Nutritional Interventions for Patients with Melanoma: From Prevention to Therapy-An Update.

Melanoma is an aggressive skin cancer, whose incidence rates have increased over the past few decades. Risk factors for melanoma are both intrinsic (genetic and familiar predisposition) and extrinsic (environment, including sun exposure, and lifestyle). The recent advent of targeted and immune-based therapies has revolutionized the treatment of melanoma, and research is focusing on strategies to optimize them. Obesity is an established risk factor for several cancer types, but its possible role in the etiology of melanoma is controversial. Body mass index, body surface area, and height have been related to the risk for cutaneous melanoma, although an 'obesity paradox' has been described too. Increasing evidence suggests the role of nutritional factors in the prevention and management of melanoma. Several studies have demonstrated the impact of dietary attitudes, specific foods, and nutrients both on the risk for melanoma and on the progression of the disease, via the effects on the oncological treatments. The aim of this narrative review was to summarize the main literature results regarding the preventive and therapeutic role of nutritional schemes, specific foods, and nutrients on melanoma incidence and progression.

Are anti-inflammatory foods associated with a protective effect for cutaneous melanoma?

The aim of this systematic narrative review is to answer the following research question: are anti-inflammatory foods or food components associated with a protective effect for melanoma development? Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, a systematic review was conducted. All cohort studies (n = 18) so far on diet and cutaneous melanoma were reviewed. Out of the 18 cohort studies, seven investigated the role of coffee on melanoma and six studies found a protective effect. Food components considered as anti-inflammatory, such as vitamin D, vitamin A, folic acid, niacin, vitamin C, omega-3 fatty acids, and carotenoids (ß-carotene, lutein, zeaxanthin, and lycopene), were not associated with a protective effect for melanoma. Other anti-inflammatory food items, such as tea, fruits, and vegetables, except for citrus fruits that were borderline associated with an increased risk, were not associated with cutaneous melanoma. In conclusion, the only anti-inflammatory food item that was consistently associated with a protective effect for cutaneous was coffee in particular caffeinated coffee.

Dietary Supplementation with the Red Seaweed Porphyra umbilicalis Protects against DNA Damage and Pre-Malignant Dysplastic Skin Lesions in HPV-Transgenic Mice.

Some diet profiles are associated with the risk of developing cancer; however, some nutrients show protective effects. Porphyra umbilicalis is widely consumed, having a balanced nutritional profile; however, its potential for cancer chemoprevention still needs comprehensive studies. In this study, we incorporated P. umbilicalis into the diet of mice transgenic for the human papillomavirus type 16 (HPV16), which spontaneously develop pre-malignant and malignant lesions, and determined whether this seaweed was able to block lesion development. Forty-four 20-week-old HPV+/- and HPV-/- mice were fed either a base diet or a diet supplemented with 10% seaweed. At the end of the study, skin samples were examined to classify HPV16-induced lesions. The liver was also screened for potential toxic effects of the seaweed. Blood was used to study toxicological parameters and to perform comet and micronucleus genotoxicity tests. P. umbilicalis significantly reduced the incidence of pre-malignant dysplastic lesions, completely abrogating them in the chest skin. These results suggest that P. umbilicalis dietary supplementation has the potential to block the development of pre-malignant skin lesions and indicate its antigenotoxic activity against HPV-induced DNA damage. Further studies are needed to establish the seaweed as a functional food and clarify the mechanisms whereby this seaweed blocks multistep carcinogenesis induced by HPV.

Synergistic Interplay between Curcumin and Polyphenol-Rich Foods in the Mediterranean Diet: Therapeutic Prospects for Neurofibromatosis 1 Patients.

