BACKGROUND:Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation-induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. METHODS:In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life. RESULTS:A total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P = 0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups. CONCLUSIONS:In this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.).

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 (NAM), an amide form of vitamin B3, has been recognized as an effective chemopreventive agent for keratinocyte cancers (KCs) (basal cell carcinoma and squamous cell carcinoma [SCC]) and actinic keratoses. The ONTRAC study (Oral Nicotinamide To Reduce Actinic Cancer, Australian New Zealand Clinical Trials Registry number ACTRN12612000625875) was a multicenter, phase 3, double-blinded, controlled trial in which NAM (500 mg) or placebo was given twice daily for 12 months to immunocompetent patients who had at least two KCs in the previous 5 years. In this high-risk population, NAM reduced the incidence of new KCs by 23%, with similar efficacy in preventing both SCC and basal cell carcinoma (Chen et al., 2015Chen A.C. Martin A.J. Choy B. Fernández-Peñas P. Dalziell R.A. McKenzie C.A. et al.A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention.N Engl J Med. 2015; 373: 1618-1626Crossref PubMed Scopus (363) Google Scholar). Chemopreventive efficacy has also been reported in immunocompromised transplant recipients (Bostom et al., 2016Bostom A.G. Merhi B. Walker J. Robinson-Bostom L. More than skin deep? Potential nicotinamide treatment applications in chronic kidney transplant recipients.World J Transpl. 2016; 6: 658-664Crossref PubMed Google Scholar, Drago et al., 2016Drago F. Ciccarese G. Parodi A. Nicotinamide for skin-cancer chemoprevention.N Engl J Med. 2016; 374: 789-790Crossref PubMed Scopus (14) Google Scholar). UVR diminishes antigen-presenting capability and induces immunosuppressive cytokines (Halliday, 2005Halliday G.M. Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis.Mutat Res. 2005; 571: 107-120Crossref PubMed Scopus (362) Google Scholar). The photoprotective effects of NAM on skin immunity (Damian et al., 2008Damian D.L. Patterson C.R. Stapelberg M. Park J. Barnetson R.S. Halliday G.M. UV radiation-induced immunosuppression is greater in men and prevented by topical nicotinamide.J Invest Dermatol. 2008; 128: 447-454Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar) may be due to its ability to enhance DNA repair, thereby reducing DNA photolesions (Surjana et al., 2013Surjana D. Halliday G.M. Damian D.L. Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in human keratinocytes and ex vivo skin.Carcinogenesis. 2013; 34: 1144-1149Crossref PubMed Scopus (86) Google Scholar), which are a trigger for UV-induced immunosuppression (Kripke et al., 1992Kripke M.L. Cox P.A. Alas L.G. Yarosh D.B. Pyrimidine dimers in DNA initiate systemic immunosuppression in UV-irradiated mice.Proc Natl Acad Sci USA. 1992; 89: 7516-7520Crossref PubMed Scopus (463) Google Scholar). Understanding the immune mechanisms in skin cancer, including the roles of T and B lymphocytes, macrophages, and dendritic cells, can provide a basis for chemopreventive and therapeutic opportunities (Rangwala and Tsai, 2011Rangwala S. Tsai K.Y. Roles of the immune system in skin cancer.Br J Dermatol. 