Combined BRAF-Targeted Therapy with Immunotherapy in BRAF-Mutated Advanced Melanoma Patients.

PURPOSE OF REVIEW: To review evidence on the efficacy and safety of combined BRAF-targeted therapy and immune checkpoint inhibitors in patients with BRAF-mutated metastatic melanoma. RECENT FINDINGS: Programmed death-1 pathway inhibitors administered with BRAF/MEK inhibitors showed promising anti-tumour activity in BRAF-mutated advanced melanoma and were investigated for safety and efficacy in three large international clinical trials. Although, in two out of those three randomized phase III studies, progression-free survival (PFS) did not reach statistical significance, results showed that duration of response (DOR) and overall survival (OS) were improved using combined therapy, sustaining the scientific rationale for its use at least in a subset of metastatic melanomas. However, the frequent occurrence of autoimmunity-induced toxicities should be considered since it is limiting the continuity and the wide application of these regimens. Novel treatment modalities combining targeted therapy with checkpoint inhibitors require further clinical investigation and elucidation of their effect on the immune system and cancer cell modulation.

Survival of Women Previously Diagnosed of Melanoma with Subsequent Pregnancy: A Systematic Review and Meta-Analysis and a Single-Center Experience.

Melanoma incidence has increased over the last few decades. How the prognosis of a previously diagnosed melanoma may be affected by a woman's subsequent pregnancy has been debated in the literature since the 1950s, and the outcomes are essential to women who are melanoma survivors in their childbearing years. The main objective of this systematic review is to improve the understanding of whether the course of melanoma in a woman may be altered by a subsequent pregnancy and to help clinicians' diagnosis. Eligible studies for the systematic review were clinical trials, observational cohort studies and case-control studies that compared prognosis outcomes for non-pregnant patients with melanoma, or pregnant before melanoma diagnosis, versus pregnant patients after a diagnosis of melanoma. The search strategy yielded 1101 articles, of which 4 met the inclusion criteria for the systematic review. All the studies were retrospective non-randomised cohorts with patients with melanomas diagnosed before pregnancy. According to our findings, a subsequent pregnancy was not a significant influence on the outcome of a previous melanoma. However, given the small number of identified studies and the heterogeneous data included, it is recommended to approach these patients with caution, and counselling should be given by known prognostic factors. We also reviewed the medical records of 84 patients of childbearing age (35.8 ± 6.3 years, range 21-45 years) who were diagnosed with cutaneous invasive melanoma in our hospital between 2008 and 2018 (N = 724). Of these, 11 (13.1%) had a pregnancy after melanoma diagnosis (age at pregnancy: 35.6 ± 6.3 years). No statistical differences in outcome were detected.

Interferon alpha for the adjuvant treatment of cutaneous melanoma.

