Neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma: NEO-TIM, a phase II randomized non-comparative study

Background: Following the increased survival of patients with metastatic melanoma thanks to immunotherapy and targeted therapy, neoadjuvant approaches are being investigated to address the unmet needs of unresponsive and intolerant patients. We aim to investigate the efficacy of neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma. Methods: The study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable, BRAF-mutated and wild-type melanoma, with three possible treatments: (1) vemurafenib 960 mg twice daily from day 1 to 42; (2) vemurafenib 720 mg twice daily from day 1 to 42; (3) cobimetinib 60 mg once daily from day 1 to 21 and from day 29 to 42; and (4) atezolizumab 840 mg for two cycles (day 22 and day 43). Patients will be randomized to three different arms: A) BRAF-mutated patients will receive over 6 weeks (1) + (3); B) BRAF-mutated patients will receive over 6 weeks (2) + (3) + (4); C) BRAF wild-type patients will receive over 6 weeks (3) + (4). All patients will also receive atezolizumab 1200 mg every 3 weeks for 17 cycles after surgery and after a second screening period (up to 6 weeks). Discussion: Neoadjuvant therapy for regional metastases may improve operability and outcomes and facilitate the identification of biomarkers that can guide further lines of treatment. Patients with clinical stage III melanoma may especially benefit from neoadjuvant treatment, as the outcomes of surgery alone are very poor. It is expected that the combination of neoadjuvant and adjuvant treatment may reduce the incidence of relapse and improve survival

Melanoma immunotherapy: strategies to overcome pharmacological resistance

Introduction: Although checkpoint inhibitors have provided a breakthrough in how melanoma is treated, about half of patients still do not respond due to primary or acquired resistance. New strategies are, therefore, required to increase the number of patients benefiting from immunotherapy. This systematic review investigates novel combinations that may overcome immune resistance in patients with melanoma. Areas covered: We provide an overview of immune-related resistance mechanisms and the various therapeutic strategies that can be considered in attempting to overcome these barriers, including combined immunotherapy approaches and combinations with chemotherapy, radiotherapy, and targeted therapy. Expert opinion: The immune response is a dynamic process in which the tumor microenvironment and immune cells interact in a variety of ways. New treatment approaches aim to enrich the tumor microenvironment with immune-infiltrate and increase response to immune checkpoint inhibitors

Characterization of elderly, stroke and chorea populations using gait variability and stability indexes

Research question: Are gait variability and stability indexes representative of specific diseases? And can they explain the physiological deficit of motor control in these pathologies? Introduction: The importance of stability and variability indexes in the assessment of motor functionality is known [1\u20134]; however much effort is still required to identify which indexes are representative of specific diseases and consequently which physiological aspects each index analyzes. To improve these aspects the ability of the indexes to discriminate (a) young healthy subjects from pathological ones and (b) different pathologies was assessed. Materials and methods: The study was conducted on 10 healthy young people (Y), 10 elderly subjects (E), 10 stroke patients (S) and 10 subjects with choreic movement disorder (C). The participants performed an instrumented over ground gait task wearing three inertial measurement units (IMUs): one located on the trunk at the height of the fifth lumbar vertebra to acquire trunk acceleration, and two attached above the ankles, allowing the strides detection according to [5]. 5 stability and 7 variability indexes were calculated on stride time and trunk acceleration data during gait, for antero-posterior, medio-lateral and vertical directions. Statistical analyses were performed (a) to verify if the indexes were able to discriminate young healthy subjects from pathological ones and (b) to evaluate the ability of the indexes to describe different pathologies. Results: Two variability indexes (Standard Deviation and Coefficient of Variation) and one stability index (Multiscale Sample Entropy) were able to discriminate pathological people from healthy young ones. None of the evaluated indexes was able to discriminate all the different pathologies (S C E); conversely, clusters of indexes representative of elderly and stroke subjects were found. Discussion: The obtained results shown that the variability of the stride time and the complexity of acceleration signals are able to discriminate healthy young people from pathological ones; this not surprising since gait pattern of healthy and pathological subjects are very different. Indeed these features are the first to be influenced by the ability of the subject to implement a right motor-control. The indexes that are able to discriminate S from C and E are about the smoothness of the signal. This could be explained with the nature of the pathologies; indeed stroke subjects have important impairments only in one side of the body, instead old age and chorea are degenerative diseases that affect the whole body. The indexes that are able to discriminate E from C and S are about the recurrences of the signal. This could suggest that the variability of gait pattern is lower in elderly than in chorea and stroke subjects

Safety of treatment with high-dose daptomycin in 102 patients with infective endocarditis

Daptomycin is commonly used at doses >6 mg/kg/day for various indications, including infective endocarditis (IE). A systematic assessment of skeletal muscle, renal, haematological, hepatic and pulmonary toxicity of high-dose daptomycin (HDD) in IE is lacking. A total of 102 IE patients treated with HDD were included in this non-comparative, observational, single-centre cohort study conducted from 2007 to 2014. The incidence, timing, severity and evolution of adverse events (AEs) were assessed. Patients had a median age of 61.5 years and a high prevalence of co-morbidities. Staphylococci were cultured in 87.2% of cases (62.2% meticillin-resistant). The median daptomycin dose was 8.2 mg/kg/day for a median of 20 days (range, 1–60 days). HDD was withdrawn due to AEs in 12 patients (11.8%). On-treatment death occurred in 4 cases (3.9%, none HDD-related). Muscle toxicity occurred in 15 patients in a median of 15 days after HDD starts, which was largely mild and reversible with ongoing HDD use. Mild renal toxicity was observed in 9 patients (8.8%) after a median of 12 days of HDD (RIFLE—Risk in 8, Injury in 1). A rise of peripheral blood eosinophils occurred in 16 patients (15.7%). There were three cases of eosinophilic interstitial pneumonia. Four patients (3.9%) had mild allergic or idiosyncratic reactions. No other hepatic or haematological AEs were observed. Our current experience with 102 patients suggests that HDD is safe in significantly ill IE patients with multiple co-morbidities. Muscle toxicity was clinically negligible. Most importantly, there was no significant renal toxicity. Eosinophils should be carefully monitored

Light electric vehicle enabled by smart systems integration

For the first time in history, the majority of people live now in urban areas. What is more, in the next four decades, the number of people living in the world's urban areas is expected to grow from 3.5 billion to 5.2 billion. At the same time, populations around the world are rapidly ageing. By 2050, the global population of people aged 60 years and over is expected to reach almost 2 billion, with the proportion of older people doubling between 2006 and 2050. This growth and ageing of the population will pose great challenges for urban mobility, which will be addressed within the SilverStream project. In particular, it will develop and demonstrate a radically new light and affordable Light Electric Vehicle concept for the ageing population in congested European cities with scarce parking space