2011; 165: 953-965Crossref PubMed Scopus (130) Google Scholar). We analyzed KCs collected at the Royal Prince Alfred Hospital ONTRAC study site (Sydney, Australia) (n = 130), using a range of immunological markers to better understand the mechanisms by which NAM reduced skin carcinogenesis. We also assessed DNA damage in tumors arising at sun-exposed sites on NAM and on placebo by staining for cyclobutane pyrimidine dimers (CPDs) and 7,8-dihydro-8-oxoguanine (8oxoG). A total of 130 tumors from 78 patients were included in the study (70 and 60 arose in patients receiving placebo and NAM, respectively). The study was approved by the Ethics Committees of the University of Sydney and the Sydney Local Health District, and all patients provided written informed consent. Selection of tumors was made blinded to treatment allocation (see Supplementary Figure S1 online). To minimie the risk of false-p ositive results arising from multiple hypothesis testing, we a priori grouped the immunological markers, on the basis of their intercorrelation, to form four indices (see Supplementary Figure S2 online for statistical methods). Thus, the primary analyses of immunological markers comprised a family of four hypothesis tests. Index 1 reflected the abundance of lymphocyte markers and was derived from CD3 (Novocastra, Leica Biosystems, Newcastle, UK), CD4 (Cell Marque, Rocklin, CA), CD8 (Dako, Carpenteria, CA), and FoxP3 (Abcam, Melbourne, Australia). Index 2 reflected the abundance of macrophage markers and was derived from CD68 (Dako) and CD163 (Novocastra). Index 3 was the count of the dendritic cell marker CD11c (Novocastra). Index 4 was the count of the proliferative cell marker, Ki-67 (Ventana, Tuscan, AZ) (see Supplementary Materials and Methods). Tumors arising on sun-exposed sites (head, neck, elbows, forearms, and hands) were stained for DNA damage markers (CPDs and 8oxoG, n = 49 tumors). Comparisons between randomized groups were performed using a mixed linear modeling approach. The detailed methods are described in the Supplementary Materials and Methods and elsewhere (Thompson et al., 2014Thompson B.C. Surjana D. Halliday G.M. Damian D.L. Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in primary melanocytes.Exp Dermatol. 2014; 23: 509-511Crossref PubMed Scopus (47) Google Scholar). Analysis of the immunological markers showed no convincing statistical evidence of a treatment effect on Index 1 (lymphocyte markers CD3, CD4, CD8, and FoxP3; P = 0.06), Index 3 (dendritic cell marker CD11c; P = 0.06), or Index 4 (proliferative cell marker Ki-67; P = 0.94 peritumoral and P = 0.77 intratumoral) (Figure 1). The effect of NAM on Index 2 (macrophage markers CD68 and CD163 counts) was significant (P = 0.0029). Secondary analyses showed this to be driven by a prominent reduction in CD68 in patients receiving NAM (P = 0.0018), although no clear treatment effect on CD163 was noted (P = 0.15). A post hoc analysis of the ratio of CD163 to CD68 provided some evidence of a NAM effect (P = 0.0482). This reflects the disproportionately larger decrease in CD68 cells compared with CD163 cells in the NAM group of tumors (Figure 1). Analysis of the DNA damage markers found nonsignificant reductions with NAM in (i) CPD lesions of 49% in the epidermis (P = 0.21) and 21% intratumorally (P = 0.73) (Figure 2a) and (ii) 8oxoG lesions in the epidermis of 10.5% (P = 0.76) and in the tumoral region of 28.5% (P = 0.37) (Figure 2b). CPDs and 8oxoG have previously been observed in human skin SCCs and actinic keratoses (Agar et al., 2004Agar N.S. Halliday G.M. Barnetson R.S. Ananthaswamy H.N. Wheeler M. Jones A.M. The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis.Proc Natl Acad Sci USA. 2004; 101: 4954-4959Crossref PubMed Scopus (447) Google Scholar). DNA repair, essential for the prevention of UV-induced carcinogenesis, is a highly energy dependent process. NAM is a precursor of nicotinamide adenine dinucleotide and an essential coenzyme in adenosine triphosphate production (Park et al., 2010Park J. Halliday G.M. Surjana D. Damian D.L. Nicotinamide prevents ultraviolet radiation-induced cellular energy loss.Photochem Photobiol. 2010; 86: 942-948Crossref PubMed Scopus (97) Google Scholar). Consistent with previously observed effects of NAM on DNA repair in ex vivo UV-irradiated human skin (Surjana et al., 2013Surjana D. Halliday G.M. Damian D.L. Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in human keratinocytes and ex vivo skin.Carcinogenesis. 