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Melanomas frequently harbour somatic mutations in BRAF (40%) or NRAS (20%). Impact of NRAS mutations on the therapeutic outcome of immune checkpoint inhibitors (ICI) remains controversial. Potential correlation of the NRAS mutational status and programmed cell death ligand-1 (PD-L1) expression in melanoma is unknown. Advanced, non-resectable melanoma patients with known NRAS mutation status treated with first-line ICI between 06/2014 and 05/2020 in the prospective multicenter skin cancer registry ADOREG were included. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to NRAS status were analysed. A multivariate Cox model was used to analyse factors associated with PFS and OS; survival was analysed using the Kaplan–Meier approach. Among 637 BRAF wild-type patients, 310 (49%) had an NRAS mutation with Q61R (41%) and Q61K (32%). NRAS -mutated (NRAS mut) melanomas were significantly more often located on the lower extremities and trunk (p = 0.001); nodular melanoma was the most common subtype (p < 0.0001). No significant differences were found for PFS and OS for anti-PD1 monotherapy (2-year PFS 39%, [95% confidence interval (CI), 33–47] in NRAS mut patients and 41% [95% CI, 35–48] in NRAS -wild type (NRAS wt) patients; 2-year OS was 54% [95% CI, 48–61] in NRAS mut patients and 57% [95% CI, 50–64] in NRAS wt patients) and anti-PD1 plus anti-CTLA4 therapy between both cohorts (2-year PFS was 54% [95% CI, 44–66] in NRAS mut patients and 53% [95% CI, 41–67] in NRAS wt patients; 2-year OS was 58% [95% CI, 49–70] in NRAS mut patients and 62% [95% CI, 51–75] in NRA Swt patients). The ORR to anti-PD1 was 35% for NRAS wt patients and 26% for NRAS mut patients and 34% compared to 32% for combinational therapy. Data on PD-L1 expression was available in 82 patients (13%). PD-L1 expression (> 5%) was not correlated to NRAS mutational status. In multivariate analysis, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance status ≥ 1, and brain metastases were significantly associated with a higher risk of death in all patients. The PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. Similar ORR was seen in NRAS wt and NRAS mut patients. Tumour PD-L1 expression did not correlate with NRAS mutational status. • PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. • Similar response rates to anti-PD1-based ICI were seen for NRAS mut and NRAS wt patients. • There was no correlation between NRAS mutation status and programmed cell death ligand-1 expression. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to evaluate clinical outcomes and patency rates using the Viabahn endoprosthesis in complex (TASC-II C and D) femoropopliteal lesions.Background: Traditional treatment of symptomatic TASC-II C and D femoropopliteal lesions has mainly centered on open surgical options in patients deemed appropriate candidates. Endovascular treatment of these lesions with balloon angioplasty has been historically hampered by aggressive restenosis and relatively early clinical failure. The Viabahn endoprosthesis was developed with the intent of reducing restenosis while improving overall flexibility in the femoropopliteal segment.Methods: Between March 2009 and July 2011 a total of 51 limbs in 41 patients underwent implantation of one or more Viabahn endovascular stent grafts for the treatment of symptomatic TASC-II C or D lesions. Patients were followed clinically at regular intervals and also underwent routine surveillance duplex ultrasound at 1, 3, 6, and 12 months post-procedure. The average follow-up from the index procedure was 14.6 months (range 13-35.2 months).Results: A total of 22 TASC-II C and 29 TASC-II D lesions were treated (51 limbs in 41 patients). The mean lesion length was 22.4 cm. The overall 1-year primary patency rate was 74.8% (95% CI: 61.2%-88.4%), assisted primary patency rate was 87.4% (95% CI: 70.9%-95.9%), and the secondary patency rate was 94.9% (95% CI: 88.0%-100.0%).Conclusions: The Viabahn endoprosthesis is a safe and effective option for the treatment of TASC-II C and D femoropopliteal lesions. Patency rates are favorable despite the complexity of these lesions, although multiple endovascular re-interventions may be necessary to achieve an acceptable long-term result. [ABSTRACT FROM AUTHOR]

