Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study

Background

Beyond progression after tyrosine kinase inhibitor in EGFR-positive non-small-cell lung cancer patients (BE-POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a “real-life” Caucasian EGFR-mutated non-small-cell lung cancer (NSCLC) population. The sharing of multi-institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE-POSITIVE study.

Inhibition of muscle spindle afferent activity during masseter muscle fatigue in the rat

The influence of muscle fatigue on the jaw-closing muscle spindle activity has been investigated by analyzing: (1) the field potentials evoked in the trigeminal motor nucleus (Vmot) by trigeminal mesencephalic nucleus (Vmes) stimulation, (2) the orthodromic and antidromic responses evoked in the Vmes by stimulation of the peripheral and central axons of the muscle proprioceptive afferents, and (3) the extracellular unitary discharge of masseter muscle spindles recorded in the Vmes. The masseter muscle was fatigued by prolonged tetanic masseter nerve electrical stimulation. Pre- and postsynaptic components of the potentials evoked in the Vmot showed a significant reduction in amplitude following muscle fatigue. Orthodromic and antidromic potentials recorded in the Vmes also showed a similar amplitude decrease. Furthermore, muscle fatigue caused a decrease of the discharge frequency of masseter muscle spindle afferents in most of the examined units. The inhibition of the potential amplitude and discharge frequency was strictly correlated with the extent of muscle fatigue and was mediated by the group III and IV afferent muscle fibers activated by fatigue. In fact, the inhibitory effect was abolished by capsaicin injection in the masseter muscle that provokes selective degeneration of small afferent muscle fibers containing neurokinins. We concluded that fatigue signals originating from the muscle and traveling through capsaicin-sensitive fibers are able to diminish the proprioceptive input by a central presynaptic influence. In the second part of the study, we examined the central projection of the masseter small afferents sensitive to capsaicin at the electron-microscopic level. Fiber degeneration was induced by injecting capsaicin into the masseter muscle. Degenerating terminals were found on the soma and stem process in Vmes and on the dendritic tree of neurons in Vmot. This suggests that small muscle afferents may influence the muscle spindle activity through direct synapses on somata in Vmes and on dendrites of neurons in Vmot.     

Grey Matter Density Predicts the Improvement of Naming Abilities After tDCS Intervention in Agrammatic Variant of Primary Progressive Aphasia

Agrammatic variant primary progressive aphasia is a neurodegenerative disorder specifically characterized by language deficits. A recent study has demonstrated a beneficial effect of transcranial direct current stimulation (tDCS) in combination with language training on naming accuracy in these patients. The aim of the study was to evaluate whether the improvement of naming accuracy after tDCS during language training was related to regional grey matter (GM) density. Eighteen avPPA patients underwent a brain magnetic resonance imaging before receiving a treatment that consisted of tDCS over the left dorsolateral prefrontal cortex during individualized language training (10 daily therapy sessions, 5 days per week from Monday to Friday). Performances on neuropsychological tests and naming of objects (treated and untreated) and actions were assessed at baseline, post-treatment  and 3 months after treatment. Correlations between individual changes after treatment on neuropsychological tests and on picture naming task and voxel-based GM volume at baseline were performed. We found that the improvement in the naming of treated objects was positively correlated with GM volume in the left fusiform, left middle temporal, and right inferior temporal gyri whereas action naming change was related to GM density in the left middle temporal gyrus. In conclusion baseline density of GM in these brain regions was associated with greater treatment response on naming performances, suggesting that intervention in early disease stages might be most successful. These findings have implication for designing future rehabilitation protocols in language variants of frontotemporal dementia.     

Technetium-99m sestamibi single-photon emission tomography detects subclinical myocardial perfusion abnormalities in patients with systemic lupus erythematosus

In patients with systemic lupus erythematosus, involvement of the cardiovascular system is the third leading cause of death. However, although autopsy studies have demonstrated a high incidence of abnormalities in both the myocardium and coronary vessels, clinical manifestations have been reported in only a small percentage of cases. The aim of this study was to evaluate myocardial perfusion in asymptomatic lupus patients using technetium-99m sestamibi single-photon emission tomography (SPET). Twenty-eight patients without overt cardiac involvement and risk factors were studied with ^99mTc-sestamibi SPET at rest and after dipyridamole infusion. Perfusion abnormalities were detected in 18 cases: six had persistent defects, three had reversible defects, seven had both persistent and reversible defects, and two showed rest defects which normalized on dipyridamole images (”reverse redistribution pattern”). Coronary angiography was performed in eight patients with positive ^99mTc-sestamibi SPET, and showed normal epicardial vessels in all the cases. These results indicate that ^99mTc-sestamibi SPET reveals a high prevalence (18 out of 28 patients in this study, i.e. 64%) of myocardial perfusion abnormalities in asymptomatic lupus patients, probably due to the primary immunological damage of this autoimmune disease. In conclusion, rest/dipyridamole ^99mTc-sestamibi SPET can be a useful non-invasive method to identify subclinical myocardial involvement in systemic lupus erythematosus, and patients potentially at risk of later cardiac events. Received 20 November 1998 and in revised form 19 February 1999     