2013; 34: 1144-1149Crossref PubMed Scopus (86) Google Scholar), tumors arising in NAM-supplemented participants tended to have lower levels of CPD and 8oxoG photolesions, although this failed to reach significance. It is likely that there was high variability in intensity and time since sun exposure, as well as variability in DNA repair efficiency, in our study participants. This would have resulted in a large spread in the data. We found a significant decrease in the number of macrophages in KCs that arose in patients receiving NAM compared with placebo. This was restricted to a significant reduction in tumor-associated cells expressing CD68+, which is a marker identifying both M1 and M2 macrophages. This is consistent with the observation of higher numbers of CD68+ macrophages in SCC compared with normal skin (Pettersen et al., 2011Pettersen J.S. Fuentes-Duculan J. Suarez-Farinas M. Pierson K.C. Pitts-Kiefer A. Fan L. et al.Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated.J Invest Dermatol. 2011; 131: 1322-1330Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar) and the association of CD68+ cells with inflammation and higher 10-year uveal melanoma mortality (Mäkitie et al., 2001Mäkitie T. Summanen P. Tarkkanen A. Kivelä T. Tumor-infiltrating macrophages (CD68+ cells) and prognosis in malignant uveal melanoma.Invest Ophthalmol Vis Sci. 2001; 42: 1414-1421PubMed Google Scholar). CD163, which is associated with an M2 macrophage functional program, was not significantly reduced. This suggests that M1 macrophages are specifically depleted by NAM. NAM's effects on macrophages have been sparsely documented, although it has been reported that in diabetic patients NAM suppresses inflammatory cytokine production by monocytes and macrophages (Krętowski et al., 2000Krętowski A. Myśliwiec J. Szelachowska M. Kinalski M. Kinalska I. Nicotinamide inhibits enhanced in vitro production of interleukin-12 and tumour necrosis factor-α in peripheral whole blood of people at high risk of developing type 1 diabetes and people with newly diagnosed type 1 diabetes.Diabetes Res Clin Pract. 2000; 47: 81-86Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). Inflammation and reactive oxygen/nitrogen species, which are produced by M1 macrophages (Tan et al., 2016Tan H.Y. Wang N. Li S. Hong M. Wang X. Feng Y. The reactive oxygen species in macrophage polarization: reflecting its dual role in progression and treatment of human diseases.Oxid Med Cell Longev. 2016; 2016: 2795090Crossref PubMed Scopus (326) Google Scholar), are recognized promoters of skin carcinogenesis (Halliday, 2005Halliday G.M. Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis.Mutat Res. 2005; 571: 107-120Crossref PubMed Scopus (362) Google Scholar), and NAM inhibition of inflammatory cytokine production by macrophages may therefore contribute to its chemopreventive effects on skin cancer. The tumors studied, however, are the subset that resisted chemoprevention by NAM, and the effects of NAM on cancers that failed to grow could not determined. The authors state no conflict of interest. This work was supported by funding from the Sydney Medical School Foundation, The Australasian College of Dermatologists, National Health & Medical Research Council project grant number 1026977. RM was supported by two University of Sydney scholarships: The Postgraduate Scholarship in Dermatology and the Walter Eberhard Schroeder Dermatology Research Scholarship. RAS is supported by an Australian National Health and Medical Research Council practitioner fellowship. We would also like to acknowledge the kind contribution of the patients who participated in the ONTRAC study. Assistance from colleagues in the Tissue Pathology and Diagnostic Oncology departments at the Royal Prince Alfred Hospital and the Melanoma Institute Australia's Melanoma Pathology Translational Research group is also gratefully acknowledged. Download .pdf (.81 MB) Help with pdf files Supplementary Data