Abstract: Economic decision making is a complex process of integrating and comparing various aspects of economically relevant choice options. Neuroeconomics has made important progress in grounding these aspects of decision making in neural systems and the neurotransmitters therein. The dopaminergic and serotoninergic brain systems have been identified as key neurotransmitter systems involved in economic behavior. Both are known to be prone to significant changes during the adult lifespan. Similarly, economic behavior undergoes significant age-related changes over the course of the adult lifespan. Here we propose a triadic relationship between (a) economic decision making, (b) dopaminergic and serotonergic neuromodulation, and (c) aging. In this review, we describe the different relationships around this triad in detail and summarize current evidence that supports them. Based on the reviewed evidence, we propose new research agendas that take the entire triad into account. [Copyright &y& Elsevier]

Abstract: Sulfonylureido thiazoles were identified from a HTS campaign and optimized through a combination of structure–activity studies, X-ray crystallography and molecular modeling to yield potent inhibitors of fructose-1,6-bisphosphatase. Compound 12 showed favorable ADME properties, for example, F =70%, and a robust 32% glucose reduction in the acute db/db mouse model for Type-2 diabetes. [Copyright &y& Elsevier]

Abstract: SAR studies of a recently described SST5R selective benzoxazole piperidine lead series are described with particular focus on the substitution pattern on the benzyl and benzoxazole side-chains. Introduction of a second meta substituent at the benzyl unit significantly lowers residual hH1 activity and insertion of substituents onto the benzoxazole periphery entirely removes remaining h5-HT2B activity. Compounds with single digit nM activity, functional antagonism and favorable physicochemical properties endowed with a good pharmacokinetic profile in rats are described which should become valuable tools for exploring the pharmacological role of the SST5 receptor in vivo. [Copyright &y& Elsevier]

Background: Limited information exists on the influence of preoperative renal dysfunction on in-hospital mortality after valve and combined valve and coronary procedures. The impact of preoperative renal dysfunction on patient outcome was investigated. Methods: This was a retrospective observational study of 916 patients who underwent solitary valve or combined procedures. Primary outcome was in-hospital mortality. Preoperative estimated glomerular filtration rate (eGFR) was calculated with the abbreviated Modification of Diet in Renal Disease formula. Results: Independent predictors of death were prolonged stay in the intensive care unit (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01 to 1.05), preoperative atrial fibrillation (OR, 1.61; 95% CI, 1.02 to 2.54), chronic obstructive pulmonary disease (OR, 2.2; 95% CI, 1.06 to 4.55), and prolonged operation time (OR, 1.01; 95% CI, 1.00 to 1.01). Each unit of the eGFR (mL/min/1.73m2) above average exerted a renoprotective effect (OR, 0.97; 95% CI, 0.96 to 0.98). The final regression model showed no lack of fit (Hosmer-Lemeshow test, p = 0.38) and a good discrimination performance in a receiver operating characteristic analysis (area under the curve, 0.84; 95% CI, 0.80 to 0.88). The lower the preoperative eGFR rate, the longer the postoperative stay at the intensive care unit. Conclusions: Renal dysfunction is an important independent predictor of in-hospital mortality in adult patients after valve and combined valve and coronary procedures. [Copyright &y& Elsevier]

