggests that cSCC must be a highly immunogenic tumor. The tumor immune microenvironment is altered in cSCC from OTRs. It has reduced anti-tumor properties and instead provides an environment that facilitates tumor growth and survival. Understanding the composition and function of the tumor immune microenvironment in cSCC from OTRs is useful for prognostication and therapeutic decisions., Competing Interests: The authors have nothing to disclose., (Copyright © The Korean Dermatological Association and The Korean Society for Investigative Dermatology.)

Skin cancers are the most common malignancy in Australia. Regular sunscreen use can reduce the incidence of cutaneous squamous cell carcinomas and actinic keratoses and has been associated with reducing the incidence of basal cell carcinomas and melanomas. However, sunscreen effectiveness is limited by the failure of the population to use it routinely. Interventions that promote the daily application of sunscreen may reduce the morbidity, mortality, and economic burden associated with skin malignancies. We reviewed the literature that examines the effectiveness of interventions to increase routine sunscreen use and found that no one strategy has been shown to be clearly effective in adults and that relatively few studies have aimed to increase routine use in groups at extreme skin cancer risk. Future research should consider how interventions can be best designed and how sunscreen use is measured so that cost-effective, feasible strategies that result in improved sunscreen use in adults can be established.

Nicotinamide (NAM), an amide form of vitamin B3, replenishes cellular energy after ultraviolet radiation (UVR) exposure, thereby enhancing DNA repair and reducing UVR's immunosuppressive effects. NAM reduces actinic keratoses and new keratinocyte cancers in high risk individuals, but its effects on melanoma are unknown. Melanomas arising on NAM or placebo within the ONTRAC skin cancer chemoprevention trial (Oral Nicotinamide To Reduce Actinic Cancer) were examined by immunohistochemistry. The effects of NAM (50 μM, 5 mM and 20 mM) on the viability, proliferation and invasiveness of four human melanoma cell lines and on the viability and proliferation of two human melanocyte lines, with and without UV irradiation were also investigated. 50 μM NAM did not affect viability, proliferation or invasion of melanoma or melanocyte cell lines, whereas concentrations too high to be achievable in vivo reduced viability and proliferation. Nicotinamide did not enhance melanoma viability, proliferation or invasiveness in vitro, providing additional confidence in its safety for use in clinical trials in high risk patients. Peritumoral and tumour infiltrating CD4+ and CD8+ lymphocytes were significantly increased in melanomas arising on NAM compared to those arising on placebo. Given the chemopreventive activity of nicotinamide against keratinocyte cancers, its DNA repair enhancing effects in melanocytes and now its potential enhancement of tumour-infiltrating lymphocytes and lack of adverse effects on melanoma cell growth and proliferation, clinical trials of nicotinamide for melanoma chemoprevention are now indicated.

Nicotinamide (vitamin B3) has photoprotective effects and reduces skin cancer incidence in high risk patients. Nicotinamide also improves cognition in animal models. As part of the ONTRAC (Oral Nicotinamide To Reduce Actinic Cancer) phase III placebo-controlled, randomized trial to assess nicotinamide's efficacy in skin cancer prevention, we included clinical neurocognitive function and patient-reported quality of life assessments at baseline and after 12 months of intervention in individuals with previous skin cancer in order to assess any effect of oral nicotinamide (500 mg po twice daily) on cognitive function and quality of life. In our sample of 310 participants who completed neurocognitive function testing at baseline and at 12 months, we were not able to detect any significant effect of oral nicotinamide on cognitive function nor on quality of life. Further studies of nicotinamide's effects on cognition in humans might include individuals with pre-existing mild cognitive impairment, and it may be that higher doses of nicotinamide are required to significantly influence cognitive function compared to doses required to reduce skin cancer.

