Severe progressive scarring pembrolizumab-induced lichen planopilaris in a patient with metastatic melanoma.

Lichenoid reactions are one of the many cutaneous immune-related adverse events seen with the use of immune checkpoint inhibitors, particularly anti-PD1 inhibitors. We present a rare care of severe lichen planopilaris secondary to pembrolizumab, with progression even after cessation of immunotherapy. It is important to recognise the significant long-term impact of these cutaneous adverse effects on patient's quality of life.

Imidazothiazole-based potent inhibitors of V600E-B-RAF kinase with promising anti-melanoma activity: biological and computational studies.

A series of imidazothiazole derivatives possessing potential activity against melanoma cells were investigated for molecular mechanism of action. The target compounds were tested against V600E-B-RAF and RAF1 kinases. Compound 1zb is the most potent against both kinases with IC50 values 0.978 and 8.2 nM, respectively. It showed relative selectivity against V600E mutant B-RAF kinase. Compound 1zb was also tested against four melanoma cell lines and exerted superior potency (IC50 0.18-0.59 µM) compared to the reference standard drug, sorafenib (IC50 1.95-5.45 µM). Compound 1zb demonstrated also prominent selectivity towards melanoma cells than normal skin cells. It was further tested in whole-cell kinase assay and showed in-cell V600E-B-RAF kinase inhibition with IC50 of 0.19 µM. Compound 1zb induces apoptosis not necrosis in the most sensitive melanoma cell line, UACC-62. Furthermore, molecular dynamic and 3D-QSAR studies were done to investigate the binding mode and understand the pharmacophoric features of this series of compounds.

Modulation of dietary methionine intake elicits potent, yet distinct, anticancer effects on primary versus metastatic tumors.

Methionine dependency describes the characteristic rapid in vitro death of most tumor cells in the absence of methionine. Combining chemotherapy with dietary methionine deprivation [methionine-deficient diet (MDD)] at tolerable levels has vast potential in tumor treatment; however, it is limited by MDD-induced toxicity during extended deprivation. Recent advances in imaging and irradiation delivery have created the field of stereotactic body radiotherapy (SBRT), where fewer large-dose fractions delivered in less time result in increased local-tumor control, which could be maximally synergistic with an MDD short course. Identification of the lowest effective methionine dietary intake not associated with toxicity will further enhance the cancer therapy potential. In this study, we investigated the effects of MDD and methionine-restricted diet (MRD) in primary and metastatic melanoma models in combination with radiotherapy (RT). In vitro, MDD dose-dependently sensitized mouse and human melanoma cell lines to RT. In vivo in mice, MDD substantially potentiated the effects of RT by a significant delay in tumor growth, in comparison with administering MDD or RT alone. The antitumor effects of an MDD/RT approach were due to effects on one-carbon metabolism, resulting in impaired methionine biotransformation via downregulation of Mat2a, which encodes methionine adenosyltransferase 2A. Furthermore, and probably most importantly, MDD and MRD substantially diminished metastatic potential; the antitumor MRD effects were not associated with toxicity to normal tissue. Our findings suggest that modulation of methionine intake holds substantial promise for use with short-course SBRT for cancer treatment.

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.

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.

Chloroquine-mediated lysosomal dysfunction enhances the anticancer effect of nutrient deprivation.

PURPOSE: To investigate the ability of chloroquine, a lysosomotropic autophagy inhibitor, to enhance the anticancer effect of nutrient deprivation. METHODS: Serum-deprived U251 glioma, B16 melanoma and L929 fibrosarcoma cells were treated with chloroquine in vitro. Cell viability was measured by crystal violet and MTT assay. Oxidative stress, apoptosis/necrosis and intracellular acidification were analyzed by flow cytometry. Cell morphology was examined by light and electron microscopy. Activation of AMP-activated protein kinase (AMPK) and autophagy were monitored by immunoblotting. RNA interference was used for AMPK and LC3b knockdown. The anticancer efficiency of intraperitoneal chloroquine in calorie-restricted mice was assessed using a B16 mouse melanoma model. RESULTS: Chloroquine rapidly killed serum-starved cancer cells in vitro. This effect was not mimicked by autophagy inhibitors or LC3b shRNA, indicating autophagy-independent mechanism. Chloroquine-induced lysosomal accumulation and oxidative stress, leading to mitochondrial depolarization, caspase activation and mixed apoptotic/necrotic cell death, were prevented by lysosomal acidification inhibitor bafilomycin. AMPK downregulation participated in chloroquine action, as AMPK activation reduced, and AMPK shRNA mimicked chloroquine toxicity. Chloroquine inhibited melanoma growth in calorie-restricted mice, causing lysosomal accumulation, mitochondrial disintegration and selective necrosis of tumor cells. CONCLUSION: Combined treatment with chloroquine and calorie restriction might be useful in cancer therapy.