Abstract: The model-based analysis of the effects of management options at stand and regional levels on forest functions such as carbon storage and groundwater recharge provides a basis for optimisation of forest planning under global change. The physiologically based model 4C (‘FORESEE’—FORESt Ecosystems in a changing Environment) can be used to evaluate a broad variety of silvicultural treatments for mono- and mixed-species forest stands. In this study, we present the testing and evaluation of the 4C management submodel, using data from long-term experimental plots in selected stands in the Federal State of Brandenburg, Germany. Comparison of experimental data with model simulations, by means of diameter distributions, demonstrated that the applied thinning operations preserved the diameter distribution of the stands. 4C realistically described the effects of management options on stand dynamics as proved by long-term simulations. Furthermore, the investigation of the effects of management options, thinning intensity, and rotation length on carbon storage in biomass and soil, yield, and groundwater recharge showed the applicability of the model 4C for the evaluation of forest functions in managed forests. We present the analysis of management effects on forest functions at a regional scale, based on a grid of forest monitoring sites (“Ökologische Waldzustandskontrolle”—ÖWK) in Brandenburg, which is mainly dominated by Scots pine (Pinus sylvestris L.). The model was applied at the sites with three management options under current climate and a climate change scenario (i.e., temperature increase of 1.4°K by 2055). The results of 50-year simulation runs were analysed for forest growth units with respect to total carbon storage (C sum) and groundwater recharge. More intensive management decreased the C sum after 50 years and slightly increased groundwater recharge. Climate change led to a reduction of groundwater recharge by about 40%, averaged over all sites. C sum was increased at some sites because of the extension of the growing season in spite of slight decreases in precipitation, but at several other sites, C sum decreased due to increased dryness. The question arises whether these negative effects of climate change can be minimised by adaptive management operations. In this study, we concluded that the potentials of adaptive management based on changes in rotation length and thinning is very limited in this region, which is characterised by poor sites and dry climatic conditions. We concluded that it is necessary to include forest transformation strategies in management impact analyses for forest planning under global change. [Copyright &y& Elsevier]

Activating hot spot R29S mutations in RAC1, a small GTPase influencing several cellular processes including cell proliferation and cytoskeleton rearrangement, have been reported in up to 9% of sun-exposed melanomas. Clinical characteristics and treatment implications of RAC1 mutations in melanoma remain unclear. We investigated the largest set (n = 64) of RAC1 mutated melanoma patients reported to date, including a retrospective single institution cohort (n = 34) from the University Hospital Essen and a prospective multicentre cohort (n = 30) from the translational study Tissue Registry in Melanoma (TRIM; CA209-578), for patient and tumour characteristics as well as therapy outcomes. From 3037 sequenced melanoma samples screened RAC1 mutations occurred in ∼2% of samples (64/3037). The most common RAC1 mutation was P29S (95%, 61/64). The majority of tumours had co-occuring MAP kinase mutations (88%, 56/64); mostly activating NRAS (47%, 30/64) mutations, followed by activating BRAF (28%, 18/64) and NF1 (25%, 16/64) mutations. RAC1 mutated melanomas were almost exclusively of cutaneous origin (84%, 54/64) or of unknown primary (MUP, 14%, 9/64). C > T alterations were the most frequent mutation type identified demonstrating a UV-signature for RAC1 mutated melanoma. Most patients with unresectable disease (39) received immune checkpoint inhibitors (ICI) (77%, 30/39). Objective response rate of first-line treatment in patients with stage III/IV disease was 21%; median overall survival was 47.8 months. RAC1 mutated melanomas are rare, mostly of cutaneous origin and frequently harbour concomitant MAP kinase mutations, particularly in NRAS. Patients with advanced disease benefit from systemic treatment with ICI. • RAC1 mutations occur in UV-exposed melanoma. • RAC1 mutations frequently co-occur with NRAS mutations. • Solitary RAC1 mutation without co-occurrence of other MAP kinase mutations is rare. • Metastatic RAC1 patients benefit from immune checkpoint inhibition (ICI). [ABSTRACT FROM AUTHOR]

An abstract of the article "The Quantum SI: A Possible New International System of Units," by Peter J. Mohr is presented.

An abstract of the article "Extensive Calculations of High-Precision Energy Levels in Hydrogen and Deuterium Through a Least-Squares Adjustment," by Eric-Olivier Le Bigot and colleagues is presented.

