Genetic counseling in melanoma

Genetic counseling may be offered to families with melanoma and to individuals with multiple melanomas to better understand the genetic susceptibility of the disease, the influence of environmental factors, the inheritance of the risk, and behavior that decreases the risk of dying from melanoma, including specific dermatological follow‐up such as total body photography and digital dermoscopy. Genetic testing may be offered to those individuals with more than a 10% chance of being a carrier of a mutation. This risk varies according to the incidence of melanoma in the country and sun behavior. In countries with a low‐medium incidence of melanoma, genetic testing should be offered to families with two cases of melanoma or an individual with two primary melanomas. In countries with a high incidence, families with three cases of melanoma, with two melanomas and one pancreatic adenocarcinoma, or patients with three primary melanomas, may benefit from genetic testing

Neuropsychiatric symptoms after liver transplantation in a 65-year-old male patient

The development of immunosuppressants has been key for the advancement of solid organ transplant surgery. Specifically, cyclosporine, tacrolimus, or everolimus have significantly increased the survival rate of patients by reducing the risk of a rejection of the transplanted organ and limiting graft-versus-host disease. We report the case of a 65-year-old man who, after undergoing a liver transplantation and receiving an immunosuppressive treatment with cyclosporine and everolimus, presented severe obsessive, psychotic, and behavioral symptoms over the past three years, and describe the pharmacological and non-pharmacological interventions implemented against these symptoms. In this case, the immunosuppressants used have been cyclosporine and, preferably, everolimus. On the other hand, potential adverse reactions to the treatment have been observed, including neuropsychiatric symptoms such as tremor, anxiety, dysthymia, psychosis, and behavioral disorders, which make it necessary to use corrective psychoactive drugs such as benzodiazepines, antidepressants, and antipsychotics, combined with non-pharmacological interventions. A transversal approach, from the medical and psychosocial disciplines, facilitates success in managing neuropsychiatric symptoms after soft organ transplantsS

Induced Vitiligo due to Talimogene Laherparepvec Injection for Metastatic Melanoma Associated with Long-term Complete Response

Talimogene laherparepvec (T-VEC) (Imlygic, Amgen) is the first oncolytic virus approved for use in therapy for metastatic melanoma. T-VEC provides a treatment option for patients with limited metastatic disease. T-VEC is a genetically modified, live, attenuated herpes simplex virus type 1 designed to replicate in tumour cells and promote an enhanced anti-tumour response (1) T-VEC is administered by injection into cutaneous, subcutaneous or nodal lesions, which are visible and/or palpable and/ or visualized by ultrasonography (2). Other local management options have been used to control metastatic disease in stage IIIB, but almost all have shown only a local effect and rapid disease relapse (3, 4). With T-VEC, responses occurred in injected and uninjected lesions, including a greater than 50% decrease in size in 15% of uninjected visceral lesions. The appearance of vitiligo has been described as an adverse event after administration of immune checkpoint inhibitors (5, 6). It has been reported as a marker of activity of the drug and long-term results, inducing clinicians to use it as a predictor of drug response (7). A T-VEC phase II study has reported 85% adverse events, all of which were grade 1 or 2. The appearance of vitiligo has been described in 3 patients out of 50 (8), although no details regarding duration and appearance have been reported

Shiny White Streaks: A Sign of Malignancy at Dermoscopy of Pigmented Skin Lesions

The aim of this study was to evaluate the practical importance of the presence of shiny white streaks (SWS) (chrysalis or crystalline structures in polarized dermoscopy) for suspicion of malignancy, diagnosis of melanoma, and pre-operative estimation of Breslow thickness and its correlation with total dermoscopy score (TDS). SWS were present in 13.6% of 800 consecutive excised lesions. The presence of SWS was associated with malignancy (odds ratio (OR) 10.534, 95% confidence interval (95% CI) 6.357-17.455, p < 0.0005) in the context of melanocytic lesions with invasive melanoma (OR 10.333, 95% CI 3.812-28.014) and melanomas with high TDS (OR 6.286, 95% CI 1.673-23.619), but was also a factor in the diagnosis of featureless and some thin melanomas. These results corroborate the clinical applicability of SWS in aiding the diagnosis of malignancy and helping to raise the general dermatologist's awareness in cases of doubt and featureless lesions

Development of cutaneous toxicities during selective anti-BRAF therapies: preventive role of combination with MEK inhibitors

Activated BRAF mutations affecting the mitogen-activated protein kinases (MAPK) pathway are present in 50% of metastatic melanomas. Targeted therapies have been developed to block such mutations (1, 2). There is a risk of other components of the MAPK signalling pathway, such as MEK, being reactivated after the use of BRAF inhibitors (3-5). Given the evidence of drug resistance and side-effects of BRAF inhibitors, combined treatments with BRAF and MEK inhibitors are being tested in clinical trials for metastatic melanoma. Trametinib is one of these MEK inhibitors. Skin toxicities from BRAF inhibitors, such as photosensitivity, palmoplantar keratoderma (PPK) and keratosis pilaris (KP), have been reported (4, 6-11). Also, non-melanoma skin cancers (NMSC) are considered one of the most significant sideeffects (3, 11). We report here the profile of skin toxicities from vemurafenib, dabrafenib alone, or dabrafenib and trametinib combined treatment

