Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

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 for skin cancer chemoprevention: effects of nicotinamide on melanoma in vitro and in vivo.

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 for photoprotection and skin cancer chemoprevention: A review of efficacy and safety.

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.

A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention.

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.).

Melanoma and nonmelanoma skin cancer chemoprevention: A role for nicotinamide?

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 B3 ) 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.

Nicotinamide for skin cancer chemoprevention.

Nicotinamide (vitamin B3 ) 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.

Nicotinamide and neurocognitive function.

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.

Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER).

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.

Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in primary melanocytes.

Cutaneous melanoma is a significant cause of morbidity and mortality. Nicotinamide is a safe, widely available vitamin that reduces the immune suppressive effects of UV, enhances DNA repair in keratinocytes and has shown promise in the chemoprevention of non-melanoma skin cancer. Here, we report the effect of nicotinamide on DNA damage and repair in primary human melanocytes. Nicotinamide significantly enhanced the repair of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanosine) and cyclobutane pyrimidine dimers induced by UV exposure. It also enhanced the repair of 8-oxo-7,8-dihydro-2'-deoxyguanosine induced by the culture conditions in unirradiated melanocytes. A significant increase in the percentage of melanocytes undergoing unscheduled but not scheduled DNA synthesis was observed, confirming that nicotinamide enhances DNA repair in human melanocytes. In summary, nicotinamide, by enhancing DNA repair in melanocytes, is a potential agent for the chemoprevention of cutaneous melanoma.

Topical immunotherapy with diphencyprone for in transit and cutaneously metastatic melanoma.

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.

Oral and systemic photoprotection.

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.

Primary oesophageal melanoma - a case report.

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.

Nicotinamide and the skin.

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.

Cutaneous malignancies in chronic lymphocytic leukemia.

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.

A review of skin cancer primary prevention activities in primary care settings.

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.

Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in human keratinocytes and ex vivo skin.

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.

Implementing structured pathology reporting protocol for non-melanocytic skin cancers: practical considerations.

Non-melanocytic skin cancers (NMSCs) account for five times the incidence of all other cancers combined and cost US $6 billion annually. These are the most frequent specimens encountered in community pathology practice in many Western countries. Lack of standardised structured pathology reporting protocols (SPRPs) can result in omission of critical information or miscommunication leading to suboptimal patient management. The lack of standardised data has significant downstream public health implications, including insufficient data for reliable development of prognostic tools and health-economy planning. The Royal College of Pathologists of Australasia has developed an NMSC SPRP. A multidisciplinary expert committee including pathologists, surgeons, dermatologists, and radiation and medical oncologists from high volume cancer centres was convened. A systematic literature review was performed to identify evidence for including elements as mandatory standards or best practice guidelines. The SPRP and accompanying commentary of evidence, definitions and criteria was peer reviewed by external stakeholders. Finally, the protocol was revised following feedback and trialled in multiple centres prior to implementation. Some parameters utilised clinically for determining management and prognosis including tumour depth, lymphovascular invasion or distance to the margins lack high level evidence in NMSC. Dermatologists, surgeons, and radiation oncologists welcomed the SPRP. Pathologists indicated that the variety of NMSC specimens ranging from curettes to radical resections as well as significant differences in the biological behaviour of different tumours covered by the NMSC umbrella made use of a single protocol difficult. The feedback included that using a SPRP for low risk NMSC was neither clinically justified nor compensated adequately by the Australian Medicare Reimbursement Schedule. Following stakeholder feedback, the SPRP implementation was restricted to excision specimens of head and neck NMSC; and low-risk NMSC, such as superficial basal cell carcinoma, were excluded. Implementing NMSC SPRP fulfils an unmet clinical need. Unlike other cancers, NMSCs generate a range of specimen types and are reported in a wide range of pathology practices. Limiting use of SPRP to NMSC at higher risk of progression and providing formatted templates for easy incorporation into laboratory information systems were essential to successful deployment. In the future, further consideration should be given to implementing the SPRP to include all relevant specimens, including non-head and neck and low-risk NMSC specimens.

Interventions to Increase Sunscreen Use in Adults: A Review of the Literature.

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.