Immune checkpoint inhibition (ICI) currently is the most effective treatment to induce durable responses in metastatic melanoma. The aims of this study are the characterization of patients with early, late and non-response to ICI and analysis of survival outcomes in a real-world patient cohort. Patients who received PD-1-based immunotherapy for non-resectable stage-IV melanoma in any therapy line were selected from the prospective multicenter real-world DeCOG study ADOREG-TRIM (NCT05750511). Patients showing complete (CR) or partial (PR) response already during the first 3 months of treatment (Early Responders, EarlyR) were compared to patients showing CR/PR at a later time (Late Responders, LateR), a stable disease (SD) and to patients showing progressive disease (Non-Responders, NonR). Of 522 patients, 8.2 % were EarlyR (n = 43), 19.0 % were LateR (n = 99), 37.0 % had a SD (n = 193) and 35.8 % were NonR (n = 187). EarlyR, LateR and SD patients had comparable baseline characteristics. Multivariate logbinomial regression analyses adjusted for age and sex revealed positive tumor PD-L1 (RR=1.99, 95 %-CI=1.14–3.46, p = 0.015), and normal serum CRP (RR=1.59, 95 %-CI=0.93–2.70, p = 0.036) as independently associated with the achievement of an early response compared to NonR. The median progression-free and overall survival was 46.0 months (95 % CI 19.1; NR) and 47.8 months (95 %-CI 36.9; NR) for EarlyR, NR (95 %-CI NR; NR) for LateR, 8.1 months (7.0; 10.4) and 35.4 months (29.2; NR) for SD, and 2.0 months (95 %-CI 1.9; 2.1) and 6.1 months (95 %-CI 4.6; 8.8) for NonR patients. Less than 10 % of metastatic melanoma patients achieved an early response during the first 3 months of PD-1-based immunotherapy. Early responders were not superior to late responders in terms of response durability and survival. • Early response to immunotherapy was achieved in 8 % of metastatic melanoma patients. • Only 63 % of Early Responders had a durable treatment response. • Apositive tumor PD-L1 and normal serum CRP are associated with an early response. • Clinical course of patients with early and late response was comparable. [ABSTRACT FROM AUTHOR]

Background: Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up.Methods: KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment.Findings: Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhoea (eight [2%] vs one [<1%]), rash (seven [1%] vs two [<1%]), autoimmune hepatitis (seven [1%] vs two [<1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported.Interpretation: Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting.Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co. [ABSTRACT FROM AUTHOR]

Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5–10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date. Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV. 184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4–9) and mOS was 24.8 months (95 % CI: 14.2–53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9–8.5) and mOS was 29.18 months (95 % CI: 17.5–46.2). While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations. • Unknown if PD1+IPI is better than PD1 for patients with triple wild-type melanomas. • We did not find a prolonged PFS nor OS after either first line therapy of those. • PFS and OS were shorter than reported for melanomas with known oncogene mutations. [ABSTRACT FROM AUTHOR]

The combination of anti-PD-1 and anti-CTLA-4 has been associated with improvement in response and survival over anti-PD-1 monotherapy in unselected patients with advanced melanoma. Whether patients with liver metastases also benefit from the combination of anti-PD-1 and anti-CTLA-4 over anti-PD-1, is unclear. In this study, we sought to assess whether the combination of anti-PD-1 and anti-CTLA-4 leads to better response, progression-free survival and overall survival, compared with anti-PD-1 monotherapy for patients with liver metastases. We have conducted an international multicentre retrospective study. Patients with advanced melanoma with liver metastases treated with 1st line anti-PD1 monotherapy or with anti-CTLA-4 were included. The endpoints of this study were: objective response rate, progression-free survival and overall survival. With a median follow-up from commencement of anti-PD-1 monotherapy or in combination with anti-CTLA-4 of 47 months (95% CI, 42–51), objective response rate was higher with combination therapy (47%) versus anti-PD-1 monotherapy (35%) (p = 0.0027), while progression-free survival and overall survival were not statistically different between both treatment groups. However, on multivariable analysis with multiple imputation for missing values and adjusting for predefined variables, combination of anti-PD1 and anti-CTLA-4 was associated with higher objective response (OR 2.21, 1.46 – 3.36; p < 0.001), progression-free survival (HR 0.73, 0.57 – 0.92; p = 0.009) and overall survival (HR 0.71, 0.54 – 0.94; p = 0.018) compared to anti-PD1 monotherapy. Findings from this study will help guide treatment selection for patients who present with liver metastases, suggesting that combination therapy should be considered for this group of patients. • It's unclear if PD1 +IPI is better than PD1 for melanoma patients with liver metastases. • In this study, PD1 +IPI was associated with better ORR, PFS and OS over PD1 in these patients. • PD1 +IPI should be considered for melanoma patients with liver metastases. [ABSTRACT FROM AUTHOR]

Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30–40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes. Patients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG. We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2–2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4–7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2–20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response. BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi. • Targeted therapy after progression on PD-1-inhibition shows meaningful clinical activity. • A minority of patients achieves long-term disease control on second-line targeted therapy. • Rates of long-term benefit and survival were similar to those reported for first-line MAPKi. [ABSTRACT FROM AUTHOR]

Around 50% of cutaneous melanomas harbour therapeutically targetable BRAF V600 mutations. Reliable clinical biomarkers predicting duration of response to BRAF -targeted therapies are still lacking. Recent in vitro studies demonstrated that BRAF-MEK inhibitor therapy response is associated with tumour TERT promoter mutation status. We assessed this potential association in a clinical setting. The study cohort comprised 232 patients with metastatic or unresectable BRAF V600-mutated melanoma receiving combined BRAF/MEK inhibitor treatment, including a single-centre retrospective discovery cohort (N = 120) and a prospectively collected multicenter validation cohort (N = 112). Patients were excluded if they received BRAF or MEK inhibitors in an adjuvant setting, as monotherapy, or in combination with immunotherapy. Kaplan–Meier and univariate/multivariate Cox regression analyses were performed as appropriate. median age at first diagnosis was 54 years (range 16–84 years). The majority of patients were men 147/232 (63.4%). Most tumours harboured TERT promoter mutations (72%, N = 167). A survival advantage was observed in both progression-free survival (PFS) and overall survival (OS) for patients with TERT promoter-mutant versus wild-type tumours in both the discovery cohort (mPFS of 9.6 months [ N = 87] vs 5.0 months [ N = 33]; hazard ratio [HR] = 0.56 [95% confidence interval {CI} 0.33–0.96] and mOS of 33.6 months vs 15.0 months; HR = 0.47 [95%CI 0.32–0.70]) as well as the validation cohort (mPFS of 7.3 months [ N = 80] vs 5.8 months [ N = 32]; HR = 0.67 [95%CI 0.41–1.10] and mOS of 51.1 months vs 15.0 months; HR = 0.33 [95%CI 0.18–0.63]). In the pooled cohort of TERT promoter-mutant (N = 167) versus wild-type (N = 65) tumours, respectively, PFS was 8.9 versus 5.5 months, (HR = 0.62; 95%CI 0.45–0.87; P = 0.004), and OS was 33.6 versus 17.0 months, (HR = 0.51; 95%CI 0.35–0.75, P = 0.0001). In patients with melanoma receiving BRAF/MEK-targeted therapies, TERT promoter mutations are associated with longer survival. If validated in larger studies, TERT promoter mutation status should be included as a predictive biomarker in treatment algorithms for advanced melanoma. • TERT promoter mutations are associated with prolonged progression-free and overall survival in patients receiving MAPKi therapy. • TERT promoter mutations may serve as a biomarker for response to MAPKi ther apy. • In BRAF V600 mutant melanoma patients TERT promoter mutation status may be relevant for deciding which therapy to give. [ABSTRACT FROM AUTHOR]