Neurofibromas are the hallmark lesions in Neurofibromatosis 1 (NF1); these tumors are classified as cutaneous, subcutaneous and plexiform. In contrast to cutaneous and subcutaneous neurofibromas, plexiform neurofibromas can grow quickly and progress to malignancy. Curcumin, a turmeric-derived polyphenol, has been shown to interact with several molecular targets implicated in carcinogenesis. Here, we describe the impact of different dietary patterns, namely Mediterranean diet (MedDiet) compared to the Western diet (WesDiet), both with or without curcumin, on NF1 patients' health. After six months, patients adopting a traditional MedDiet enriched with 1200 mg curcumin per day (MedDietCurcumin) presented a significant reduction in the number and volume of cutaneous neurofibromas; these results were confirmed in subsequent evaluations. Notably, in one patient, a large cranial plexiform neurofibroma exhibited a reduction in volume (28%) confirmed by Magnetic Resonance Imaging. Conversely, neither unenriched MedDiet nor WesDiet enriched with curcumin exhibited any significant positive effect. We hypothesize that the combination of a polyphenol-rich Mediterranean diet and curcumin was responsible for the beneficial effect observed on NF1. This is, to the best of our knowledge, the first experience with curcumin supplementation in NF1 patients. Our report suggests that an integrated nutritional approach may effectively aid in the management of NF1.

Dietary proanthocyanidins prevent ultraviolet radiation-induced non-melanoma skin cancer through enhanced repair of damaged DNA-dependent activation of immune sensitivity.

Numerous plant products have been used to prevent and manage a wide variety of diseases for centuries. These products are now considered as promising options for the development of more effective and less toxic alternatives to the systems of medicine developed primarily in developed countries in the modern era. Grape seed proanthocyanidins (GSPs) are of great interest due to their anti-carcinogenic effects that have been demonstrated using various tumor models including ultraviolet (UV) radiation-induced non-melanoma skin cancer. In a pre-clinical mouse model supplementation of a control diet (AIN76A) with GSPs at concentrations of 0.2% and 0.5% (w/w) significantly inhibits the growth and multiplicity of UVB radiation-induced skin tumors. In this review, we summarize the evidence that this inhibition of UVB-induced skin tumor development by dietary GSPs is mediated by a multiplicity of coordinated effects including: (i) Promotion of the repair of damaged DNA by nuclear excision repair mechanisms, and (ii) DNA repair-dependent stimulation of the immune system following the functional activation of dendritic cells and effector T cells. Dietary GSPs hold promise for the development of an effective alternative strategy for the prevention of excessive solar UVB radiation exposure-induced skin diseases including the risk of non-melanoma skin cancer in humans.

Fasting boosts sensitivity of human skin melanoma to cisplatin-induced cell death.

Melanoma is one of leading cause of tumor death worldwide. Anti-cancer strategy includes combination of different chemo-therapeutic agents as well as radiation; however these treatments have limited efficacy and induce significant toxic effects on healthy cells. One of most promising novel therapeutic approach to cancer therapy is the combination of anti-cancer drugs with calorie restriction. Here we investigated the effect Cisplatin (CDDP), one of the most potent chemotherapeutic agent used to treat tumors, in association with fasting in wild type and mutated BRAFV600E melanoma cell lines. Here we show that nutrient deprivation can consistently enhance the sensitivity of tumor cells to cell death induction by CDDP, also of those malignancies particularly resistant to any treatment, such as oncogenic BRAF melanomas. Mechanistic studies revealed that the combined therapy induced cell death is characterized by ROS accumulation and ATF4 in the absence of ER-stress. In addition, we show that autophagy is not involved in the enhanced sensitivity of melanoma cells to combined CDDP/EBSS-induced apoptosis. While, the exposure to 2-DG further enhanced the apoptotic rate observed in SK Mel 28 cells upon treatment with both CDDP and EBSS.

Citrus consumption and risk of basal cell carcinoma and squamous cell carcinoma of the skin.