Immune Checkpoint Inhibitor-induced Bilateral Vestibulopathy.

Checkpoint inhibitors (CPI), such as anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen-4antibodies cause serious, rarely fatal immune-related adverse events (irAE) potentially in all organ systems. Neurological immune-related adverse events occur in 1%-5% of patients on CPI therapy and may present with dramatic clinical symptoms of the sensory organs. After exclusion of other causes, a high-dose treatment with corticosteroids is crucial for clinical outcome with lower risk of sequelae. We present a severe case of CPI-related ongoing and most likely irreversible bilateral vestibular affection. A 59-year-old male melanoma patient with brain metastasis undergoing immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death-1 antibodies developed severe debilitating rotatory vertigo. Bilateral vestibulopathy was diagnosed as a result of the CPI therapy after a thorough analysis including magnetic resonance imaging, laboratory tests of blood and cerebrospinal fluid as well as neurological and otorhinolaryngology examinations. The vertigo improved slightly during a 10-day course of steroid therapy and intensive balance training but did not resolve completely.

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.

Patterns of Omega-3 and Omega-6 Fatty Acid Dietary Intake and Melanoma Thickness at Diagnosis.

BACKGROUND: Experimental evidence suggests that dietary intakes of omega-3 and omega-6 polyunsaturated fatty acids have divergent effects on melanoma growth, but epidemiologic evidence on their combined effect is lacking. METHODS: In 634 Australian patients with primary melanoma, we assessed prediagnosis consumption of 39 food groups by food frequency questionnaires completed within 2 months of diagnosis. We derived, by reduced rank regression, dietary patterns that explained variability in selected omega-3 and omega-6 fatty acid intakes. Prevalence ratios (PR) and 95% confidence intervals (CI) for the association between tertiles of dietary patterns and melanoma thickness >2 mm versus ≤2 mm were estimated using Poisson regression. RESULTS: Overall omega-3 fatty acid intakes were low. Two major fatty acid dietary patterns were identified: "meat, fish, and fat," positively correlated with intakes of all fatty acids; and "fish, low-meat, and low-fat," positively correlated with long-chain omega-3 fatty acid intake, and inversely with medium-chain omega-3 and omega-6 fatty acid intakes. Prevalence of thick melanomas was significantly higher in those in the highest compared with lowest tertile of the "meat, fish, and fat" pattern (PR, 1.40; 95% CI, 1.01-1.94), especially those with serious comorbidity (PR, 1.83; 95% CI, 1.15-2.92) or a family history (PR, 2.32; 95% CI, 1.00-5.35). The "fish, low-meat, and low-fat" pattern was not associated with melanoma thickness. CONCLUSIONS: People with high meat, fish, and fat intakes, who thus consumed relatively high levels of omega-3 and high omega-6 fatty acid intakes, are more likely to be diagnosed with thick than thin melanomas. IMPACT: High omega-3 and omega-6 fatty acid intakes may contribute to patients' presentation with thick melanomas.

Gas­filled ultrasound microbubbles enhance the immunoactivity of the HSP70­MAGEA1 fusion protein against MAGEA1­expressing tumours.

Advanced malignant melanoma is characterized by rapid development, poor prognosis and insensitivity to chemoradiotherapy. Immunotherapy has become one of the primary clinical treatments for malignant melanomas. In recent decades, identifying specific tumour antigens and the enhanced immunoactivity of tumour vaccines has become critical for engineering successful tumour vaccines. As a widely used vaccine carrier, heat shock protein 70 (HSP70) clearly increases the immunogenicity of tumour antigens, such as melanoma­associated antigen A1 (MAGEA1). Based on previous studies, gas­filled ultrasound microbubbles (MBs) were engineered to carry an HSP70­MAGEA1 fusion protein (FP). Following subcutaneous injection around the lymphatic nodes the FP was directly released into the lymph nodes under ultrasonic imaging. The results indicated that the microbubbles enhanced the immunoactivity of FPs more effectively than HSP70­MAGEA1 fusion alone. Additionally, HSP70­MAGEA1 delivered via microbubbles clearly inhibited and delayed the growth of MAGEA1­expressing B16 melanomas in mice and improved the survival times of these animals compared with the fusion protein alone. The results of the present study demonstrated that controlled MBs enhance the immunoactivity of FPs and also highlights novel, potential vaccine carriers and a new strategy for engineering controllable tumour vaccine designs.

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review.