NF1 -mutated tumours represent a small subset (10–15%) of melanomas, not sufficiently analysed in large clinical cohorts. This study investigated the largest multicentre collection of NF1 -mutated melanomas to date. This study analysed a multicentre tumour tissue sample cohort from 266 patients with NF1 -mutated melanoma. Targeted next-generation sequencing of the TERT promoter and 29 relevant melanoma genes was performed. Survival was compared with NF1 wild-type cohorts from the Tissue Registry in Melanoma project (n = 432). Most NF1 -mutated melanoma arose in the head-and-neck region of patients >60 years. NF1 alterations were frequently inactivating, primarily non-sense, less frequently truncating mutations. Non-inactivating NF1 mutations more frequently co-occurred with activating BRAF and RAS mutations. NF1 -mutated tumours had higher numbers of gene mutations and UV signature C>T and CC>TT transitions than BRAF , RAS and triple wild-type melanomas. NF1- mutated acral and mucosal melanomas harboured a different mutation signature and were frequent in women (69% and 83%, respectively), differing from non-acral cutaneous NF1 -mutated melanomas (men 73%, women 27%). Overall survival in stage IV disease was comparable for patients with NF1 -mutated or wild-type melanoma. However, in patients receiving first-line immune checkpoint inhibitor treatment, better median overall survival (mOS) was observed for NF1- mutated than wild-type tumours (mOS = not reached vs mOS = 25.82, p = 0.0154, n = 80 and 432, respectively). Cutaneous, acral and mucosal NF1 -mutated melanomas vary in clinical and genetic characteristics and demonstrate a favourable outcome on immune checkpoint inhibition therapy. • NF1- mutated melanoma respond favourably to programmed death-1-based immunotherapy. • NF1 -mutated metastatic melanoma had a similar overall survival to NF1 wild-type. • Non-acral, acral and mucosal NF1 -mutated melanoma are clinically distinct. • NF1 -mutated melanomas exhibit a large amount of UV signature mutations. [ABSTRACT FROM AUTHOR]

Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. Among 173 BRAF V600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4–1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2–2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3–1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8–2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6–1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5–1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. Among BRAF -mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone. [Display omitted] • This multicentre cohort study investigated 403 melanoma patients with elevated LDH. • End-points were progression-free and overall survival (OS) in first-line therapy. • Targeted therapy (TT) achieved the highest response rates in BRAF- mutant patients. • OS appears longer for combined anti-PD-1 and anti-CTLA-4 than for TT. • OS appears longer for combined anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone. [ABSTRACT FROM AUTHOR]

Abstract Background Primary findings from the METRIC (TMT212A2301) study demonstrated that trametinib improved progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in patients with unresectable or metastatic cutaneous melanoma with a BRAF V600 E/K mutation. However, clinical data characterising the long-term use of these therapies in combination with BRAF inhibitors or as monotherapies are limited. Methods In this open-label, phase 3 study, 322 patients with BRAF V600 E/K–mutant metastatic melanoma were randomised in a 2:1 ratio to receive trametinib (2 mg orally, once daily; n = 214) or chemotherapy (dacarbazine [1000 mg/m2] or paclitaxel [175 mg/m2] intravenously, every 3 weeks; n = 108). Patients who progressed on chemotherapy were allowed to cross over and receive trametinib. Five-year results of efficacy and safety analyses are reported. Results The median PFS was 4.9 months in the trametinib arm versus 1.5 months in the chemotherapy arm (hazard ratio, 0.54; 95% confidence interval, 0.41–0.73). Landmark OS rates for trametinib versus chemotherapy arms at 1 year, 2 years and 5 years were 60.9% versus 49.6%, 32.0% versus 29.4% and 13.3% versus 17.0%, respectively. Most patients (n = 70 [65%]) from the chemotherapy arm crossed over to the trametinib arm early in their treatment. No unexpected adverse events were reported. Conclusions This 5-year follow-up of patients with BRAF V600 E/K–mutant metastatic melanoma on a targeted therapy demonstrates that long-term use of trametinib is possible with no new or unexpected adverse events. Some patients experienced long-term survival benefit with trametinib monotherapy (METRIC ClinicalTrials.gov number, NCT01245062.). Highlights • Patients experienced long-term survival benefit with trametinib in the 5-year follow-up analysis of METRIC study. • No statistically significant difference in overall survival was seen between the treatment arms. • Trametinib could be considered as an alternative therapeutic option for patients. • The findings can be a basis for future indirect comparisons against ongoing long-term studies of dabrafenib + trametinib. [ABSTRACT FROM AUTHOR]