Nicotinamide is a water-soluble vitamin B3 derivative that has many roles in medicine. This review examines the role of nicotinamide in dermatology and its actions in preventing photoageing and skin cancers in humans. Nicotinamide prevents ultraviolet radiation (UV) from reducing ATP levels and inhibiting glycolysis, thus preventing the UV radiation-induced energy crisis. This enhances DNA repair and reduces UV-induced suppression of immunity. Randomised controlled clinical trials have also shown that nicotinamide reduces transepidermal water loss and the development of new non-melanoma skin cancers in high-risk humans. This review also examines nicotinamide's safety profile., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Ultraviolet radiation (UVR) causes DNA damage in melanocytes by producing photolesions such as cyclobutane pyrimidine dimers and 8-oxo-7-hydrodeoxyguanosine. The production of reactive oxygen species by UVR also induces inflammatory cytokines that, together with the inherent immunosuppressive properties of UVR, propagate carcinogenesis. Nicotinamide (Vitamin B 3 ) enhances DNA repair, modulates the inflammatory environment produced by UVR, and reduces UV-induced immunosuppression. As nicotinamide reduces the incidence of actinic keratoses and nonmelanoma skin cancers in high-risk individuals and enhances repair of DNA damage in melanocytes, it is a promising agent for the chemoprevention of melanoma in high-risk populations., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Nicotinamide (vitamin B 3 ) has a range of photoprotective effects in vitro and in vivo; it enhances DNA repair, reduces UV radiation-induced suppression of skin immune responses, modulates inflammatory cytokine production and skin barrier function and restores cellular energy levels after UV exposure. Pharmacological doses of nicotinamide have been shown to reduce actinic keratoses and nonmelanoma skin cancer incidence in high-risk individuals, making this a nontoxic and accessible option for skin cancer chemoprevention in this population., (© 2017 The Australasian College of Dermatologists.)

Background: Nonmelanoma skin cancers, such as basal-cell carcinoma and squamous-cell carcinoma, are common cancers that are caused principally by ultraviolet (UV) radiation. Nicotinamide (vitamin B3) has been shown to have protective effects against damage caused by UV radiation and to reduce the rate of new premalignant actinic keratoses., Methods: In this phase 3, double-blind, randomized, controlled trial, we randomly assigned, in a 1:1 ratio, 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years to receive 500 mg of nicotinamide twice daily or placebo for 12 months. Participants were evaluated by dermatologists at 3-month intervals for 18 months. The primary end point was the number of new nonmelanoma skin cancers (i.e., basal-cell carcinomas plus squamous-cell carcinomas) during the 12-month intervention period. Secondary end points included the number of new squamous-cell carcinomas and basal-cell carcinomas and the number of actinic keratoses during the 12-month intervention period, the number of nonmelanoma skin cancers in the 6-month postintervention period, and the safety of nicotinamide., Results: At 12 months, the rate of new nonmelanoma skin cancers was lower by 23% (95% confidence interval [CI], 4 to 38) in the nicotinamide group than in the placebo group (P=0.02). Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20% [95% CI, -6 to 39] lower rate with nicotinamide, P=0.12) and new squamous-cell carcinomas (30% [95% CI, 0 to 51] lower rate, P=0.05). The number of actinic keratoses was 11% lower in the nicotinamide group than in the placebo group at 3 months (P=0.01), 14% lower at 6 months (P<0.001), 20% lower at 9 months (P<0.001), and 13% lower at 12 months (P=0.001). No noteworthy between-group differences were found with respect to the number or types of adverse events during the 12-month intervention period, and there was no evidence of benefit after nicotinamide was discontinued., Conclusions: Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients. (Funded by the National Health and Medical Research Council; ONTRAC Australian New Zealand Clinical Trials Registry number, ACTRN12612000625875.).

