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.

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.

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.

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.

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.

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.

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.

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.

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.

Case-control study of melanoma and dietary vitamin D: implications for advocacy of sun protection and sunscreen use.

The rapid increase in melanoma incidence and mortality has given rise to nationwide and international campaigns that encourage the public to protect themselves from solar radiation with clothing, sunscreens, and other measures. The basis of these campaigns has been challenged by proponents of the theory that vitamin D, which is generated in the skin by ultraviolet B radiation, inhibits the development of melanoma. The present investigation tests this theory by examining the relation between dietary vitamin D and melanoma risk in a case-control study. Vitamin D intake was assessed by a food-frequency questionnaire in 165 melanoma patients and 209 controls. After controlling for age, hair color, and family history of melanoma, there was no association of melanoma risk with total vitamin D intake, calorie-adjusted vitamin D intake, vitamin D intake from foods, or consumption of milk or vitamin D supplements. We find no evidence to suggest that vitamin D protects against melanoma, and therefore continue to support the ongoing public health campaigns aimed at reducing sun exposure for the prevention of melanoma.

Dietary supplementation with secoisolariciresinol diglycoside (SDG) reduces experimental metastasis of melanoma cells in mice.

We investigated the effect of dietary supplementation with secoisolariciresinol diglycoside (SDG), a lignan precursor isolated from flaxseed, on experimental metastasis of B16BL6 murine melanoma cells in C57BL/6 mice. Four diets were compared: a basal diet (control group) and the basal diet supplemented with SDG at 73, 147 or 293 micromol/kg (equivalent to SDG provided in the 2.5, 5 or 10% flaxseed diet). Mice were fed the diet for 2 weeks before and after an intravenous injection of 0.6 x 10(5) tumor cells. At necropsy, the number and size of tumors that formed in the lungs were determined. The median number of tumors in the control group was 62, and those in the SDG-supplemented groups were 38, 36 and 29, respectively. The last was significantly different from the control (P < 0.01). Dietary supplementation with SDG at 73, 147 and 293 micromol/kg also decreased tumor size (tumor cross-sectional area and volume) in a dose-dependent manner compared with the control values. These results show that SDG reduced pulmonary metastasis of melanoma cells and inhibited the growth of metastatic tumors that formed in the lungs. It is concluded that dietary supplementation with SDG reduces experimental metastasis of melanoma cells in mice.

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.

Influence of selenium on 3-methylcholanthrene induced skin carcinogenesis in mice.

Incidence of skin papillomas/tumors have been studied in ICRC male mice after surface application of 3-methylcholanthrene (MCA) after selenium treatment. Decrease in percentage incidence and tumor burden was noticed. Also increase in latent period of induction was observed. As no influence of selenium was noticed on arylhydrocarbon-hydroxylase activity in skin and liver, so activation/inactivation of carcinogen is ruled out with selenium treatment. Since there is significant increase in glutathione S-transferase activity with selenium treatment, hence detoxication pathways may be active in suppression of carcinogenic activity with selenium treatment.

Five-year survival rates of melanoma patients treated by diet therapy after the manner of Gerson: a retrospective review.

OBJECTIVE: Compare 5-year melanoma survival rates to rates in medical literature. DESIGN: Retrospective. SETTING: Hospital in Tijuana, Mexico. PATIENTS: White adult patients (N = 153) with superficial spreading and nodular melanoma, aged 25-72 years. INTERVENTION: Gerson's diet therapy: lactovegetarian; low sodium, fat and (temporarily) protein; high potassium, fluid, and nutrients (hourly raw vegetable/fruit juices). Metabolism increased by thyroid; calorie supply limited to 2600-3200 calories per day. Coffee enemas as needed for pain and appetite. MAIN OUTCOME MEASURE: 5-year survival rates by stage at admission. RESULTS: Of 14 patients with stages I and II (localized) melanoma, 100% survived for 5 years, compared with 79% of 15,798 reported by Balch. Of 17 with stage IIIA (regionally metastasized) melanoma, 82% were alive at 5 years, in contrast to 39% of 103 from Fachklinik Hornheide. Of 33 with combined stages IIIA + IIIB (regionally metastasized) melanoma, 70% lived 5 years, compared with 41% of 134 from Fachklinik Hornheide. We propose a new stage division: IVA (distant lymph, skin, and subcutaneous tissue metastases), and IVB (visceral metastases). Of 18 with stage IVA melanoma, 39% were alive at 5 years, compared with only 6% of 194 from the Eastern Cooperative Oncology Group. Survival impact was not assessed for stage IVB. Male and female survival rates were identical for stages I-IIIB, but stage IVA women had a strong survival advantage. CONCLUSIONS: The 5-year survival rates reported here are considerably higher than those reported elsewhere. Stage IIIA/B males had exceptionally high survival rates compared with those reported by other centers.