A simplified genomic profiling approach predicts outcome in metastatic colorectal cancer

The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy

Clinical Multigene Panel Sequencing Identifies Distinct Mutational Association Patterns in Metastatic Colorectal Cancer

Extensive molecular characterization of human colorectal cancer (CRC) via Next Generation Sequencing (NGS) indicated that genetic or epigenetic dysregulation of a relevant, but limited, number of molecular pathways typically occurs in this tumor. The molecular picture of the disease is significantly complicated by the frequent occurrence of individually rare genetic aberrations, which expand tumor heterogeneity. Inter- and intratumor molecular heterogeneity is very likely responsible for the remarkable individual variability in the response to conventional and target-driven first-line therapies, in metastatic CRC (mCRC) patients, whose median overall survival remains unsatisfactory. Implementation of an extensive molecular characterization of mCRC in the clinical routine does not yet appear feasible on a large scale, while multigene panel sequencing of most commonly mutated oncogene/oncosuppressor hotspots is more easily achievable. Here, we report that clinical multigene panel sequencing performed for anti-EGFR therapy predictive purposes in 639 formalin-fixed paraffin-embedded (FFPE) mCRC specimens revealed previously unknown pairwise mutation associations and a high proportion of cases carrying actionable gene mutations. Most importantly, a simple principal component analysis directed the delineation of a new molecular stratification of mCRC patients in eight groups characterized by non-random, specific mutational association patterns (MAPs), aggregating samples with similar biology. These data were validated on a The Cancer Genome Atlas (TCGA) CRC dataset. The proposed stratification may provide great opportunities to direct more informed therapeutic decisions in the majority of mCRC cases

Integration of serious games and wearable haptic interfaces for Neuro Rehabilitation of children with movement disorders: A feasibility study

The past decade has seen the emergence of rehabilitation treatments using virtual reality environments. One of the advantages in using this technology is the potential to create positive motivation, by means of engaging environments and tasks shaped in the form of serious games. In this work, we propose a novel Neuro Rehabilitation System for children with movement disorders, that is based on serious games in immersive virtual reality with haptic feedback. The system design aims to enhance involvement and engagement of patients, to provide congruent multi-sensory afferent feedback during motor exercises, and to benefit from the flexibility of virtual reality in adapting exercises to the patient's needs. We present a feasibility study of the method conducted through an experimental rehabilitation session in a group of 4 children with Cerebral Palsy and Developmental Dyspraxia, 4 Typically Developing children and 4 healthy adults. Subjects and patients were able to accomplish the proposed rehabilitation session and average performance of the motor exercises in patients were lower, although comparable, to healthy subjects. Together with positive comments reported by children after the rehabilitation session, results are encouraging for application of the method in a prolonged rehabilitation treatment

Positive effects of robotic exoskeleton training of upper limb reaching movements after stroke

Abstract This study, conducted in a group of nine chronic patients with right-side hemiparesis after stroke, investigated the effects of a robotic-assisted rehabilitation training with an upper limb robotic exoskeleton for the restoration of motor function in spatial reaching movements. The robotic assisted rehabilitation training was administered for a period of 6 weeks including reaching and spatial antigravity movements. To assess the carry-over of the observed improvements in movement during training into improved function, a kinesiologic assessment of the effects of the training was performed by means of motion and dynamic electromyographic analysis of reaching movements performed before and after training. The same kinesiologic measurements were performed in a healthy control group of seven volunteers, to determine a benchmark for the experimental observations in the patients’ group. Moreover degree of functional impairment at the enrolment and discharge was measured by clinical evaluation with upper limb Fugl-Meyer Assessment scale (FMA, 0–66 points), Modified Ashworth scale (MA, 0–60 pts) and active ranges of motion. The robot aided training induced, independently by time of stroke, statistical significant improvements of kinesiologic (movement time, smoothness of motion) and clinical (4.6 ± 4.2 increase in FMA, 3.2 ± 2.1 decrease in MA) parameters, as a result of the increased active ranges of motion and improved co-contraction index for shoulder extension/flexion. Kinesiologic parameters correlated significantly with clinical assessment values, and their changes after the training were affected by the direction of motion (inward vs. outward movement) and position of target to be reached (ipsilateral, central and contralateral peripersonal space). These changes can be explained as a result of the motor recovery induced by the robotic training, in terms of regained ability to execute single joint movements and of improved interjoint coordination of elbow and shoulder joints.</p

Increased serum levels of lipogenic enzymes in patients with severe liver steatosis

Abstract Background Lipid metabolism is altered in subjects with liver steatosis. FAS is a key enzyme in de novo lipogenesis and both FAS gene expression and enzymatic activity are primarily regulated by metabolic signals in the liver. Lipoprotein lipase (LPL), the rate-limiting enzyme for the hydrolysis of core triglycerides, plays a pivotal role in lipid metabolism. This study aims to investigate if circulating levels of FAS and LPL could be clinically associated with liver steatosis. Methods In this work, we present data obtained from a subsample of 94 subjects with liver steatosis enrolled by NUTRIEPA study, a nutritional trial in subjects with liver steatosis. Serum levels of FAS protein and LPL activity were evaluated by ELISA test and by a fluorescent method, respectively. The diagnosis and the degree of liver steatosis were based on laboratory and ecographic measurements. Statistical methods included Kruskal-Wallis analysis of variance and Wilcoxon signed-rank test, where appropriate. The χ2 test has been performed to analyse categorical variables. Results The subjects with severe steatosis had significantly higher serum levels of FAS protein and LPL activity compared to subjects with mild and moderate liver steatosis. Moreover, a positive trend in serum levels of FAS expression from lower to higher degree of steatosis was also detected. Conclusions We describe a relationship between human liver steatosis and elevated levels of circulating lipogenic enzymes. Increased serum levels of FAS expression and LPL activity could be considered a marker of severe liver steatosis.</p