Nicotinamide, or vitamin B3, is a precursor of nicotinamide adenine dinucleotide (NAD(+)) and is involved in a multitude of intra- and inter-cellular processes, which regulate some of the cell's metabolic, stress, and immune responses to physiological or pathological signals. As a precursor of NAD(+), which is a key coenzyme in the production of adenosine triphosphate or cellular energy, nicotinamide has been investigated for potential neuroprotective effects in cellular, animal, and human studies. Objectives We aimed to summarize the current evidence on the effect of dietary and supplemental nicotinamide on cognitive function. Methods A literature review was conducted on the effects of nicotinamide and its derivatives as a preventive and therapeutic agent for disorders of neurocognitive function. Specific conditions examined include age-related cognitive decline, Alzheimer's disease, Parkinson's disease, and ischaemic and traumatic brain injury. Results Data from animal and human interventional studies and epidemiological research suggests that nicotinamide may be beneficial in preserving and enhancing neurocognitive function. Discussion Nicotinamide is non-toxic, inexpensive and widely available, and interventional studies in humans, using supplemental doses of nicotinamide, are now warranted.

Arsenic-induced skin cancer is a significant global health burden. In areas with arsenic contamination of water sources, such as China, Pakistan, Myanmar, Cambodia and especially Bangladesh and West Bengal, large populations are at risk of arsenic-induced skin cancer. Arsenic acts as a co-carcinogen with ultraviolet (UV) radiation and affects DNA damage and repair. Nicotinamide (vitamin B3) reduces premalignant keratoses in sun-damaged skin, likely by prevention of UV-induced cellular energy depletion and enhancement of DNA repair. We investigated whether nicotinamide modifies DNA repair following exposure to UV radiation and sodium arsenite. HaCaT keratinocytes and ex vivo human skin were exposed to 2μM sodium arsenite and low dose (2J/cm2) solar-simulated UV, with and without nicotinamide supplementation. DNA photolesions in the form of 8-oxo-7,8-dihydro-2'-deoxyguanosine and cyclobutane pyrimidine dimers were detected by immunofluorescence. Arsenic exposure significantly increased levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine in irradiated cells. Nicotinamide reduced both types of photolesions in HaCaT keratinocytes and in ex vivo human skin, likely by enhancing DNA repair. These results demonstrate a reduction of two different photolesions over time in two different models in UV and arsenic exposed cells. Nicotinamide is a nontoxic, inexpensive agent with potential for chemoprevention of arsenic induced skin cancer.

Nicotinamide has shown potential as a safe and effective intervention for the prevention of malignant and premalignant skin lesions. Recent studies have shown that nicotinamide, in both oral and topical forms, is able to prevent ultraviolet-induced immunosuppression in humans [1,2,3] and mice [4,5]. Immunosuppression is a known factor for the progression of premalignant lesions, such as actinic keratosis [6]. Murine studies have shown that nicotinamide is also able to protect against photocarcinogenesis [4,5]. Preliminary human studies suggest that nicotinamide may help prevent skin cancers and enhance the regression of actinic keratoses., (© 2015 S. Karger AG, Basel.)

Nicotinamide, an amide form of vitamin B3, boosts cellular energy and regulates poly-ADP-ribose-polymerase 1, an enzyme with important roles in DNA repair and the expression of inflammatory cytokines. Nicotinamide shows promise for the treatment of a wide range of dermatological conditions, including autoimmune blistering disorders, acne, rosacea, ageing skin and atopic dermatitis. In particular, recent studies have also shown it to be a potential agent for reducing actinic keratoses and preventing skin cancers., (© 2014 The Australasian College of Dermatologists.)

Photoprotection can be provided not only by ultraviolet (UV) blockers but also by oral substances. Epidemiologically identified associations between foods and skin cancer and interventional experiments have discovered mechanisms of UV skin damage. These approaches have identified oral substances that are photoprotective in humans. UV inhibits adenosine triphosphate (ATP) production causing an energy crisis, which prevents optimal skin immunity and DNA repair. Enhancing ATP production with oral nicotinamide protects from UV immunosuppression, enhances DNA repair and reduces skin cancer in humans. Reactive oxygen species also contribute to photodamage. Nontoxic substances consumed in the diet, or available as oral supplements, can protect the skin by multiple potential mechanisms. These substances include polyphenols in fruit, vegetables, wine, tea and caffeine-containing foods. UV-induced prostaglandin E2 (PGE2 ) contributes to photodamage. Nonsteroidal anti-inflammatory drugs and food substances reduce production of this lipid mediator. Fish oils are photoprotective, at least partially by reducing PGE2 . Orally consumed substances, either in the diet or as supplements, can influence cutaneous responses to UV. A current research goal is to develop an oral supplement that could be used in conjunction with other sun protective strategies in order to provide improved protection from sunlight., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Primary upper gastrointestinal tract melanoma is a rare but well recognised entity, with a poor prognosis because of delay in diagnosis. Furthermore, it may be difficult to determine whether a gastrointestinal melanoma represents a metastasis or a primary tumour. We report a 67-year-old man with a primary oesophageal melanoma, treated with surgical resection, who remains disease-free two years post resection.

