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Background Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors. Methods Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, beta-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received. Results Patients with high intratumoral, but not peritumoral, CD8(+) T cells and concomitantly low CD163(+) myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23-44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16-0.72, p = 0.005) compared to those with intratumoral low CD8(+) T cells and high CD163(+) myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor beta-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21-1.06, p = 0.068). Conclusions Analysis of the spatially constrained distribution of CD8(+) and CD163(+) cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways.

We sought to obtain normative values for radial nerve F-wave variables, recording with surface electrodes from the anconeus muscle.We tested 30 healthy participants (17 women, 13 men) and measured the following variables: number of F waves/40 traces (F%); minimum, maximum, and mean F-wave latency (FMIN, FMAX, FMED, respectively); F-wave chronodispersion (FCHR); interside differences of F% and FMIN (DF% and DFMIN, respectively).The mean F% was 41.3%; the normative values of FMIN, FMED, FMAX, and FCHR were21.2,22.1,23.3, and4.0 ms, respectively; and normative values of DF% and DFMIN were16.6% and1.1 ms, respectively. Height was the sole independent predictor in a regression model of FMIN, FMED, and FMAX; this explained 37%-44% of the variability.We identified a feasible and useful technique to record radial nerve F waves from the anconeus muscle and obtained normative values of F-wave variables. Muscle Nerve 59:244-246, 2019.

Scalp/neck melanomas have a poor prognosis, possibly because of a rich vascular supply that prompts tumor cells' dissemination. METHODS: We compared the accuracy of immunohistochemical (IHC) staining with morphology for the identification of lymphovascular invasion in 156 scalp/neck melanomas. We then analyzed the association of vessel invasion and density with pathological features and survival. RESULTS: IHC-detected lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) were identified in 34.6% and 13.5% of cases, respectively. IHC increased the LVI/BVI detection compared to morphology (40.4% vs 16.6%; p

The evaluation of transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) promises valuable information about fundamental brain related mechanisms and may serve as a diagnostic tool for clinical monitoring of therapeutic progress or surgery procedures. However, reports about spontaneous fluctuations of MEP amplitudes causing high intra-individual variability have led to increased concerns about the reliability of this measure. One possible cause for high variability of MEPs could be neuronal oscillatory activity, which reflects fluctuations of membrane potentials that systematically increase and decrease the excitability of neuronal networks. Here, we investigate the dependence of MEP amplitude on oscillation power and phase by combining the application of single pulse TMS over the primary motor cortex with concurrent recordings of electromyography and electroencephalography. Our results show that MEP amplitude is correlated to alpha phase, alpha power as well as beta phase. These findings may help explain corticospinal excitability fluctuations by highlighting the modulatory effect of alpha and beta phase on MEPs. In the future, controlling for such a causal relationship may allow for the development of new protocols, improve this method as a (diagnostic) tool and increase the specificity and efficacy of general TMS applications.

Background: Second generation direct acting antivirals (DAAs) drastically changed the landscape of chronic HCV (CHCV). Aim of this paper was to assess the effectiveness of DAAs, also looking at the demographic characteristics of subjects enrolled. Research design and methods: Ambispective multi-center real-life study conducted among patients with CHCV treated with DAAs in Campania Region (Southern Italy). Patient were enrolled in two cohorts according to time of enrolment. Results: 1,479 patients were enrolled. Patients aged ≥60 years were 74.7% in the historic cohort (953 patients) and 70.2% in the prospective cohort (526 patients. Patients aged ≥ 60 years showed a higher prevalence of genotype 1b (p

Visuomotor transformations at the cortical level occur along a network where posterior parietal regions are connected to homologous premotor regions. Grasping-related activity is represented in a diffuse, ventral and dorsal system in the posterior parietal regions, but no systematic causal description of a premotor counterpart of a similar diffuse grasping representation is available. To fill this gap, we measured the kinematics of right finger movements in 17 male and female human participants during grasping of three objects of different sizes. Single-pulse transcranial magnetic stimulation was applied 100 ms after visual presentation of the object over a regular grid of 8 spots covering the left premotor cortex (PMC) and 2 Sham stimulations. Maximum finger aperture during reach was used as the feature to classify object size in different types of classifiers. Classification accuracy was taken as a measure of the efficiency of visuomotor transformations for grasping. Results showed that transcranial magnetic stimulation reduced classification accuracy compared with Sham stimulation when it was applied to 2 spots in the ventral PMC and 1 spot in the medial PMC, corresponding approximately to the ventral PMC and the dorsal portion of the supplementary motor area. Our results indicate a multifocal representation of object geometry for grasping in the PMC that matches the known multifocal parietal maps of grasping representations. Additionally, we confirm that, by applying a uniform spatial sampling procedure, transcranial magnetic stimulation can produce cortical functional maps independent of a priori spatial assumptions. SIGNIFICANCE STATEMENT Visually guided actions activate a large frontoparietal network. Here, we used a dense grid of transcranial magnetic stimulation spots covering the whole premotor cortex (PMC), to identify with accurate spatial mapping the functional specialization of the human PMC during grasping movement. Results corroborate previous findings about the role of the ventral PMC in preshaping the fingers according to the size of the target. Crucially, we found that the medial part of PMC, putatively covering the supplementary motor area, plays a direct role in object grasping. In concert with findings in nonhuman primates, these results indicate a multifocal representation of object geometry for grasping in the PMC and expand our understanding of how our brain integrates visual and motor information to perform visually guided actions.