Wearable Haptics and Immersive Virtual Reality Rehabilitation Training in Children with Neuromotor Impairments

The past decade has seen the emergence of rehabilitation treatments using virtual reality (VR) environments although translation into clinical practice has been limited so far. In this paper, an immersive VR rehabilitation training system endowed with wearable haptics is proposed for children with neuromotor impairments: it aims to enhance involvement and engagement of patients, to provide congruent multi-sensory afferent feedback during motor exercises and to benefit from the flexibility of VR in adapting exercises to the patient's need. An experimental rehabilitation session conducted with children with cerebral palsy (CP) and developmental dyspraxia (DD) has been performed to evaluate the usability of the system and proof of concept trial of the proposed approach. We compared CP/DD performance with both typically developing children and adult control group. Results show the system was compliant with different levels of motor skills and allowed patients to complete the experimental rehabilitation session, with performance varying according to the expected motor abilities of different groups. Moreover, a kinematic assessmentbased on the presented system has been designed. Obtained results reflected different motor abilities of patients and participants, suggesting suitability of the proposed kinematic assessment as a motor function outcome

Higher Body Mass Index, Uric Acid Levels, and Lower Cholesterol Levels are Associated with Greater Weight Loss

Background: Identifying predictive factors that contribute to changes in body weight may well be an interesting approach to the management of obesity. Objective: This study was firstly aimed at examining the effect of a one-year lifestyle program based on improvements of the habitual diet and increased levels of physical activity on weight loss. Secondly, it was focused on identifying anthropometric, and serum hormonal, metabolic and haematochemical factors which can be associated with the degree of weight loss in Kg. Methods: 488 overweight or obese subjects, 383 women and 105 men, aged 18-67 years, were enrolled in the study. Body mass index, waist circumference, serum blood glucose, lipids, uric acid, creatinine, insulin, TSH, FT3, FT4, and 24-h urine catecholamines were measured. Results: Weight loss was positively associated with BMI (P &lt; 0.01), waist circumference (P &lt; 0.01), uric acid (P &lt; 0.01), creatinine (P &lt; 0.05), smoking (P &lt; 0.01), and negatively correlated with age (P &lt; 0.01), total cholesterol (P &lt; 0.05), LDL-cholesterol (P &lt; 0.01), HDL cholesterol (P &lt; 0.05). In a multiple regression model considering weight loss as a dependent variable, and smoking, age, BMI, uric acid, creatinine, total cholesterol, LDL-cholesterol and HDL cholesterol as independent variables, weight loss maintained a direct independent relationship with BMI (P &lt; 0.001), uric acid (P &lt; 0.05), LDL-cholesterol (P &lt; 0.05), and HDL-cholesterol (P &lt; 0.05), and an inverse independent association with cholesterol (P &lt; 0.01). Conclusions: This study suggests that higher BMI and uric acid levels, and lower total cholesterol concentrations are associated with a greater potential to lose weight

Serious game and wearable haptic devices for neuro motor rehabilitation of children with cerebral palsy

Cerebral palsy (CP) is a group of disorders that affect the development of movement and posture, resulting in limited activities. To optimize pediatric neuro-rehabilitation and to complement conventional occupational therapies, serious game based therapies for upper limb (UL) rehabilitation have been developed or adapted for the pediatric field during recent years. In this work, we present the design and development of UL rehabilitation scenario for CP patients, based on Serious Games (SG) and enhanced by immersive virtual reality (VR) with haptic feedback to increase engagement and provide rich, congruent multi-sensory feedback during virtual interaction. © Springer International Publishing AG 2017

Rhegmatogenous Retinal Detachment with a High Risk of Proliferative Vitreoretinopathy Treated with Episcleral Surgery and an Intravitreal Dexamethasone 0.7-mg Implant

Purpose: To report a case of rhegmatogenous retinal detachment with a high risk of proliferative vitreoretinopathy (PVR) effectively treated with episcleral surgery and an intravitreal dexamethasone 0.7-mg implant. Methods: A 35-year-old Caucasian man with a macula-off rhegmatogenous subtotal retinal detachment that had persisted for 1 month in his myopic left eye presented several risk factors that could have led to the development of PVR after retinal detachment surgery. His best corrected visual acuity was hand motion. He received an intravitreal dexamethasone 0.7-mg implant (Ozurdex®) after episcleral surgery to prevent this complication. Results: At least 9 months after surgery, no sign of PVR or pucker has developed in the treated eye. Visual acuity improved to 0.2, the retina was attached and no complications were observed. Conclusion: Intravitreal dexamethasone 0.7-mg implant (Ozurdex) could be considered as off-label treatment following episcleral surgery to prevent PVR