AIM: Pembrolizumab is a fully humanized anti-PD-1 agent currently approved for the treatment of advanced melanoma and pretreated non-small-cell lung cancer (NSCLC). OBJECTIVE: To assess the efficacy and safety of different dose schedules of pembrolizumab in the treatment of patients with advanced NSCLC and melanoma. Search method: MEDLINE database has been searched. Reference lists of original studies and review articles were checked for other related articles. SELECTION CRITERIA: Prospective clinical trials reporting the outcomes of more than one dose schedule of pembrolizumab in the treatment of advanced NSCLC and melanoma. DATA COLLECTION & ANALYSIS: The review author extracted information on the outcomes of the study for this review, and presented the results. MAIN RESULTS: Four trials with 3425 patients were included in this systematic review. Pooled analysis for the odds ratio of objective response rate comparing 2 versus 10 mg/kg every 3 weeks in advanced melanoma was 1.03 (95% CI: 0.71-1.49; p = 0.89), while for advanced NSCLC, it was 0.97 (95% CI: 0.66-1.43; p = 0.87). Moreover, odds ratio for selected side effects between the two doses was as follows: rash: 0.83 (95 CI: 0.58-1.18; p = 0.29); vitiligo: 1.27 (95% CI: 0.62-2.61; p = 0.52); diarrhea: 0.94 (95% CI: 0.63-1.42; p = 0.79); hypothyroidism: 0.97 (95% CI: 0.63-1.50; p = 0.90); hepatitis/elevated transaminases: 1.86 (95% CI: 0.91-3.79; p = 0.09); nephritis: 0.88 (95% CI: 0.32-2.44; p = 0.80); pneumonitis: 1.17 (95% CI: 0.62-2.23; p = 0.63). CONCLUSIONS: Given the equivalence in efficacy and safety between lower doses and higher doses of pembrolizumab, 2 mg/kg every 3 weeks seems to be an appropriate dose for routine practice in advanced pretreated NSCLC and melanoma.

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.

The effect of a phenylalanine and tyrosine restricted diet on elemental balance studies and plasma aminograms of patients with disseminated malignant melanoma.

Previous studies indicate dietary phenylalanine and tyrosine restriction may be of value in managing advanced cancer patients. To further evaluate this approach, we performed a 60-day study in which four patients with advanced malignant melanoma received formula diets via nasogastric tube containing only 8 mg total phenylalanine and tyrosine per kg lean body mass per day. Two of three patients completing elemental balance studies were in negative nitrogen, potassium, and phosphorus balance, suggesting an essential nutrient deficiency. Three patients tolerated the diet well, but one was non-compliant. Although no serious toxicity developed, serum albumin, total iron binding capacity and cholesterol significantly decreased (p less than 0.01) in the three complaint patients. Fasting plasma phenylalanine and tyrosine values did not significantly change during the study, but two-hour postprandial plasma phenylalanine and tyrosine concentrations fell below normal and were significantly lower than preprandial levels (p less than 0.01). There were no tumor responses.

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.

Improvement of the recurrence-free interval using biological adjuvant therapy in uveal melanoma.

This study was an attempt to compensate for an alleged aetiological deficiency in melanoma by the prophylactic oral administration of the essential biological components missing. Nine random patients suffering from high-risk uveal melanoma (T3) were, in this preliminary study, treated secondarily with biological dietary adjuvants after primary standard therapy, enucleation or brachytherapy. Secondary treatment consisted of certain natural amino-acids, trace-element salts, folic acid and a diet containing neurogenic lipid components. It entailed no side-effects, no toxicity and was inexpensive. None of these nine patients has suffered recurrent disease. The mean follow-up time was over 80 months (median 69, range 58-140 months). Local tumour control was 100%. This clinical result is significantly better (p = 0.018) as compared to similar T3 uveal melanoma patients in standard care who did not receive adjuvant dietary remedies after primary treatment. The control patients consisted of similar adjusted T3 cases selected from the Swedish official registries, and T2 patients from Germany. Based on the previous positive clinical results obtained with cutaneous malignant melanoma in bioimmunotherapy this additional positive result supports the notion that biological components administered orally may compensate for the etiological deficiency leading to malignant melanoma.

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.

[The national cancer fund (Koningin Wilhelmina Fonds) and the Houtsmuller-therapy for cancer]. / Het Koningin Wilhelmina Fonds en de Houtsmuller-therapie bij kanker.

Dr. Houtsmuller, a retired internist, introduced an anticancer diet ten years ago. He claimed to have cured himself from metastatic melanoma by following a diet consisting of healthy nutrients, large amounts of vitamins, minerals, antioxidants and shark cartilage powder in combination with psychological support. The efficacy of the therapy was never described in a scientific article. Currently about 63% of all cancer patients in the Netherlands using a diet use the Houtsmuller diet. The national cancer fund (Koningin Wilhelmina Fonds) invited him to speak at their 50-year commemorative symposium. Shortly before he admitted that his medical history did not mention metastatic melanoma. Dr. Houtsmuller has seriously damaged the position of physicians in the Netherlands by addressing patients directly without first seeking support from his scientific medical peers. Cancer organizations such as Koningin Wilhelmina Fonds are urged to properly inform the public about the real value or lack of value of alternative treatments in general and of alternative diets in particular.