Immunotherapy and Targeted Therapy in Patients With Advanced Melanoma and the V600 BRAF Mutation: Which One First? / Inmunoterapia vs. terapia diana en el paciente con melanoma avanzado y mutación BRAF V600, ¿por cuál comenzar?

Systemic treatment with immunotherapy or targeted therapy can significantly improve survival in patients with advanced (metastatic or high-risk) melanoma. Fifty percent of patients with melanoma have a BRAF mutation. Decisions on optimal sequencing of systemic treatments should take into account drug- and tumor-related factors and patient characteristics. Although the combination of ipilimumab and nivolumab is associated with the best survival outcomes, it is associated with significant toxicity. Targeted therapy may be a more favorable option in certain clinical situations. We review the literature on immunotherapy and targeted therapy in melanoma and present an algorithm for guiding decision-making on their use as first-line systemic treatments for advanced BRAF-mutated melanoma.

[Translated article] Immunotherapy and Targeted Therapy in Patients With Advanced Melanoma and the V600 BRAF Mutation: Which One First?

Systemic treatment with immunotherapy or targeted therapy can significantly improve survival in patients with advanced (metastatic or high-risk) melanoma. Fifty percent of patients with melanoma have a BRAF mutation. Decisions on optimal sequencing of systemic treatments should take into account drug- and tumor-related factors and patient characteristics. Although the combination of ipilimumab and nivolumab is associated with the best survival outcomes, it is associated with significant toxicity. Targeted therapy may be a more favorable option in certain clinical situations. We review the literature on immunotherapy and targeted therapy in melanoma and present an algorithm for guiding decision-making on their use as first-line systemic treatments for advanced BRAF-mutated melanoma.

Teledermatology-driven topical therapy of actinic keratosis: a comparative study of clinical effectiveness and compliance.

BACKGROUND: Teledermatology (TD) provides efficient care for skin cancer patients. OBJECTIVE: To compare the clinical effectiveness of imiquimod 5% for the treatment of AK with in-person care and through TD. METHODS: Longitudinal prospective controlled study including patients with single AK diagnosed and treated at face-to-face visits (FTF group) or through teledermatology (TD group) with imiquimod 5% cream. The main outcome measures assessed were the complete and global response percentage (CR and GR) under per-protocol (PP) and intention-to-treat (ITT) analysis. RESULTS: A total of 157 patients were enrolled (FTF = 75, TD = 82). PP analysis showed CR in 66.7% of FTF patients and 65.6% in TD patients (P > 0.05). The ITT yielded CR in 64.0% and 51.2% in FTF visits and TD, respectively (P = 0.073). The analysis showed an advantage of FTF care against TD in achieving GR (84.0% vs. 70.7%; P = 0.036). Facial location and local adverse reactions were the only explanatory factors of complete response in the ITT approach. Treatment completion was found in 90.7% and 72.0% in the FTF and TD groups, respectively (P = 0.004). CONCLUSIONS: Improvements in patient counselling at the primary care centre are needed before the implementation of TD as a routine methodology for the management of AK.

Survival analysis and sentinel lymph node status in thin cutaneous melanoma: A multicenter observational study.

Mitotic rate is no longer considered a staging criterion for thin melanoma in the 8th edition of the American Joint Committee on Cancer Staging Manual. The aim of this observational study was to identify prognostic factors for thin melanoma and predictors and prognostic significance of sentinel lymph node (SLN) involvement in a large multicenter cohort of patients with melanoma from nine tertiary care hospitals. A total of 4249 consecutive patients with thin melanoma diagnosed from January 1, 1998 to December 31, 2016 were included. The main outcomes were disease-free interval and melanoma-specific survival for the overall population and predictors of SLN metastasis (n = 1083). Associations between survival and SLN status and different clinical and pathologic variables (sex, age, tumor location, mitosis, ulceration, regression, lymphovascular invasion, histologic subtype, Clark level, and Breslow thickness) were analyzed by Cox proportional hazards regression and logistic regression. SLN status was the most important prognostic factor for melanoma-specific survival (hazard ratio, 13.8; 95% CI, 6.1-31.2; P < 0.001), followed by sex, ulceration, and Clark level for patients who underwent SLNB. A mitotic rate of >2 mitoses/mm2 was the only factor associated with a positive SLN biopsy (odds ratio, 2.9; 95% CI, 1.22-7; P = 0.01. SLN status is the most important prognostic factor in thin melanoma. A high mitotic rate is associated with metastatic SLN involvement. SLN biopsy should be discussed and recommended in patients with thin melanoma and a high mitotic rate.

Thick melanoma: the problem continues.