Limitations in daily activities and general perception of quality of life: Long term follow‐up in patients with anti‐myelin‐glycoprotein antibody polyneuropathy

In this study, we assessed the modifications over time of daily activities and quality of life (QoL) in 32 subjects with anti‐myelin‐glycoprotein (MAG) antibody neuropathy. A widespread panel including clinical scores and patient‐reported questionnaires, in compliance of the terms by the International Classification of Functioning, Disability, and Health (ICF) of the World Health Organization (WHO), was employed at enrollment (T0) and at follow‐up evaluation (T1) after a mean interval of 15.4 ± 5.7 months. The Sensory Modality Sum score (SMS) at four limbs showed a significant worsening over time (mean score 27.2 ± 3.9 at T0 vs 25.7 ± 3 at T1 at upper limbs, P = .03; 20.5 ± 4.8 at T0 vs 18.6 ± 5.9 at T1 at lower limbs, P = .04). The Visual Analogue Scale (VAS) for pain significantly worsened at upper limbs at T1 (mean values 0.84 ± 1.95 at T0 vs 1.78 ± 2.6 at T1, P = .03). All the other tests did not show significant differences between T0 and T1. In the subgroup who underwent rituximab (15/32 treated before T0, 3/32 patients treated between T0 and T1 with median interval of 1 year), no significant differences were observed between T0 and T1. Despite the quite long follow‐up, statistical significance was not achieved either for the limited number of patients or for the lack of sensitive outcome measures. In our cohort, the significant worsening of the SMS and VAS after a median of 14 months can be considered as a reliable expression of the natural history of the disease, and suggest that these scales might represent possible outcome measures in anti‐MAG antibody neuropathy.     

Organizational and welfare mode of breast centers network: a survey of Sicilian radiologists

The European Society of Breast Cancer Specialists has created quality indicators for breast units to establish the minimum standards of care for patients. In Italy, each region differs, indeed, in terms of health care and services warranted to patients suffering from breast cancer. Since Sicilian Regional Administration today is still disregarding implementation of the provisions contained in the proposal of the Ministry of Health entitled “Guidelines on Organizational and Health Care Methods of Breast Centers Network” in November 2015 the Sicilian Regional Group of the Italian Society of Radiology (SIRM) decided to carry out a survey to see the position of the Sicilian Healthcare System and define the gap to bridge over. Sicilian breast imaging radiologists were asked to fill in a questionnaire concerning the type of job relationship (public or private sector), qualification (Manager, Department Manager, Freelancer) and years of experience on breast imaging. With regard to technological requirements, were answered the questions about the number, type, age and completeness of accessories of the equipment supplied in the Sicilian healthcare facilities. The data showed that over 64% of breast imagers in Sicilian centers work in breast units, whereas only 18% are involved in screening programs. A majority of radiologists (81%) working in the breast health care system is very experienced (more than 10 years of experience in the field). The result provided concerning the medical and technical staff demonstrates an uneven situation, but overall an inadequate value compared with the required guidelines especially in interventional procedures. The aim of this paper is to illustrate the method used and the results obtained. These data have to be shared with policy makers to enhance quality improvement in Sicilian Breast Center Network.     

Synthesis and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-D-aspartate receptors

As an extension of our studies, novel indole derivatives were rationally designed and synthesized as ligands targeted to GluN2B/NMDA receptors. The 2-(4-benzylpiperidin-1-yl)-1-(6-hydroxy-1H-indol-3-yl)ethanone (4i) and 1-(4-benzylpiperidin-1-yl)-2-(6-hydroxy-1H-indol-3-yl)ethane-1,2-dione (6i) showed high binding affinity in [3H]ifenprodil displacement assay. By computational studies, we suggested the hypothetical interactions playing a significant role during the binding process. However, in functional and in vivo studies the most potent compound 4i did not show any activity whereas it displayed relevant affinity toward the σ2 receptor.     

Strategies of multi-objective optimization in drug discovery and development

Introduction: Drug discovery and development is a typical multi-objective problem and its successes or failures depend on the simultaneous control of numerous, often conflicting, molecular and pharmacological properties. Multi-objective optimization strategies represent a new approach to capture the occurrence of varying optimal solutions based on trade-offs among the objectives taken into account. In view of this, multi-objective optimization aims to discover a set of satisfactory compromises that may in turn be used to find the global optimal solution by optimizing numerous dependent properties simultaneously. Areas covered: The authors review the potential of multi-objective strategies in a number of fields including: drug library design; substructure mining; the derivation of quantitative structure-activity relationship models; ranking of docking poses. The authors also discuss the potential of multi-objective strategies in controlling competing properties for absorption, distribution, metabolism and elimination/toxicity optimization. Expert opinion: It is very clear to those who work in drug discovery and development that the success of rational drug design is largely dependent on the control of a number of, often conflicting, objectives. Therefore, multi-objective optimization methods, which have recently been introduced to the field of molecular discovery, represent the ultimate frontier in chemoinformatics. The widespread use of these multi-objective techniques has provided new opportunities in medicinal chemistry as seen through its use in a number of applications for chemoinformatics both within academia and the pharmaceutical industry.