Background Advanced cutaneous squamous cell carcinoma (aSCC) is an area of unmet medical need and no treatment standards are established. Recently, an anti-PD-1 inhibitor received FDA breakthrough therapy designation. The aim of the study was to describe the clinical course, therapeutic management and prognosis of aSCC under real-life conditions. Patients and methods In a retrospective study performed in 24 German and Austrian hospitals and doctor's offices, patient and tumour characteristics of patients diagnosed with aSCC between January 1, 2010 and December 31, 2011 and their disease course was documented. Advanced SCC comprised either locally advanced SCCs (laSCC) or metastatic SCCs (mSCC) with any kind of metastatic spread. Results Data of 190 patients with aSCC were analysed. Median age at time of diagnosis of aSCC was 78 years. LaSCC was diagnosed in 76 patients (40%), 114 patients (60%) had mSCC. Once diagnosed with laSCC, most patients (59%) did not receive any therapy, whereas in 92% of mSCC patients at least one type of therapy was performed. Only 32 patients (29 mSCC, 3 laSCC) received systemic antitumour therapies, mostly EGFR inhibitor-based regimens. Mean duration of response was short (17-months laSCC patients, 3-months mSCC patients). Only 2 patients achieved a complete response, 27% had a partial response, 43% disease stabilisation. At diagnosis of aSCC, ECOG status was 0–1 in most patients. Non-malignant comorbidities influenced the decision on SCC-specific therapy in 39 patients (21%). Conclusions Our data show the high medical need for efficient and tolerable antitumour therapies and demonstrate that despite older age and comorbidities, most patients can be expected to be fit for treatment. This study provides a historical context for emerging aSCC treatments. [ABSTRACT FROM AUTHOR]

Background Targeted therapies with BRAF plus MEK inhibitors (BRAFi; MEKi) represent the major treatment strategy for patients with BRAF-mutated metastatic melanoma (MM). Previous analyses suggested a correlation between programmed death-ligand 1 (PD-L1) expression in tumour tissues and the outcome of targeted therapies. This study investigated PD-L1 as a potential predictive biomarker of BRAFi-based targeted therapies in MM patients. Patients and methods We analysed two independent cohorts of BRAF V600-mutated MM patients undergoing BRAFi-based therapies for PD-L1 expression in pre-treatment tumour tissues. The oligocentre cohort 1 included 83 patients whose tumour tissues were analysed retrospectively with the anti-PD-L1 antibody clone E1L3N. The multicentre cohort 2 included 58 patients whose tumour tissues were analysed prospectively within the framework of the “Registry of the Arbeitsgemeinschaft Dermatologische Onkologie” (ADOREG) and “Tissue Registry in Melanoma” (TRIM) project using the anti-PD-L1 antibody clone 28–8. Results PD-L1 expression in pre-treatment tumour tissue did not correlate with response or survival to BRAFi-based therapies in both MM patient cohorts. This finding was not influenced by retrospective versus prospective immunohistochemistry analyses, oligocentre versus multicentre cohorts or the different anti-PD-L1 antibody clones used. In cohort 1, PD-L1 positivity was detected in tumour tissue of 41.0% and 18.1% of patients (cut-off 1% and 5%, respectively). In cohort 2, 58.6% and 39.7% of patients showed PD-L1 positivity (cut-off 1% and 5%, respectively). Conclusion In two independent cohorts including a total of 141 MM patients, PD-L1 expression in tumour tissue did not correlate with the outcome of BRAFi-based treatment. Therefore, PD-L1 cannot be recommended for the use as a predictive biomarker of BRAFi-based therapy in BRAF V600-mutated MM. [ABSTRACT FROM AUTHOR]