BACKGROUND: The incidence of melanoma and its associated mortality has stabilized over the recent years, due in part to efforts directed at better prevention and detection of these lesions. We analysed the trends in the distribution of melanomas, mainly according to their thickness. METHODS: Data from the Dermatology Service of 'Virgen de la Victoria' University Hospital in Malaga (Spain) showed a total of 459 cases of melanoma between 1990 and 2005, both inclusive. The lesions were stratified according to year of diagnosis (1990-96 and 1997-2005), sex, age (0-49, > or = 50), thickness (0-0.99, 1.00-1.99, and > or = 2 mm) and the histological subtype [lentigo maligna melanoma (LMM), superficial spreading melanoma (SSM), nodular melanoma (NM) and acral lentiginous melanoma (ALM)]. Particular attention was given to the distribution of the groups according to thickness. RESULTS: The number of new cases rose by 92% between the two study periods (1990-1996 and 1997-2005). However, the number of new cases of thick melanoma remained almost constant over the two periods, being associated with persons over 50 years of age (65.1% vs. 64.3%), with men having half the cases (48.4% vs. 47%). The proportion of nodular melanomas within the group of thick melanomas was high in both periods (36.5% and 39.3%, respectively). CONCLUSIONS: This study shows that despite the large increase in new melanomas, the diagnosis of thick melanomas has remained constant, mainly in persons over the age 50 years, with a relative increase in men. New strategies and education programmes are, therefore, required for the early detection of this type of tumour to reduce its incidence in these patients.

Bactericidal activity of daptomycin, vancomycin, teicoplanin and linezolid against Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium using human peak free serum drug concentrations.

The bactericidal activities of daptomycin, vancomycin, teicoplanin and linezolid at human peak free serum concentrations (C(max,free)) were determined against Staphylococcus aureus (one methicillin-susceptible and two methicillin-resistant strains), Enterococcus faecalis and Enterococcus faecium (one vancomycin-susceptible and one vancomycin-resistant strain of each). Daptomycin was rapidly bactericidal against 7/7 strains at C(max,free) of 22.0 mg/L (corresponding to 63% protein binding) and against 3/7 strains at 4.8 mg/L (corresponding to 92% protein binding). Vancomycin (18.0 mg/L) was bactericidal against only two strains. Both teicoplanin (4.5 mg/L) and linezolid (10.4 mg/L) were consistently bacteriostatic. Daptomycin is a useful option for the treatment of Gram-positive infections owing to its strong bactericidal activity.

Combining metabolomic analysis and microarray gene expression analysis in the characterization of the medicinal plant Chelidonium majus L.

BACKGROUND AND OBJECTIVE: Even though herbal medicines have played an important role in disease management and health for many centuries, their present frequent use is challenged by the necessity to determine their complex composition and their multitarget mode of action. In the present study, modern methods were investigated towards their potential in the characterization of herbal substances. As a model the herbal substance Chelidonii herba was used, for which several reports on liver toxicities exist. Extracts of Chelidonii herba with different solvents were characterized phytochemically and functionally by experiments with HepG2 liver cells. METHODS: Chelidonii herba was extracted with four solvents of different polarity (dichloromethane, water, ethanol, and ethanol 50% (V/V); four replicates each). The different extracts were characterized metabolomically by (1)H-NMR fingerprinting analysis and principal component analysis (PCA). The content of alkaloids was additionally determined by RP-HPLC. Functional characterization was achieved by the determination of cell proliferation and by transcriptomics techniques (Whole Genome Gene Expression Microarrays v2, Agilent Technologies) in HepG2 cells after exposure to the different extracts (four experimental replicates each). RESULTS: Based on data from (1)H-NMR fingerprints and RP-HPLC analyses the different extracts showed a divergent composition of constituents depending on the solvent used. HepG2 liver cells responded differentially to the four extracts. Microarray analysis revealed a significant regulation of genes and signal cascades related to biotransformation. Also liver-toxic signal cascades were activated. Neither the activated genes nor the proliferation response could be clearly related to the differing alkaloid content of the extracts. CONCLUSION: Different manufacturing processes lead to different herbal preparations. A systems biology approach combining a metabolomic plant analysis with a functional characterization by gene expression profiling in HepG2 cells is an appropriate strategy to characterize variations in plant extracts. Safety assessments of herbal substances may benefit from such complementary analyses.

[Longitudinal study of different metastatic patterns in the progression of cutaneous melanoma]. / Estudio temporal de los diferentes patrones metastásicos en la progresión del melanoma cutáneo.

INTRODUCTION: Compared with other tumors, melanoma has displayed one of the largest increases in incidence in recent years, and it is known to have a high metastatic potential. In cases of metastasis, approximately two-thirds of patients have lymph-node metastases and one-third develop systemic metastases. However, few studies have been reported that analyzed different metastatic patterns according to the natural history of melanoma. The main aim of this study was to analyze the different metastatic pathways and patterns and to assess the time course of development of metastases from cutaneous melanoma. MATERIAL AND METHODS: A retrospective study was performed in 575 patients with onset of primary melanoma between 1990 and 2004. During follow-up, 67 patients developed metastases. Different pathways for metastasis were established and evaluated. We identified 4 metastatic pathways according to the metastatic pattern during progression of the melanoma. The time course of metastases was also evaluated. Finally, we analyzed melanomas with local recurrence in terms of whether or not systemic progression occurred. RESULTS: Melanoma metastases first occurred in local lymph nodes in 55.2 % of the patients. Initial metastasis was systemic in 14.9 % of the patients. The anatomical location and tumor thickness influenced which metastatic pathway was followed. Distant metastases occurred after a mean of 25 months regardless of the pathway followed CONCLUSIONS: The development of distant metastases displays a constant time course and the time to onset is independent of the metastatic pathway. This observation may explain why sentinel lymph node biopsy has a limited impact on overall survival of melanoma patients.