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.

DEAR EDITOR, Immunosuppressed organ transplant recipients have an 80-fold increased risk of squamous cell carcinoma (SCC) and a 16-fold increased risk of basal cell carcinoma (BCC); SCCs are more aggressive and more likely to metastasize in these patients. While mammalian target of rapamycin (mTOR) inhibitors may help reduce the incidence of SCC, the current mainstay of nonmelanoma skin cancer (NMSC) chemoprevention post-transplant is oral retinoids, which have side-effects, including liver and lipid abnormalities, mucocutaneous dryness and teratogenicity. Nicotinamide (vitamin B3) enhances repair of photodamaged DNA and prevents the inhibitory effects of ultraviolet radiation on the immune system without altering baseline immune reponses. In 386 immunocompetent participants at high risk of having skin cancer, nicotinamide 500 mg twice daily reduced new NMSCs by 23% (P = 0 02), with 20% fewer BCCs and 30% fewer SCCs compared with placebo. Actinic keratoses (AKs) were also significantly reduced by nicotinamide in the same phase III randomized controlled trial. However, it is unknown whether nicotinamide prevents NMSCs and is safe in immunosuppressed renal transplant recipients. Eligible adult immunosuppressed participants included those who had received a renal transplant ≥ 12 months ago, had stable renal function and a history of ≥ 2 NMSCs in the previous 12 months. Participants were ineligible if they commenced retinoids or mTOR inhibitors within 6 months, or used nicotinamide supplements or AK field treatments within the 4 weeks prior to enrolment. This double-blind study was conducted at the Royal Prince Alfred Hospital (Sydney, Australia; Australian New Zealand Clinical Trials Registry ACTRN12612000628842) after ethical approval was received. All participants provided written informed consent. Participants were enrolled (by A.C.C. and R.A.D.) and randomized 1:1 to receive either nicotinamide 500 mg twice daily or matched placebo (Insolar; Blackmores, Warriewood, Australia) by centralized randomization (permuted blocks; National Health and Medical Research Council Clinical Trials Centre) stratified by lifetime NMSC history (< 6 or ≥ 6 NMSCs), oral retinoid use and mTOR inhibitor use. Compliance was monitored by tablet counts at each visit (A.C.C). Skin cancer checks were performed at baseline and twice monthly up to 6 months by dermatologists blinded to treatment allocation (D.L.D., P.M.L.). AKs on the face, scalp, forearms and hands were counted at baseline and twice monthly up to 6 months by a dermatology Fellow blinded to allocation (A.C.C). All squamous lesions were reviewed by a single (blinded) histopathologist (C.A.M.) to ensure consistent reporting of SCC differentiation. Blood and urine samples were taken at baseline, 2 and 4 weeks, and 2, 4 and 6 months for full blood count, electrolytes, renal and liver function tests, drug levels and urine microalbumin/creatinine ratio. Blood pressure and weight were measured at baseline and twice monthly for 6 months. The primary end point was the number of new NMSCs (BCC + SCC, including invasive and in situ SCC) up to 6 months. Secondary end points included new BCCs, new SCCs, AK counts up to 6 months and safety. The planned sample size was 80 participants, in order to provide 80% power to detect a 50% reduction in the 6-month NMSC rate at the 5% level of significance, assuming that NMSC counts followed a Poisson distribution with a mean of 1 5 for the placebo group, allowing for ≤ 10% noncompliance. However, owing to slow recruitment because of an overestimation of the eligible participant population at our site, the study was stopped early; 22 participants were recruited over 1 5 years. Analyses were by intention to treat. As per the provision specified in the statistical analysis plan, a negative binomial model was used to analyse NMSC, SCC and BCC data, owing to overdispersion that rendered the Poisson model inappropriate. Models included an offset term to account for variation in follow-up duration. The 2-monthly postbaseline AK data were analysed using a mixed model for repeated measures, including treatment group, baseline value, time point and a time-by-treatment group interaction as covariates. From August 2012 to March 2014, 25 participants were assessed for eligibility and 22 were randomized [11 in each group; Figure S1 (see Supporting Information)]. The groups had similar baseline characteristics (Table 1). Follow-up was from August 2012 to August 2014. Median compliance was 93% and 98% for the placebo and nicotinamide groups, respectively. The 6-month NMSC rate was not significantly lower for the nicotinamide group [mean 2 7, 95% confidence interval (CI) 1 4–5 3; total 30 cancers] compared with placebo (mean 4 2, 95% CI 2 2–7 8; total 45 cancers); however, the numeric trend was dominated by one patient in the placebo group

Classification of high risk basal cell carcinoma subtypes: experience of the ONTRAC study with proposed definitions and guidelines for pathological reporting CATRIONA A. MCKENZIE, ANDREW C. CHEN, BONITA CHOY, PABLO FERNANDEZ-PENAS, DIONA L. DAMIAN AND RICHARD A. SCOLYER 1Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, 2Dermatology and Bosch Institute, The University of Sydney at Royal Prince Alfred Hospital, 3Dermatology, The University of Sydney at Westmead Hospital, 4Melanoma Institute Australia, North Sydney, Sydney, and 5Discipline of Pathology, Sydney Medical School, The University of Sydney, NSW, Australia

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 agerelated 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.