Animal experiments have demonstrated the photocarcinogenic properties of furocoumarins, a group of naturally occurring chemicals that are rich in citrus products. We conducted a prospective study for citrus consumption and risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin based on data from 41530 men in the Health Professionals Follow-up Study (1986-2010) and 63759 women in the Nurses' Health Study (1984-2010) who were free of cancers at baseline. Over 24-26 years of follow-up, we documented 20840 incident BCCs and 3544 incident SCCs. Compared to those who consumed citrus products less than twice per week, the pooled multivariable-adjusted hazard ratios were 1.03 [95% confidence interval (95% CI): 0.99-1.08] for BCC and 1.14 (95% CI: 1.00-1.30) for SCC for those who consumed two to four times per week, 1.06 (95% CI: 1.01-1.11) for BCC and 1.15 (95% CI: 1.02-1.28) for SCC for five to six times per week, 1.11 (95% CI: 1.06-1.16) for BCC and 1.22 (95% CI: 1.08-1.37) for SCC for once to 1.4 times per day and 1.16 (95% CI: 1.09-1.23) for BCC and 1.21 (95% Cl: 1.06-1.38) for SCC for 1.5 times per day or more (P trend = 0.001 for BCC and 0.04 for SCC). In contrast, consumption of non-citrus fruit and juice appeared to be inversely associated with risk of BCC and SCC. Our findings support positive associations between citrus consumption and risk of cutaneous BCC and SCC in two cohorts of men and women, and call for further investigations to better understand the potential photocarcinogenesis associated with dietary intakes.

BRAF mutation screening in melanoma: is sentinel lymph node reliable?

As the detection of the BRAF V600E mutation has a direct impact on treatment decision, an accurate screening for BRAF mutations in patients with advanced or metastatic melanoma is mandatory. Nevertheless, BRAF oncogene mutation status between different samples from the same patient has been studied with conflicting results. This study investigated the intrapatient homogeneity of BRAF mutation status using pyrosequencing in primary tumors and different metastatic sites of melanoma patients. Paired samples of lymphatic, visceral, and subcutaneous metastases and primary melanoma from 45 metastatic melanoma patients were tested for BRAF mutations using a pyrosequencing assay and by Sanger sequencing. Overall, sequencing for BRAF mutation status was performed in 114 paired samples from 45 patients. Eighteen patients (40%) carried a BRAF mutation, including BRAF V600E (12/18), BRAF V600K (5/18), and BRAF V600R (1/18) mutations. Multiple BRAF mutations (V600E and V600K) were found in one patient. Among the patients with BRAF mutations, a good agreement in BRAF mutation status was found between the first and second tumor samples genotyped (91%; Cohen's κ coefficient: 0.81). Discordance in BRAF mutation status was found only in four patients, involving all three patients in whom sentinel lymph node (SLN) metastases were sampled. These SLNs exhibited a wild-type genotype and were discordant with the other BRAF-mutated samples found in the same patient. The intrapatient BRAF status was predominantly homogeneous. However, SLN genotyping using pyrosequencing might be inaccurate in determining the actual mutation status of melanoma. Further studies are required to confirm the lack of reliability of SLN.

Diet in dermatology: Part I. Atopic dermatitis, acne, and nonmelanoma skin cancer.

Patients commonly inquire about dietary modifications as a means to prevent or manage skin disease. Answering these questions is often challenging, given the vast and conflicting evidence that exists on this topic. This 2-part continuing medical education article summarizes the evidence to date to enable physicians to answer patients' questions in an evidence-based manner. Part I includes atopic dermatitis, acne, and nonmelanoma skin cancer. The role of dietary supplementation, dietary exclusion, food allergy, maternal diet, and breastfeeding in the development and/or prevention of atopic dermatitis is summarized. The dermatoendocrinologic mechanism for the effects of glycemic index/glycemic load and milk on acne is described, as well as related clinical evidence for dietary modifications. Finally, evidence and recommendations for restriction or supplementation of dietary factors in the prevention of nonmelanoma skin cancer, including fat, vitamins A, C, D, and E, and selenium, are reported.

Diet in dermatology: Part II. Melanoma, chronic urticaria, and psoriasis.

The roles of dietary factors in aggravating, preventing, or treating skin diseases are common questions encountered in dermatology practice. Part II of this two-part series reviews dietary modifications that can potentially be utilized in the management of melanoma, chronic urticaria, and psoriasis patients. Specifically, we examine the effect of alcohol consumption and supplementation with vitamins D and E, polyunsaturated fatty acids, selenium, green tea, resveratrol, and lycopene on melanoma risk. The relationships between chronic urticaria symptoms and dietary pseudoallergens, gluten, and vitamin D are analyzed. We explore weight loss, reduced alcohol consumption, and gluten avoidance as means of reducing psoriasis-associated morbidity, as well as the possible utility of supplementation with polyunsaturated fatty acids, folic acid, vitamin D, and antioxidants. With proper knowledge of the role of diet in these cutaneous disease processes, dermatologists can better answer patient inquiries and consider implementation of dietary modifications as adjuncts to other treatments and preventative measures.