Benefits of oral Polypodium Leucotomos extract in MM high-risk patients

Background: UV radiation and the presence of melanocytic nevi are the main risk factors of sporadic melanoma (MM). Protection of skin by an oral photoprotective agent would have substantial benefits. Objective: We investigated the possible role of an oral Polypodium leucotomos (PL) extract to improve systemic photoprotection in patients at risk of skin cancer analyzing the ability to decrease UV‐induced erythema. We also studied the interaction among MC1R polymorphisms and CDKN2A status with the minimal erythematous dose (MED) and their influence in the response after oral PL. Methods: A total of 61 patients (25 with familial and/or multiple MM, 20 with sporadic MM and 16 with atypical mole syndrome without history of MM) were exposed to varying doses of artificial UVB radiation without and after oral administration of a total dose of 1080mg of PL. Results: Oral PL treatment significantly increased the MED mean in all group patients (0.123 to 0.161 J/cm2, p<0.05). Although not significant, we noticed a stronger effect of PL on the MED of patients with familial MM compared to those with MM (U=273, p=0.06). Among the patients with familial MM, those exhibiting a mutated CDKN2A and/or polymorphisms in MC1R had the bigger differences in response to treatment with PL. Limitations: Reduced number of patients. No control population. Conclusions: Administration of PL leads to a significant reduction of sensitivity to UVR (p<0.05) in all patients. Dark‐eye patients and patients with higher UVR sensibility (lower basal MED) would be the most benefited from oral PL treatment

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele

Clinical and Dermoscopic Evaluation of Melanocytic Lesions in Patients with Chronic Graft Versus Host Disease

Patients treated with haematopoietic stem cell transplantation are at increased risk of cutaneous malignant neoplasms. There are no reports on the characteristics of melanocytic lesions in patients with chronic graft versus host disease and the value of recognizing these difficult lesions in high-risk patients. The objective of this study is to describe the clinical and dermo scopic characteristics of melanocytic lesions in patients with chronic graft versus host disease in order to understand their morphology. A prospective cross-sectional study was performed; 10 melanocytic lesions on the trunk and extremities were selected from each patient. A statistically significant association was found between regression and high total dermoscopic score and 7-point checklist score. Lesions were excised or included in short-term digital follow-up. Melanocytic lesions in patients with chronic graft versus host disease developing after allogeneic-haematopoietic stem cell transplantation exhibit marked structural and colour changes similar to melanoma. This is believed to result from the inflammatory process associated with graft versus host disease

Inherited MC1R variants in patients with melanoma are associated with better survival in women

Background: Women have a better melanoma prognosis, and fairer skin/hair colour. The presence of inherited MC1R variants has been associated with a better melanoma prognosis, but its interaction with sex is unknown. Objectives: To evaluate the relationship between germline MC1R status and survival, and determine any association with sex. Methods: This was a cohort study including 1341 patients with melanoma from the Melanoma Unit of the Hospital Clinic of Barcelona, between January 1996 and April 2018. We examined known sex‐related prognosis factors as they relate to features of melanoma and evaluated the sex‐specific role of MC1R in overall and melanoma‐specific survival. Hazard ratios (HRs) were calculated using univariate and multivariate Cox logistic regression. Results: Men showed lower overall survival than women (P < 0·001) and the presence of inherited MC1R variants was not associated with better survival in our cohort. However, in women the presence of MC1R variants was associated with better overall survival in the multivariate analysis [HR 0·57, 95% confidence interval (CI) 0·38-0·85; P = 0·006] but not in men [HR 1·26, 95% CI 0·89-1·79; P = 0·185 (P‐value for interaction 0·004)]. Analysis performed for melanoma‐specific survival showed the same level of significance. Conclusions: Inherited MC1R variants are associated with improved overall survival in women with melanoma but not in men. Intrinsic sex‐dependent features can modify the role of specific genes in melanoma prognosis. We believe that survival studies of patients with melanoma should include analysis by sex and MC1R genotype

Sutton Naevi as melanoma simulators: Can confocal microscopy help in the diagnosis?

Sutton naevi can sometimes present a challenging appearance with atypical presentation, also by dermoscopy. Reflectance confocal microscopy could help in making a diagnosis. This study prospectively collected two groups of Sutton nevi: the first one was composed by typical white halo naevi monitored for one year (13, 23%) and the second one was made up of atypical lesions excised in order to rule out melanoma, which were histologically diagnosed as Sutton naevi (21, 37%). These two groups of Sutton naevi were compared to a retrospectively collected cohort of thin melanomas with histologic regression features (23, 40%). On dermoscopy, atypical Sutton naevi and melanomas were indistinguishable. Reflectance confocal microscopy demonstrated significant differences at the dermo-epidermal junction: marked dermo-epidermal junction thickening and non-edged papilla were associated with melanoma, while the presence of nests was associated with Sutton naevi. However, reflectance confocal microscopy also detected marked intraepidermal pagetoid cells in Sutton naevi that were a combination of MelanA+ and CD1a+ cells. Sutton naevi can simulate melanoma, under both dermoscopy and reflectance confocal microscopy. Nevertheless, relevant confocal dermo-epidermal junction features and the clinical scenario can be helpful to make a final diagnosis, especially in those situations where melanoma must be ruled out