Topical diphencyprone (DPCP) can be used to treat in transit and cutaneously metastastatic melanoma. To date, 50 patients have received DPCP therapy for at least 1 month at our institution, with complete clearance of cutaneous disease in 46% and partial response in a further 38% of patients. Topical immunotherapy with DPCP is inexpensive and well-tolerated and should be considered in patients with skin metastases unsuitable for or refractory to other forms of therapy., (© 2013 Wiley Periodicals, Inc.)

Vitamin D production requires UVB. In turn, we have shown that vitamin D compounds reduce UV-induced damage, including inflammation, sunburn, thymine dimers, the most frequent type of cyclobutane pyrimidine dimer, immunosuppression, and photocarcinogenesis. Our previous studies have shown most of the photoprotective effects by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) occurred through the nongenomic pathway because similar protection was seen with an analog, 1α,25-dihydroxylumistrol3 (JN), which has little ability to alter gene expression and also because a nongenomic antagonist of 1,25(OH)2D3 abolished protection. In the current study, we tested whether this photoprotective effect would extend to other types of DNA damage, and whether this could be demonstrated in human ex vivo skin, as this model would be suited to pre-clinical testing of topical formulations for photoprotection. In particular, using skin explants, we examined a time course for thymine dimers (TDs), the most abundant DNA photolesion, as well as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which is a mutagenic DNA base lesion arising from UV-induced oxidative stress, and 8-nitroguanosine (8-NG). Nitric oxide products, known markers for chronic inflammation and carcinogenesis, are also induced by UV. This study showed that 1,25(OH)2D3 significantly reduced TD and 8-NG as early as 30min post UV, and 8-oxodG at 3h post UV, confirming the photoprotective effect of 1,25(OH)2D3 against DNA photoproducts in human skin explants. At least in part, the mechanism of photoprotection by 1,25(OH)2D3 is likely to be through the reduction of reactive nitrogen species and the subsequent reduction in oxidative and nitrosative damage. This article is part of a Special Issue entitled 'Vitamin D Workshop'., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