BACKGROUND: Interferon alpha is the only agent approved for the postoperative adjuvant treatment of high-risk cutaneous melanoma. However, the survival advantage associated with this treatment is unclear, especially in terms of overall survival. Thus, adjuvant interferon is not universally considered a gold standard treatment by all oncologists. OBJECTIVES: To assess the disease-free survival and overall survival effects of interferon alpha as adjuvant treatment for people with high-risk cutaneous melanoma. SEARCH METHODS: We searched the following databases up to August 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, issue 8), MEDLINE (from 2005), EMBASE (from 2010), AMED (from 1985), and LILACS (from 1982). We also searched trials databases in 2011, and proceedings of the ASCO annual meeting from 2000 to 2011. We checked the reference lists of selected articles for further references to relevant trials. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) comparing interferon alpha to observation (or any other treatment) for the postoperative (adjuvant) treatment of patients with high-risk skin melanoma, that is, people with regional lymph node metastasis (American Joint Committee on Cancer (AJCC) TNM (tumour, lymph node, metastasis) stage III) undergoing radical lymph node dissection, or people without nodal disease but with primary tumour thickness greater than 1 mm (AJCC TNM stage II). DATA COLLECTION AND ANALYSIS: Two authors extracted data, and a third author independently verified the extracted data. The main outcome measure was the hazard ratio (HR), which is the ratio of the risk of the event occurring in the treatment arm (adjuvant interferon) compared to the control arm (no adjuvant interferon). The survival data were either entered directly into Review Manager (RevMan) or extrapolated from Kaplan-Meier plots and then entered into RevMan. Based on the presence of between-study heterogeneity, we applied a fixed-effect or random-effects model for calculating the pooled estimates of treatment efficacy. MAIN RESULTS: Eighteen RCTs enrolling a total of 10,499 participants were eligible for the review. The results from 17 of 18 of these RCTs, published between 1995 and 2011, were suitable for meta-analysis and allowed us to quantify the therapeutic efficacy of interferon in terms of disease-free survival (17 trials) and overall survival (15 trials). Adjuvant interferon was associated with significantly improved disease-free survival (HR (hazard ratio) = 0.83; 95% CI (confidence interval) 0.78 to 0.87, P value < 0.00001) and overall survival (HR = 0.91; 95% CI 0.85 to 0.97; P value = 0.003). We detected no significant between-study heterogeneity (disease-free survival: I² statistic = 16%, Q-test P value = 0.27; overall survival: I² statistic = 6%; Q-test P value = 0.38).Considering that the 5-year overall survival rate for TNM stage II-III cutaneous melanoma is 60%, the number needed to treat (NNT) is 35 participants (95% CI = 21 to 108 participants) in order to prevent 1 death. The results of subgroup analysis failed to answer the question of whether some treatment features (i.e. dosage, duration) might have an impact on interferon efficacy or whether some participant subgroups (i.e. with or without lymph node positivity) might benefit differently from interferon adjuvant treatment.Grade 3 and 4 toxicity was observed in a minority of participants: In some trials, no-one had fever or fatigue of Grade 3 severity, but in other trials, up to 8% had fever and up to 23% had fatigue of Grade 3 severity. Less than 1% of participants had fever and fatigue of Grade 4 severity. Although it impaired quality of life, toxicity disappeared after treatment discontinuation. AUTHORS' CONCLUSIONS: The results of this meta-analysis support the therapeutic efficacy of adjuvant interferon alpha for the treatment of people with high-risk (AJCC TNM stage II-III) cutaneous melanoma in terms of both disease-free survival and, though to a lower extent, overall survival. Interferon is also valid as a reference treatment in RCTs investigating new therapeutic agents for the adjuvant treatment of this participant population. Further investigation is required to select people who are most likely to benefit from this treatment.

Ipilimumab targeting CD28-CTLA-4 axis: new hope in the treatment of melanoma.

Ipilimumab, a fully human monoclonal antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), is the new hope in the treatment of patients with advanced melanoma. Anti-CTLA-4 antibodies enhance T cell responses in vitro and in vivo and activate proliferation of tumour-specific T cells. The blockade of CTLA-4 by ipilimumab leads to immune-mediated tumor regression. Ipilimumab has been studied in metastatic melanoma in a number of clinical trials. Recently, a phase III, multi-center, randomized, double-blind trial showed a significant improvement in overall survival in patients with advanced melanomas treated with ipilimumab. Thus, ipilimumab was the first drug to demonstrate effect on overall survival in patients with metastatic melanoma. However, patients treated with ipilimumab develop various immune-related adverse events (irAEs), which are associated with objective and durable clinical responses. Use of new immune-related response criteria is recommended in patients on ipilimumab therapy to avoid premature treatment discontinuation. Further research is necessary to elucidate role of ipilimumab in adjuvant setting as well as in synergy with other novel modalities for the treatment of metastatic melanoma.

Recent progresses in application of fullerenes in cosmetics.