Consumption of omega-3 fatty acids and the risk of skin cancers: a systematic review and meta-analysis.

Skin cancers have a higher incidence than all other cancers combined and are a major cause of morbidity worldwide. Laboratory data suggest certain dietary constituents, notably omega-3 polyunsaturated fatty acids (n-3 PUFAs), could potentially protect against skin malignancy, although no large-scale review has been conducted in humans. The objective of this review and meta-analysis was to determine the relationship between dietary n-3 PUFAs and skin cancer incidence. It considered all published randomized controlled trials and observational studies up to March 2013. Five studies (two case-control and three cohort) were identified pertaining to oral n-3 PUFA consumption and incidence of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), melanoma (or a combination) and were included in a random-effects meta-analysis. A further six studies considering nondietary n-3 PUFA exposure (e.g., by tissue analysis) and/or recognized biological markers of skin cancer risk (e.g., p53 expression) were analyzed qualitatively. Dietary n-3 PUFAs were not associated with BCC (pooled OR 1.05, 95% CIs 0.86-1.28). Consumption of high levels of n-3 PUFAs were inversely associated with melanoma, although with only one estimate available (OR 0.52, 95% CI 0.34-0.78), and SCC, although nonsignificantly (pooled OR 0.86, 95% CIs 0.59-1.23). Available evidence is suggestive, but currently inadequate, to support the hypothesis that n-3 PUFAs protect against skin malignancy.

[Vitamin D and cancers]. / Vitamine D et cancers.

Low vitamin D plasmatic rates have been correlated to an increased risk of developing cancer. It has been proved that vitamin D could facilitate cell differentiation and have anti-inflammatory, anti-angiogenic and pro-apoptotic effects. Epidemiological studies are likely to show a protective role regarding colon cancer and possibly towards breast cancer.

Epigenetic cancer prevention mechanisms in skin cancer.

Epigenetics is an important emerging area for study of mechanisms of cancer prevention. In recent years, it has been realized that cancer prevention agents, derived from natural dietary sources, impact cancer cell survival by modulating epigenetic processes. In the present manuscript, we review key epigenetic regulatory mechanisms and examine the impact of sulforaphane and green tea polyphenols on these processes. We also discuss available information on the epigenetics in the context of skin cancer. These studies indicate that diet-derived chemopreventive agents modulate DNA methylation status and histone modification via multiple processes and point to additional areas for study of epigenetic mechanisms in skin cancer.

Hábitos alimentarios y riesgo de cancer de piel no melanoma / Diet and risk of non melanoma skin cancer

A case-control study was carried out in order to analyze the association between diet and risk of non melanoma skin cancer -basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with adjustments for demographic, anthropometric and phenotypic characteristics, sunburns history, skin cancerfamily history, sun-exposure history and skin sensitivity to sun exposure. A full-body skin examination was performed. Dietary data were obtained applying a standardized semi-quantitative questionnaire of consumption frequency. Cases (n=27; age: 65,5+15,1 years) and controls (n=37; age: 63,9+12,3 years) were attended at the same facilities. A decreased risk ofBCC and SCC tumors (Adjusted Odd Ratio=0.10; IC 95 percent= 0.02-0.63; p=0.01) was found for high intakes of green leafy vegetables (more than 40 gr/day). However, results obtained for fruits, cruciferous, vitamin A and carotene-rich vegetables and other vegetables were not statistically significant.