Background: The nuclear transcription factor c-Jun is preferentially expressed in basal-cell carcinoma. Dz13 is a deoxyribozyme that targets JUN messenger RNA and has inhibited the growth of a range of tumours in mice. We did a phase 1 study to assess safety and tolerability in human beings., Methods: Adults with nodular basal-cell carcinoma were recruited from Royal Prince Alfred Hospital, Sydney, Australia, between September, 2010, and October, 2011. Patients were assigned to receive one intratumoral injected dose of 10, 30, or 100 μg Dz13, in a 50 μL volume of lipid carrier, and were assessed for adverse effects in the first 24 h then at 7, 14, and 28 days after injection. Treated tumours were surgically excised 14 days after injection and compared with the baseline biopsy samples for expression of c-Jun and tumorigenesis markers., Findings: Nine patients were recruited, of whom three received each dose of Dz13. All patients completed the study with no drug-related serious adverse events. No systemic Dz13 exposure was detected. c-Jun expression was reduced in the excised tumours of all nine (100%) patients, compared with baseline, and histological tumour depth had decreased in five (56%) of nine. Proportions of cells positive for caspases 3, 8, and 9 and P53 were increased, but those of cells positive for Bcl-2 and MMP-9 were decreased. Infiltration by inflammatory and immune cells was stimulated., Interpretation: Dz13 was safe and well tolerated after single intratumoral injections at all doses., Funding: Cancer Institute NSW, Cancer Council Australia, and National Health and Medical Research Council., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Nicotinamide (vitamin B3) protects from ultraviolet (UV) radiation-induced carcinogenesis in mice and from UV-induced immunosuppression in mice and humans. Recent double-blinded randomized controlled Phase 2 studies in heavily sun-damaged individuals have shown that oral nicotinamide significantly reduces premalignant actinic keratoses, and may reduce new non-melanoma skin cancers. Nicotinamide is a precursor of nicotinamide adenine dinucleotide (NAD(+)), an essential coenzyme in adenosine triphosphate (ATP) production. Previously, we showed that nicotinamide prevents UV-induced ATP decline in HaCaT keratinocytes. Energy-dependent DNA repair is a key determinant of cellular survival after exposure to DNA-damaging agents such as UV radiation. Hence, in this study we investigated whether nicotinamide protection from cellular energy loss influences DNA repair. We treated HaCaT keratinocytes with nicotinamide and exposed them to low-dose solar-simulated UV (ssUV). Excision repair was quantified using an assay of unscheduled DNA synthesis. Nicotinamide increased both the proportion of cells undergoing excision repair and the repair rate in each cell. We then investigated ssUV-induced cyclobutane pyrimidine dimers (CPDs) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxoG) formation and repair by comet assay in keratinocytes and with immunohistochemistry in human skin. Nicotinamide reduced CPDs and 8oxoG in both models and the reduction appeared to be due to enhancement of DNA repair. These results show that nicotinamide enhances two different pathways for repair of UV-induced photolesions, supporting nicotinamide's potential as an inexpensive, convenient and non-toxic agent for skin cancer chemoprevention.

Non-melanoma skin cancer (NMSC) is by far the most frequently diagnosed cancer in Australia, and exposure to ultraviolet (UV) radiation is the primary cause. Both UVB and UVA radiation have been shown to cause DNA damage and immunosuppression, the important forms of biological damage that lead to NMSC. The DNA of keratinocytes absorbs UV radiation and produces photolesions such as cyclobutane pyrimidine dimers (CPDs). UV absorption by other chromophores results in the production of reactive oxygen species which cause oxidative damage to DNA such as 8-oxo-7,8-dihydroguanine (8oxoG). These photolesions can then, if not correctly repaired, lead to signature mutations. Reactive oxygen species also cause receptor activation and damage lipids and proteins. UV also deprives cells of adenosine triphosphate, and causes inflammation and cell cycle dysregulation. UV radiation has been shown to exert potent immunosuppressive effects on the skin through a number of molecular and cellular mechanisms. Many tumour suppressor genes and oncogenes have been studied and implicated in photocarcinogenesis, particularly p53, PTCH1, BRM and RAS. Clinical observations, histological analysis, as well as molecular and cytogenetic studies have shown actinic keratoses (AKs) and Bowen's disease (BD) to be precursors of squamous cell carcinomas (SCCs). Keratoacanthomas (KAs), a type of SCC, and AKs have frequently been observed to regress. Sun protective measures and sunscreens can reduce the incidence of NMSCs, although their effectiveness is limited by non-compliance. A large number of chemopreventive agents have been investigated, but to date none has been found to be clinically useful except within selected high risk groups. Therefore, further research is urgently required to find an ideal chemopreventive agent that is effective, safe, accessible and convenient.