Cosmetic industry is a fast growing industry with the continuous development of new active ingredients for skin care products. Fullerene C(60) and its derivates have been subject of intensive research in the last few years. Fullerenes display a wide range of different biological activities. Strong antioxidant capacities and effective quenching radical oxygen species (ROS) made fullerenes suitable active compounds in the formulation of skin care products. Published evidence on biological activities of fullerenes relevant for their application in cosmetics use and examples of published patents are presented. Recent trends in the use of fullerenes in topical formulations and patents are reviewed. Future investigations covering application of fullerenes in skin care are discussed.

Assessment of the kinetics of the antioxidative capacity of topical antioxidants.

While there is at least one standardized test available for evaluating the antioxidant capacity of cosmetic formulations, the authors proposed a new in vivo method to determine kinetics of squalene (SQ) photo-oxidation products (squalene monohydroperoxide, SQmOOH) as a reliable method with which to evaluate antioxidant capacity of a cosmetic formulation. Topical antioxidant formulation was applied on the foreheads of 30 volunteers. Sebum samples were collected before application of topical antioxidant and after one hour, three hours and five hours from the application of topical antioxidant. One half of the sebutape was irradiated and SQmOOH/SQ ratios in the skin lipid were analyzed using HPLC method. These results showed protective action of the topical antioxidant formulation against skin lipid peroxidation with a significant reduction of the quantity of SQmOOH (P<0.0001). Determination of the kinetics of squalene peroxidation is a reliable in vivo method in the evaluation of antioxidant capacity of cosmetic formulations.

Novel and recurrent FERMT1 gene mutations in Kindler syndrome.

Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.

Surgical excision margins for primary cutaneous melanoma.

BACKGROUND: Cutaneous melanoma accounts for 75% of skin cancer deaths. Standard treatment is surgical excision with a safety margin some distance from the borders of the primary tumour. The purpose of the safety margin is to remove both the complete primary tumour and any melanoma cells that might have spread into the surrounding skin.Excision margins are important because there could be trade-off between a better cosmetic result but poorer long-term survival if margins become too narrow. The optimal width of excision margins remains unclear. This uncertainty warrants systematic review. OBJECTIVES: To assess the effects of different excision margins for primary cutaneous melanoma. SEARCH STRATEGY: In August 2009 we searched for relevant randomised trials in the Cochrane Skin Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 3, 2009), MEDLINE, EMBASE, LILACS, and other databases including Ongoing Trials Registers. SELECTION CRITERIA: We considered all randomised controlled trials (RCTs) of surgical excision of melanoma comparing different width excision margins. DATA COLLECTION AND ANALYSIS: We assessed trial quality, and extracted and analysed data on survival and recurrence. We collected adverse effects information from included trials. MAIN RESULTS: We identified five trials. There were 1633 participants in the narrow excision margin group and 1664 in the wide excision margin group. Narrow margin definition ranged from 1 to 2 cm; wide margins ranged from 3 to 5 cm. Median follow-up ranged from 5 to 16 years. AUTHORS' CONCLUSIONS: This systematic review summarises the evidence regarding width of excision margins for primary cutaneous melanoma. None of the five published trials, nor our meta-analysis, showed a statistically significant difference in overall survival between narrow or wide excision.The summary estimate for overall survival favoured wide excision by a small degree [Hazard Ratio 1.04; 95% confidence interval 0.95 to 1.15; P = 0.40], but the result was not significantly different. This result is compatible with both a 5% relative reduction in overall mortality favouring narrower excision and a 15% relative reduction in overall mortality favouring wider excision. Therefore, a small (but potentially important) difference in overall survival between wide and narrow excision margins cannot be confidently ruled out.The summary estimate for recurrence free survival favoured wide excision [Hazard Ratio 1.13; P = 0.06; 95% confidence interval 0.99 to 1.28] but again the result did not reach statistical significance (P < 0.05 level).Current randomised trial evidence is insufficient to address optimal excision margins for primary cutaneous melanoma.

Pigmentation and vitamin D metabolism in Caucasians: low vitamin D serum levels in fair skin types in the UK.