Clinical trials demonstrated significantly improved recurrence-free survival (RFS) of melanoma patients receiving adjuvant treatment. As data from controlled trials are based on selected populations, we investigated adjuvantly treated stage III melanoma patients under real-world conditions. In a prior multicenter cohort study, stage III-IV melanoma patients were analysed for their choice of adjuvant therapy. In this follow-up study, we examined RFS, overall and melanoma-specific survival (MSS) and response to the subsequent treatment of 589 stage III patients (232 BRAF- mutated) receiving adjuvant PD-1 inhibitors (PD1; n = 479) or targeted therapy (TT; n = 110). The median follow-up of the total cohort was 25.7 months. The main reason for premature discontinuation of adjuvant therapy was disease progression in PD1- (28.8%, n = 138/479) and adverse events in TT-treated patients (28.2%, n = 31/110). Among BRAF -mutated patients, RFS at 24 months was 49% (95% CI 40.6–59.0%) for PD1- and 67% (95% CI 58–77%) for TT-treated patients. The risk of recurrence was higher for BRAF- mutated PD1 than TT (hazard ratio 1.99; 95% CI 1.34–2.96; hazard ratio adjusted for age, sex and tumour stage, 2.21; 95% CI 1.48–3.30). Twenty-four months MSS was 87% (95% CI 81.0–94.1) for PD1 and 92% (95% CI 86.6–97.0) for TT. Response to subsequent systemic treatment for unresectable disease was 22% for all PD1- and 16% for TT-treated patients. PD1-treated patients had more and earlier recurrences than TT patients. In BRAF- mutated patients, adjuvant TT might prevent early recurrences more effectively than PD1 treatment. Management of recurrence despite adjuvant treatment is challenging, with low response to current therapeutic options. • Disease progression was the main reason for premature discontinuation in PD1 patients. • Adverse events were the main reason for premature discontinuation in TT patients. • Most PD1 and TT patients presented with distant metastases at first progression. • Among BRAF -mutated patients, more and earlier recurrences were seen in PD1 patients. • Response to subsequent systemic treatment for the unresectable disease was low. [ABSTRACT FROM AUTHOR]

Summary Background Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF V 600 mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m 2 every 3 weeks or paclitaxel 175 mg/m 2 combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov , number NCT01721746 . Findings Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5–40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5–23·1) of 47 patients in the ICC group. Grade 3–4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3–4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. Interpretation Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. Funding Bristol-Myers Squibb. [ABSTRACT FROM AUTHOR]

Abstract: The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts. [Copyright &y& Elsevier]

Abstract: Interferon alfa (IFNα) and pegylated IFNα2b (PegIFNα2b) are the only agents currently approved for the adjuvant treatment of resected melanoma at high risk of recurrence. Meta-analyses showed statistically significant disease-free survival (DFS) and overall survival (OS) benefits versus controls but did not clarify optimal dose/duration. We review data from all recent clinical trials to provide the latest information on dose, duration, and potential predictive factors of treatment success. Recent data largely confirm DFS and OS benefits but optimal dose/duration is not clarified. The data suggest greater responses in patients with stage III micro-metastatic versus macro-metastatic disease, and ulceration may also predict greater sensitivity to therapy, although further investigation is needed. Presently, IFNα and PegIFNα2b remain valid adjuvant therapies following resection of high-risk melanoma; the most appropriate treatment regimen should be determined on an individual patient basis according to patient lifestyle and approach, potential for toxicity, and the available clinical evidence. [Copyright &y& Elsevier]

Abstract: A novel sulfonylureido pyridine series exemplified by compound 19 yielded potent inhibitors of FBPase showing significant glucose reduction and modest glycogen lowering in the acute db/db mouse model for Type-2 diabetes. Our inhibitors occupy the allosteric binding site and also extend into the dyad interface region of tetrameric FBPase. [Copyright &y& Elsevier]

Abstract: Nicotinamides of benzyl-substituted 4-aminopiperidines and their seven-membered analogs of generic structure 2 and 2′ have been discovered as potent and selective SST5 antagonists. The activity (K i) ranges from 2.4 to 436nM. Most compounds exhibit decent physicochemical properties and follow a clear SAR pattern. Interestingly enough, the receptor is strongly enantiodiscriminating and binds in the amino-azepane-series only the (R)-enantiomer. [Copyright &y& Elsevier]

Abstract: A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure–activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue. [Copyright &y& Elsevier]

Abstract: Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core. [Copyright &y& Elsevier]

Abstract: A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase. [Copyright &y& Elsevier]

Abstract: Design, synthesis, and SAR of novel α-alkoxy-β-arylpropionic acids as potent and balanced PPARαγ coagonists are described. One representative thereof, Aleglitazar ((S)-2Aa), was chosen for clinical development. Its X-ray structure in complex with both receptors as well as its high efficacy in animal models of T2D and dyslipidemia are also presented. [Copyright &y& Elsevier]