9000 Background: Nicotinamide (vitamin B3) enhances DNA repair and prevents cutaneous immune suppression after ultraviolet (UV) radiation exposure. It reduces photocarcinogenesis in mice, and human non-melanoma skin cancers (NMSC) in Phase 2 clinical trials. We report the outcomes of the Phase 3 Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) Study. Methods: ONTRAC was a double-blind RCT conducted in two tertiary treatment centers in Sydney, Australia from 2012-2014. 386 immune competent participants with ≥ 2 histologically-confirmed NMSC in the past 5 years were randomized (1:1) to oral nicotinamide 500mg bd (NIC) or matched placebo (PBO) for 12 months. The primary endpoint was the number of new NMSCs to 12 months. Secondary endpoints included number of squamous cell carcinomas (SCCs), basal cell carcinomas (BCCs), and actinic keratoses (AKs) to 12 months. Skin reviews by dermatologists were performed 3 monthly. The sample size provided 90% power to detect a 33% difference in NMSC rates. Analysis was by intention-to-treat. Results: The mean age of study population was 66 years, the mean number of NMSC in the past 5 years was 8, and 63% were men. Treatment discontinuation rates were 9% for PBO versus 10% for NIC. 99% of patients underwent at least one post-baseline skin assessment. The average NMSC rate was significantly lower for NIC (1.77) than PBO (2.42). The estimated relative rate reduction (RRR) was 0.23 (95% CI: 0.04 to 0.38, p = 0.02) adjusting for center and NMSC history, and 0.27 (95% CI: 0.05 to 0.44; p = 0.02) with no adjustment. Treatment effects of comparable magnitude were found for both BCCs (RRR = 0.20, 95% CI: -0.06 to 0.39, p = 0.1) and SCCs (RRR = 0.30, 95% CI: 0 to 0.51, p = 0.05). AK counts were reduced for NIC compared to PBO by 11% at 3 months (p = 0.01), 14% at 6 months (p < 0.001), 20% at 9 months (p < 0.0001) and 13% at 12 months (p < 0.005). There were no clinically relevant differences in adverse event rates between the two arms. Conclusions: Nicotinamide reduces NMSC formation in high risk patients and is well tolerated. Furthermore, it is widely accessible as an inexpensive over-the-counter vitamin supplement and presents a new chemopreventive opportunity against NMSCs that is readily translatable into clinical practice. Clinical trial information: ACTRN12612000625875.

BACKGROUNDNonmelanoma skin cancers, such as basal-cell carcinoma and squamous-cell carcinoma, are common cancers that are caused principally by ultraviolet (UV) radiation. Nicotinamide (vitamin B-3) has been shown to have protective effects against damage caused by UV radiation and to reduce the rate of new premalignant actinic keratoses.METHODSIn 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.RESULTSAt 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.CONCLUSIONSOral 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.)

Abstract 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.

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.

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 dys-regulation. 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 noncompliance. 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.

Proliferative nodules (PN) are benign lesions that arise in large congenital melanocytic naevi (LCMN). Clinically and histologically they can be difficult to differentiate from malignancies, which are also associated with LCMN. The PN in this case consisted of undifferentiated spindle cells and exhibited unusual histological features including negative stains for melanocytic markers (S100, HMB45 and MelA), negative stain for c-Kit, high mitotic index and unusual morphology of the lesional cells. As a result, a firm histological classification could not be made, which posed a challenge for the clinical management.

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 E-2 (PGE(2)) 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 PGE(2). 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.

Large congenital melanocytic naevi (LCMN) are associated with an increased risk of malignancy and neurocutaneous melanocytosis (NCM). This Australian study aims to assess both the clinical characteristics of LCMN and the risks associated with it. The authors reviewed medical records of the Sydney Children's Hospital Dermatology Outpatient Clinic for the past 10 years and identified 31 eligible patients. A total of 14 boys and 17 girls with a median age of 0.13 years were assessed; 18 lesions were on the trunk, five were on the head, five were on the lower limbs and three were on the upper limbs. In all 20 patients had satellite naevi (the median number of the satellite naevi was 7.5). The patients were followed up for a median duration of 12 months. Central nervous system magnetic resonance imaging was performed on 19 patients and two (6.5%) were found to have NCM. Biopsies were performed on five patients; one patient (3.2%) was found to have benign proliferative nodules of undifferentiated spindle cells but no patient (0%) was found to have a malignancy. The clinical characteristics for the two patients with NCM and the patient with benign proliferative nodules suggest that the risk of both NCM and benign proliferative nodules may be greater with an increased number of satellite naevi and with the LCMN being larger in size.