BACKGROUND: Vitamin D may play a protective role in many diseases. Public health messages are advocating sun avoidance to reduce skin cancer risk but the potential deleterious effects of these recommendations for vitamin D metabolism have been poorly investigated. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the association between 25-hydroxy-vitamin D (25(OH)D), skin type and ultraviolet exposure in 1414 Caucasian females in the UK. Mean age of the cohort was 47 years (18-79) and mean 25(OH)D levels were 77 nmol/L (6-289). 25(OH)D levels were strongly associated with season of sampling with higher levels in the spring and summer months (p<0.0001). Light skin types (skin type 1 and 2) have lower levels of 25(OH)D (mean 71 nmol/L) compared to darker skin types (skin type 3 and 4) (mean 82 nmol/L) after adjusting for multiple confounders (p<0.0001). The trend for increasing risk of low vitamin D with fairer skin types was highly significant despite adjustment for all confounders (p = 0.001). CONCLUSIONS/SIGNIFICANCE: Contrary to previous studies across different ethnic backgrounds, this study within Caucasian UK females shows that fair skin types have lower levels of 25(OH)D compared to darker skin types with potential detrimental health effects. Public health campaigns advocating sun avoidance in fair skinned individuals may need to be revised in view of their risk of vitamin D deficiency.

Anterior tab flap versus standard underlay myringoplasty in children.

OBJECTIVES: Tympanic membrane (TM) perforation closure can present a problem in children, especially in anterior and total perforations, because of the anterior's lack of support for the graft. It was suggested that the anterior tab flap (ATF) myringoplasty, an underlay graft with an anterior tab under the TM annulus, could provide better stability of the graft. We undertook a prospective, randomized, controlled study to compare the ATF myringoplasty with the standard underlay (SU) myringoplasty in children. METHODS: We randomly assigned 59 children to undergo ATF myringoplasty and 52 to undergo SU myringoplasty at a tertiary care pediatric institution. Surgery was performed under general anesthesia in all patients. The primary outcome was the healing of the TM; the secondary outcomes were anterior blunting of the graft and presence of retraction of the TM. Two years of follow-up were obtained in all enrolled children. RESULTS: At 2 years of follow-up, there were 55 stable TM closures in the ATF arm and 44 in the SU arm. Although the TM closure was higher in the ATF arm than in the SU arm (93.2 and 84.6%, respectively), the results were not statistically significant (odds ratio = 0.4, 95% confidence interval = 0.12-1.41). Anterior blunting and TM retraction were not encountered. CONCLUSION: The ATF myringoplasty is a safe and effective method for TM closure in children. However, compared with the SU myringoplasty, the ATF myringoplasty is not associated with an overall decrease in the incidence of the residual perforations. Further assessment in a larger study is proposed.

Use of fullerenes in cosmetics.

As cosmetic technology advances, there is an increasing need to use new active ingredients in the development of cosmetic products. In the last few years application of fullerene C(60) and its derivates in cosmetics has been intensively tested. Fullerenes display a wide range of biological activities. Potent scavenging capacities against radical oxygen species (ROS) and excellent potential as biological antioxidants made fullerenes suitable active compounds in the preparation of skin rejuvenation cosmetic formulations. Currently published evidence on biological activities of fullerenes relevant for their cosmetic use and examples of published patents to illustrate application of fullerenes in cosmetic technology are presented. Future trends in the development of cosmetic formulations including fullerenes are discussed.

Melanoma of the small intestine.

Intestinal melanomas can be primary tumours or metastases of cutaneous, ocular, or anal melanomas. Primary intestinal melanoma is extremely rare, whereas metastatic melanoma of the small bowel is common because of the tendency for cutaneous melanoma to metastasise to the gastrointestinal tract. Because distinguishing between primary and metastatic intestinal melanoma can be difficult, the main features of each are discussed, and the diagnostic images used to detect intestinal melanoma are assessed. Routine barium examinations and CT have limited sensitivity, but PET imaging can improve detection of melanoma metastases to the small bowel. Although various treatment strategies have been tried in patients with intestinal melanoma, surgical removal of intestinal metastases is the treatment of choice in patients with resectable tumours. No systemic therapy improves survival in patients with melanoma metastatic to the intestines; thus, the prognosis for these patients is poor. Patients with primary melanoma of the small intestine have a worse prognosis than do patients with metastases of cutaneous melanoma.