Background: The immune suppressive effects of topical photodynamic therapy (PDT) are potential contributors to treatment failure after PDT for nonmelanoma skin cancer. Nicotinamide (vitamin B(3) ) prevents immune suppression by ultraviolet radiation, but its effects on PDT-induced immunosuppression are unknown., Objectives: To determine the effects of topical and oral nicotinamide on PDT-induced immunosuppression in humans., Methods: Twenty healthy Mantoux-positive volunteers received 5% nicotinamide lotion or vehicle to either side of the back daily for 3 days. Another group of 30 volunteers received 500 mg oral nicotinamide or placebo twice daily for 1 week in a randomized, double-blinded, crossover design. In each study, methylaminolaevulinate cream was applied to discrete areas on the back, followed by narrowband red light irradiation (37 J cm(-2) ) delivered at high (75 mW cm(-2) ) or low (15 mW cm(-2) ) irradiance rates. Adjacent, nonirradiated sites served as controls. Delayed-type hypersensitivity (Mantoux) reactions were assessed at treatment and control sites to determine immunosuppression., Results: High irradiance rate PDT with vehicle or with placebo caused significant immunosuppression (equivalent to 48% and 50% immunosuppression, respectively; both P < 0·0001); topical and oral nicotinamide reduced this immunosuppression by 59% and 66%, respectively (both P < 0·0001). Low irradiance rate PDT was not significantly immunosuppressive in the topical nicotinamide study (15% immunosuppression, not significant), but caused 22% immunosuppression in the oral study (placebo arm; P = 0·006); nicotinamide reduced this immunosuppression by 69% (P = 0·045)., Conclusions: While the clinical relevance of these findings is currently unknown, nicotinamide may provide an inexpensive means of preventing PDT-induced immune suppression and enhancing PDT cure rates., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Low doses of sunlight that can be received during normal daily activities suppress immunity in humans. Both ultraviolet (UV) B (290-320 nm) and UVA (320-400 nm) are immunosuppressive. The wavelength dependence in humans shows distinct non-overlapping immunosuppressive peaks of solar effectiveness centred at 310 nm UVB and 370 nm UVA. In murine models of systemic immunosuppression low dose UV inhibits expansion of effector T cells in skin-draining lymph nodes, and retention of dermal effector memory CD8T cells at sites of antigen challenge. In addition to suppressing skin immunity, UV inhibits immunity in internal organs, including activation of CD8 T cells and cytotoxic T cell activity in the spleen, and memory T cell activation in the spleen and bone marrow. Neither of the chromophores responsible for UV suppression of skin immunity, DNA damage and urocanic acid, nor reactive oxygen species are involved in regulation of CD8 T cells in internal organs. Thus UVB impedes the activation and cytotoxicity of antigen-specific T cells in internal organs by mechanisms independent of suppression of skin immunity. These deleterious effects of low dose UV on skin immunity are likely to contribute to skin cancer, however UV suppression of immunity in internal organs may protect from autoimmunity. Epidemiological evidence suggests that sunlight protects from some autoimmune diseases directed towards internal organs. As UV suppression of skin and internal organ immunity appear to occur via different mechanisms, it may be possible to protect skin immunity and therefore reduce skin cancer incidence without preventing UV from reducing autoimmunity in internal organs., (Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.)

Ultraviolet A (UVA) radiation is immunosuppressive and mutagenic in humans and carcinogenic in animals. UVA suppresses immunity with a bell-shaped dose response. At doses equivalent to 15-20 minutes of sun exposure at noon, UVA contributes to approximately 75% of sunlight-induced immunosuppression. A recent action spectrum, indicating that 360-380 nm but not 320-350 nm UVA suppresses immunity in humans, suggests an important role for reactive oxygen species. UVA also causes an energy crisis in cells, and normalization of adenosine triphosphate with nicotinamide prevents UVA immunosuppression. UVA activation of the alternative complement pathway and defects in memory T-cell development are also involved. Human skin cancers contain mutations in the p53 and BRM genes that are consistent with being induced by UVA. UVA is also mutagenic in human skin equivalents. The basal layer of human skin is more susceptible to UVA-induced mutations than the upper layers. Because skin cancers arise from these basal proliferating cells, this finding is likely to be important and could be attributable to low levels of the DNA repair enzyme OGG1 in basal cells. UVA is therefore likely to make a larger contribution to UVA-induced skin carcinogenesis in humans than is predicted by small animal models as the result of being immunosuppressive and mutagenic for basal keratinocytes., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Nicotinamide (the amide form of vitamin B3) has been used in dermatology for more than 40 years for a diverse range of conditions including acne, rosacea, autoimmune bullous dermatoses, and now the treatment and prevention of photoaging and photoimmunosuppression. The broad clinical effects of nicotinamide may be explained by its role as a cellular energy precursor, a modulator of inflammatory cytokines, and an inhibitor of the nuclear enzyme poly(adenosine diphosphate-ribose) polymerase-1, which plays a significant role in DNA repair, maintenance ofgenomic stability, and cellular response to injury including inflammation and apoptosis. This review outlines the use of nicotinamide for inflammatory dermatoses and photoaging and focuses on its emerging role in photoprotection.

