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Interferon Alfa Therapy for Malignant Melanoma: A Systematic Review of Randomized Controlled Trials

PURPOSE No standard systemic adjuvant therapy has been proven to increase overall survival in melanoma patients. The effect of interferon alfa (IFNalpha) as a single agent or in combination has been widely explored in clinical trials. The purpose of this study was to assess the benefit of IFNalpha therapy in malignant melanoma. METHODS We performed a systematic review of randomized controlled trials comparing regimens with or without IFNalpha adjuvant therapy in melanoma patients. We assessed the effect of IFNalpha therapy on overall survival (OS), disease-free survival (DFS), melanoma recurrences, and toxicity. The quality of each trial was systematically evaluated. RESULTS Nine randomized controlled trials (RCTs) of IFNalpha therapy in melanoma patients were identified. Eight were published and one was unpublished. Eight trials comprising 3,178 patients fulfilled our inclusion criteria and were analyzed. Quality assessment scores ranged from 22 to 71, with a mean score of 55.4 (95% confidence interval, 53.8 to 57.0). For OS, only one trial reported a statistically significant benefit for IFNalpha, but our analysis did not confirm it. Two trials reported statistically significant benefit in DFS for the patients treated with IFNalpha, but our analysis confirmed it in only one trial. There was a wide clinical heterogeneity between included trials, making meta-analysis inappropriate. CONCLUSION In our review, results from included RCTs demonstrated no clear benefit of IFNalpha therapy on OS in melanoma patients. A large RCT is required to answer whether a full regimen of IFNalpha therapy is effective and to identify the subgroups of patients who might benefit from IFNalpha treatment.

Effect of Pregnancy on Survival in Women With Cutaneous Malignant Melanoma

PURPOSE An adverse influence of pregnancy on the risk of death in women with cutaneous melanoma was suggested historically by anecdotal reports. Previous studies included small numbers of women observed for short periods. METHODS Using data from the Swedish National and Regional Registries, we performed a retrospective cohort study of all Swedish women who were diagnosed with cutaneous melanoma during their reproductive period, from January 1, 1958, to December 31, 1999. The relationship between pregnancy status at the diagnosis of melanoma and overall survival was examined in multivariable proportional-hazards models. RESULTS The cohort comprised 185 women (3.3%) diagnosed with melanoma during pregnancy and 5,348 (96.7%) women of the same childbearing age diagnosed with melanoma while not pregnant. There was no statistically significant difference in overall survival between pregnant and nonpregnant groups (log-rank chi(2)1[r] = 0.84, P = .361). Pregnancy status at the time of diagnosis of melanoma was not related to survival in a multivariable Cox model in the 2,101 women (hazard ratio for death in the pregnant group was 1.08; 95% CI, 0.60 to 1.93). In the multivariable analysis, pregnancy status after diagnosis of melanoma was not a significant predictor of survival (hazard ratio for death in women who had pregnancy subsequent to the diagnosis of melanoma was 0.58; 95% CI, 0.32 to 1.05). CONCLUSION The survival of pregnant women with melanoma is not worse than the survival of nonpregnant women with melanoma. Pregnancy subsequent to the diagnosis of primary melanoma was not associated with an increased risk of death.

Nevus Size and Number Are Associated with Telomere Length and Represent Potential Markers of a Decreased Senescence In vivo

Nevus counts represent one of the strongest risk factors for melanoma. They appear in childhood and adolescence and involute from middle age onwards. Recent evidence has shown that nevus cells undergo oncogene-induced senescence involving the p16/retinoblastoma pathway. However, telomere length also influences senescence in proliferative somatic cells and varies between individuals. This study explores whether telomere length measured in white cells is associated with nevus count and size in 1,897 Caucasian women ages 18 to 79 years. Total body nevus counts were positively correlated with white cell telomere length (mean, 7.09 kbp; range, 5.09-9.37) after adjustment for age (P = 0.0001). Age-adjusted telomere length was also associated with nevus count for nevi above 5 mm in diameter (P = 0.04). Subjects in the top category for nevus count had an average age-adjusted telomere length 150 bp longer than those in the lowest category. The positive correlation between white cell telomere length and nevi number and size may reflect an increased replicative potential (reduced senescence) in individuals with longer telomeres, which may not be melanocyte specific. Understanding mechanisms influencing the induction and involution of nevi will not only help in understanding the pathophysiology of melanoma but should also shed light on the complex relationship between aging and cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1499–502)

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.

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.

The use of the twin model to investigate the genetics and epigenetics of skin diseases with genomic, transcriptomic and methylation data.

Twins have always fascinated medical research even before the discovery of DNA and the understanding of the differences between identical and non‐identical twins. Dermatology with the benefit of being able to visualize phenotypes was one of the first specialities reporting on the fascinating concordance in identical (MZ) twins in the 1920’s. Over the last 20 years, the heritability of skin diseases using twins has been clearly demonstrated, across a wide variety of traits including melanoma, polymorphic light eruption, psoriasis, eczema and acne. Other rarer diseases have also been shown to have a significant genetic basis such as lupus, sarcoidosis and lichen sclerosus. Following evidence of heritability for many skin disease the next step was Genome‐Wide Association Studies (GWAS) which are uncovering new genes in large twin cohorts. The twin model is also ideal for the new field of epigenetics, investigating subtle differences in DNA methylation within discordant MZ pairs for a disease, as well as differences in CNVs. Twins are also valuable for examining differences in gene function via RNA expression in twins discordant for a skin trait or disease.

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.

An impact of hormones on nevi and melanoma

as a case-control study. It is clear that the Swedish study was a cohort study conducted on 5533 women diagnosed with primary cutaneous melanoma during their childbearing years (185 diagnosed with melanoma during pregnancy; 5348 diagnosed while nonpregnant). It is absolutely crucial for the readership to distinguish a case-control study from a cohort study, which is the archetype for all epidemiologic studies. In a cohort study, groups are defined on the basis of presence of exposure to a suspected risk factor, while in the case-control studies, subjects are selected on the basis whether they do (cases) or do not have (controls) a disease under study. As a result, cohort studies provide estimates of exposure-specific rates and risks, whereas case-control studies provide only estimates of ratio measures of effect. Furthermore, Driscoll and Grant-Kels throughout the manuscript wrongly used the phrase “controlled trials” (trials are intervention studies) to define observational studies (case-control and cohort studies) and descriptive studies (case reports/series).

p53 labeling index in assessing the efficacy of a sunscreen in protection against UV-induced damage.

Background  Sunscreen efficacy is currently evaluated by the estimation of the sun protection factor (SPF). Our objective was to determine the role of the p53 labeling index in assessing the effectiveness of a sunscreen in the prevention of UV‐induced DNA damage.