Recessive dystrophic epidermolysis bullosa: presentation of two forms.

Dystrophic epidermolysis bullosa (DEB) and aplasia cutis congenita (ACC), also known as congenital localized absence of skin (CLAS) are rare clinical entities. Aplasia cutis congenita presented in conjunction with simplex, junctional, or dystrophic types of epidermolysis bullosa (EB) is classified as type-6 ACC. This association was initially described and referred in the literature as Bart syndrome. We describe two cases of recessive DEB (RDEB), one with the major Hallopeau-Siemens (RDEB-HS) subtype and one case with the minor RDEB inversa (RDEB-I) subtype associated with ACC localized on the lower extremities. Full clinical history and transmission electron microscopic findings are presented for both cases. To date, only five cases of RDEB presenting with ACC have been reported in the literature. Detailed descriptions of the association of RDEB and ACC in the literature are scarce. It seems that this condition is probably more common in clinical practice than described in the literature. Our findings confirm that the term, Bart syndrome, should not be considered as a separate entity or clinical variant of dominant dystrophic EB as it was initially described. Congenital localized absence of skin may be associated with any of the three major types of EB (simplex, junctional, or dystrophic).

Anti-CTLA4 monoclonal antibody Ipilimumab in the treatment of metastatic melanoma: recent findings.

Use of monoclonal anti-CTLA4 antibodies represents a new promising strategy to block the activation of immunosuppressive CTLA-4 and thus induce tumour regression. This review is mainly focused on the report of existing data on the clinical use of Ipilimumab (formerly MDX-010) in the treatment of metastatic melanoma. Several phase I and II trials have been conducted to evaluate safety and efficacy of this form of immunotherapy either alone or in combination with vaccines or chemotherapy in patients with stage III or stage IV melanoma. Results from these studies are presented, patented and discussed. The mechanism of ipilimumab action may take time to induce an anti-tumour immune response and thus it is recommended that ipilimumab therapy should be carried out for at least 12 weeks, even in the presence of early progressive disease. Objective response of around 15% has been reported in patients treated with ipilimumab. However, ipilimumab-mediated objective response and stable disease tend to be durable. The therapy with ipilimumab is associated with different side effects classified as immune-related adverse events (IRAEs). The most common IRAEs are enterocolitis and dermatitis. Majority of IRAEs disappear with the discontinuation of ipilimumab anti-CTLA-4 therapy. Several phase II/III trials are ongoing to evaluate ipilimumab alone or in combination with other therapeutic modalities. Results from these trials are awaited.

Systemic retinoids in chemoprevention of non-melanoma skin cancer.

BACKGROUND: The incidence of non-melanoma skin cancer is increasing worldwide. Systemic retinoids are useful for the chemoprophylaxis of non-melanoma skin cancers. Retinoids have pleiotropic effects, but their exact cancer chemopreventive mechanism is still not clear. OBJECTIVE: The aim of this study was to review published literature evaluating the use of oral retinoids in the chemoprevention of non-melanoma skin cancers. METHODS: The study reviewed all relevant papers found through a search of the electronic databases MEDLINE (from 1966 to January 2008) and Embase (from 1974 to January 2008). RESULTS/CONCLUSION: General and specific indications for retinoid chemoprophylaxis are defined. The pharmacokinetics and dose regimens of the two most commonly used oral retinoids (isotretinoin and acitretin) in the chemoprevention of non-melanoma skin cancers are presented. The use of oral retinoids is associated with adverse effects, which are discussed in detail. The future of retinoid cancer chemoprevention depends on the development and research of novel retinoids with improved bioavailability and minimized toxicity.