Mediante un diseño de casos y controles se evaluó si la dieta habitual modifica el riesgo de desarrollar cáncer de piel no melanoma: carcinomas basocelulares y carcinomas espinocelulares. En la consulta se consignaron datos demográficos, características fenotípicas y antropométricas, antecedentes de quemadura solar, antecedentes familiares de cáncer de piel y hábitos de exposición solar, y se realizó un exhaustivo examen físico cutáneo. La dieta fue evaluada por cuestionarios semi-cuantitativos de frecuencia de consumo. Se estudiaron 27 casos (edad: 65,5±15,1 años) y 37 controles (63,9±12,3) que asistieron a las mismas instituciones por otras patologías. La ingesta alta de vegetales de hojas verdes (más de 40 g/d) actuaría como factor protector (Odd Ratio ajustado= 0,10; IC 95 por ciento= 0,02-0,63; p=0,01), modificando el efecto negativo de la exposición solar. En cambio, los resultados obtenidos para frutas, crucíferas, vegetales ricos en vitamina A y carotenos y otros vegetales no resultaron estadísticamente significativos.

Primary cutaneous B-cell lymphoma.

Primary cutaneous B-cell lymphomas include extranodal marginal zone B-cell lymphoma, follicular lymphoma, large B-cell lymphoma, and, rarely, mantle cell lymphoma. Our purpose in conducting this review was to determine the clinical and behavioral characteristics of primary cutaneous B-cell lymphomas, their relationship to infectious triggers, and therapeutic response. We conducted a retrospective chart review of 23 adult patients presenting to the dermatology clinic at M. D. Anderson Cancer Center with primary cutaneous B-cell lymphoma between January 1999 and May 2003. Primary cutaneous B-cell lymphomas generally present on the head and neck, with the trunk and extremities afflicted to a lesser extent. Patients were found to have serologic evidence of prior infection with Borrelia burgdorferi (n = 10), Helicobacter pylori (n = 5), and Epstein-Barr virus (n = 6). Overall, treatment of primary cutaneous B-cell lymphoma should involve multiple modalities; however, specific treatment aimed at concurrent or suspected infection, particularly B burgdorferi, is a helpful adjunct and may achieve complete remission in a small subset of patients.

Medical therapies for non-melanoma skin cancer.

The epidemic of nonmelanoma skin cancer (NMSC) continues, in part due to aging of the world's population, the frequency of early childhood sunburns, and episodic intense recreational sun exposure as opposed to sun exposure related to outdoor occupations. A nonsurgical approach to selected skin cancers could potentially decrease the expense and morbidity of surgical treatment for NMSC. The increase of comorbid medical conditions in the elderly makes alternatives to surgical management preferable under certain circumstances. This review will discuss medical alternatives ranging from biologic response modifiers to COX-2 inhibitors to lifestyle modifications, as well as their roles in the management of NMSC. This preliminary information will expand to include more therapeutic options for NMSC in the future. Further clinical trials are needed to better elucidate possible alternative treatment strategies for NMSC.

Antimutagenic and some other effects of conjugated linoleic acid.

Conjugated linoleic acid (CLA) is a collective term for positional and geometric isomers of octadecadienoic acid in which the double bonds are conjugated, i.e. contiguous. CLA was identified as a component of milk and dairy products over 20 years ago. It is formed as an intermediate in the course of the conversion of linoleic acid to oleic acid in the rumen. The predominant naturally occurring isomer is the cis-9, trans-11 modification. Treatment of linoleic acid-rich oils such as safflower oil, soybean oil, or maize oil with base and heat will result in the formation of CLA. Two isomers predominate in the synthetic preparation, c9,t11 and t10,c12. CLA has been shown to inhibit chemically-induced skin, stomach, mammary or colon tumours in mice and rats. The inhibition of mammary tumours in rats is effective regardless of type of carcinogen or type or amount of dietary fat. CLA has also been shown to inhibit cholesterol-induced atherosclerosis in rabbits. When young animals (mice, pigs) are placed on CLA-containing diets after weaning they accumulate more body protein and less fat. Since CLA is derived from the milk of ruminant animals and is found primarily in their meat and in products derived from their milk there is a concerted world-wide effort to increase CLA content of milk by dietary means. Its effect on growth (less fat, more protein) is also a subject of active research. The mechanisms underlying the effects of CLA are still moot.