Photodynamic therapy (PDT) of non-melanoma skin cancers currently carries failure rates of 10-40%. The optimal irradiation protocol is as yet unclear. Previous studies showed profound immunosuppression after PDT, which may compromise immune-mediated clearance of these antigenic tumors. Slower irradiation prevents immunosuppression in mice, and may be at least as effective as high-fluence-rate PDT in preliminary clinical trials. The photosensitizers 5-aminolaevulinic acid and/or methyl aminolaevulinate were applied to discrete areas on the backs of healthy Mantoux-positive volunteers, followed by narrowband red light irradiation (632 nm) at varied doses and fluence rates. Delayed type hypersensitivity (Mantoux) reactions were elicited at test sites and control sites to determine immunosuppression. Human ex vivo skin received low- and high-fluence-rate PDT and was stained for oxidative DNA photolesions. PDT caused significant, dose-responsive immunosuppression at high (75 mW cm(-2)) but not low (15 or 45 mW cm(-2)) fluence rates. DNA photolesions, which may be a trigger for immunosuppression, were observed after high-fluence-rate PDT but not when light was delivered more slowly. This study demonstrates that the current clinical PDT protocol (75 mW cm(-2)) is highly immunosuppressive. Simply reducing the rate of irradiation, while maintaining the same light dose, prevented immunosuppression and genetic damage and may have the potential to improve skin cancer outcomes.

Background: The immune-suppressive effects of sunlight play a central role in skin carcinogenesis. Ultraviolet (UV) B radiation is highly immunosuppressive even at suberythemal doses, and longwave UVA is now also recognized to cause immunosuppression in humans. The relative contributions of UVA and UVB to immunosuppression by incidental daily sun exposure are, however, unclear., Objectives: We previously determined wavelength dependencies for immunosuppression by UVB and UVA wavebands in humans. We now aimed to calculate relative and solar immune-suppressive effectiveness across the UVB and UVA spectra., Methods: We used the nickel model of recall contact hypersensitivity to determine UV immunosuppression dose responses and minimum immune suppression doses (MISDs) at 11 narrowbands from 289 to 392 nm. The relative immune-suppressive effectiveness of each narrowband was then determined as 1/MISD vs. wavelength. This curve was multiplied by the solar spectrum to show the relative immune-suppressive effectiveness of each waveband in sunlight., Results: We found peaks of immune-suppressive effectiveness in the UVB waveband at 300 nm and in the UVA at 370 nm. Because of the far greater amount of longwave UVA in sunlight, the relative solar immune-suppressive effectiveness of UVA was threefold higher than that of UVB at doses equivalent to sun exposure from normal daily activities., Conclusions: Longwave UVA, which abuts the visible light spectrum and is less effectively filtered by sunscreens than UVB, is likely to be the largest contributor to immunosuppression resulting from incidental daily sun exposure., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

A 72-year-old man with a history of thrombotic CVA causing lateral medullary infarction presented with non-healing ulcers of the right side of the face of 5 months' duration. After extensive investigations, a diagnosis of trigeminal trophic syndrome was made. The ulcers progressed relentlessly despite amitriptyline and gabapentin, and he was treated with a combination of carbamazepine and thermoplastic mask occlusion of the right side of his face. Over the next 10 weeks the shallower facial ulcers began to diminish in depth and diameter, and the deeper ulcers stopped progressing. Although the patient showed early signs of healing, he died because of complications from the CVA., (© 2010 The Authors. Australasian Journal of Dermatology © 2010 The Australasian College of Dermatologists.)

The authors provide an update on a previously reported patient with in-transit metastatic melanoma of the scalp treated with topical diphencyprone (DPCP). Molecular studies implicate the thymus-derived TH17 lymphocyte subset in a remarkable immunotherapeutic regression. The authors performed RT-PCR of total RNA from paraffin-embedded tissue before and after treatment with DPCP. Before treatment with DPCP, the authors found elevated expression of IL 17C/D/E/F; after treatment there was no detectable expression. Conversely, increased expression of PLZF/CD27 and CTLA4 was seen after treatment with no expression before treatment. No expression of IL17A/B, CD7, RORgTand FoxP3 were before or after treatment. Conclusions are limited to only the time samples were obtained. Remarkable regression of an in-transit metastatic melanoma treated with the immunomodulatory agent DPCP showed gain and loss of gene expression of the TH17 pathway. Further study of this pathway from NK to NK-T to TH7 and TH1 cells both with and without accessory or dendritic cells will improve understanding of contact sensitizers as topical immunomodulators.

Background: Ultraviolet (UV) A radiation, which has both mutagenic and immune suppressive effects on the skin, is increasingly recognised as a key contributor to cutaneous carcinogenesis. Whilst short wavelength UVB (290-320 nm) is well-recognised as an environmental health hazard, the dangers of UVA (320-400 nm) are relatively unexplored., Objective: Using the nickel model of recall immunity in healthy human volunteers, we determined the wavelength dependency for UV-induced immunosuppression across the UVA spectrum., Methods: Dose-response curves were established for local suppression of contact hypersensitivity responses to nickel at 7 wavelengths between 331 and 392 nm., Results: We found a broad peak of UVA immune suppressive effectiveness at 364-385 nm. Whilst we had previously found linear dose-responses for UVB-induced immunosuppression in this model, long wavelength UVA caused bell-shaped, Gaussian dose-responses, suggesting different chromophores and mechanisms of immunosuppression for UVB and UVA., Conclusion: The immunosuppressive peak induced by longwave UVA has not been described previously for any species and being close to the border with visible light indicates an unexpected role for these long wavebands in human health and disease., (Copyright 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Calcitriol, the biologically active form of vitamin D, has been reported to cause both suppressive and protective immune effects in mice. Its immune effects in vivo in humans are unclear. We investigated the in vivo effects of topical calcitriol on minimal erythema dose and skin immune responses in healthy volunteers. We found that calcitriol did not protect from ultraviolet (UV)-induced erythema (sunburn) when applied either 24 h before or immediately after irradiation, although it decreased the density of sunburn cells and thymine dimers seen on biopsy when applied 24 h before and again immediately after irradiation. Using the Mantoux reaction as a model of skin immunity, we found that topical calcitriol applied at high total doses reduced the Mantoux responses of nearby untreated, unirradiated skin, suggesting a para-local or systemic immunosuppressive effect not observed with lower calcitriol doses. We then measured UV-induced suppression of Mantoux reactions at vehicle-treated sites and sites treated with low-dose calcitriol, and found that calcitriol neither reduced nor enhanced UV-induced immunosuppression. Despite calcitriol reducing UV-induced DNA damage, which should protect the immune system, it has immunosuppressive effects in our model which may help to explain the efficacy of analogues such as calcipotriol in the treatment of psoriasis.

Nicotinamide is a water-soluble amide form of niacin (nicotinic acid or vitamin B3). Both niacin and nicotinamide are widely available in plant and animal foods, and niacin can also be endogenously synthesized in the liver from dietary tryptophan. Nicotinamide is also commercially available in vitamin supplements and in a range of cosmetic, hair, and skin preparations. Nicotinamide is the primary precursor of nicotinamide adenine dinucleotide (NAD(+)), an essential coenzyme in ATP production and the sole substrate of the nuclear enzyme poly-ADP-ribose polymerase-1 (PARP-1). Numerous in vitro and in vivo studies have clearly shown that PARP-1 and NAD(+) status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation. This paper will examine the role of nicotinamide in the protection from carcinogenesis, DNA repair, and maintenance of genomic stability.