Background: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. Methods: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. Results: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). Conclusions: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.

In visual search, salient yet task-irrelevant distractors in the stimulus array interfere with target selection. This is due to the unwanted shift of attention towards the salient stimulus-the so-called attentional capture effect, which delays deployment of attention onto the target. Although powerful and automatic, attentional capture by a salient distractor is nonetheless antagonized by distractor-filtering mechanisms and is further modulated by cross-trial contingencies: The distractor cost is typically more robust when no distraction has been experienced in the immediate past, compared to when a distractor was present on the immediately preceding trial. Here, we used transcranial magnetic stimulation (TMS) to shed light on the causal role of two crucial nodes of the ventral attention network, namely the Temporo-Parietal Junction (TPJ) and the Middle Frontal Gyrus (MFG), in the exogenous control of attention (i.e., attentional capture) and its history-dependent modulation. Participants were asked to discriminate the direction of a target arrow while ignoring a task-irrelevant salient distractor, when present. Immediately after display onset, 10 Hz triple-pulse TMS was delivered either to TPJ or MFG on the right hemisphere. Results demonstrated that stimulation of right TPJ–but not of right MFG, strongly modulated attentional capture as a function of the type of previous trial, by somewhat enhancing the distractor-related cost when the preceding trial was a distractor-absent trial and significantly decreasing the cost when the preceding trial was a distractor-present trial. These findings indicate that TMS of right TPJ exacerbates the effect of the recent history, likely reflecting enhanced updating of the predictive model that dynamically governs proactive distractor-filtering mechanisms. More generally, the results attest to a role of TPJ in mediating the history-dependent modulation of attentional capture.

Animal brains contain behaviorally committed representations of the surrounding world, which integrate sensory and motor information. In primates, sensorimotor mechanisms reside in part in the premotor cortex (PM), where sensorimotor neurons are topographically clustered according to functional specialization. Detailed functional cartography of the human PM is still under investigation. We explored the topographic distribution of spatially dependent sensorimotor functions in healthy volunteers performing left or right, hand or foot, responses to visual cues presented in the left or right hemispace, thus combining independently stimulus side, effector side, and effector type. Event-related transcranial magnetic stimulation was applied to single spots of a dense grid of 10 points on the participants’ left hemiscalp, covering the whole PM. Results showed: (1) spatially segregated hand and foot representations, (2) focal representations of contralateral cues and movements in the dorsal PM, and (3) distributed representations of ipsilateral cues and movements in the ventral and dorso-medial PM. The present novel causal information indicates that (1) the human PM is somatotopically organized and (2) the left PM contains sensory-motor representations of both hemispaces and of both hemibodies, but the hemispace and hemibody contralateral to the PM are mapped on a distinct, nonoverlapping cortical region compared to the ipsilateral ones.

BACKGROUND: Thrombocytopenia is a serious issue for all patients with classical Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) because it causes severe and life-threatening bleeding. Lentiviral gene therapy (GT) for WAS has shown promising results in terms of immune reconstitution. However, despite the reduced severity and frequency of bleeding events, platelet counts remain low in GT-treated patients. OBJECTIVE: We carefully investigated platelet defects in terms of phenotype and function in untreated patients with WAS and assessed the effect of GT treatment on platelet dysfunction. METHODS: We analyzed a cohort of 20 patients with WAS/XLT, 15 of them receiving GT. Platelet phenotype and function were analyzed by using electron microscopy, flow cytometry, and an aggregation assay. Platelet protein composition was assessed before and after GT by means of proteomic profile analysis. RESULTS: We show that platelets from untreated patients with WAS have reduced size, abnormal ultrastructure, and a hyperactivated phenotype at steady state, whereas activation and aggregation responses to agonists are decreased. GT restores platelet size and function early after treatment and reduces the hyperactivated phenotype proportionally to WAS protein expression and length of follow-up. CONCLUSIONS: Our study highlights the coexistence of morphologic and multiple functional defects in platelets lacking WAS protein and demonstrates that GT normalizes the platelet proteomic profile with consequent restoration of platelet ultrastructure and phenotype, which might explain the observed reduction of bleeding episodes after GT. These results are instrumental also from the perspective of a future clinical trial in patients with XLT only presenting with microthrombocytopenia.

Although affective and semantic word properties are known to independently influence our sensorimotor system, less is known about their interaction. We investigated this issue applying a data-driven mixed-effects regression approach, evaluating the impact of lexical-semantic properties on electrophysiological parameters, namely facial muscles activity (left corrugator supercilii, zygomaticus major, levator labii superioris) and heartbeat, during word processing. 500 Italian words were acoustically presented to 20 native-speakers, while electrophysiological signals were continuously recorded. Stimuli varied for affective properties, namely valence (the degree of word positivity), arousal (the amount of emotional activation brought by the word), and semantic ones, namely concreteness. Results showed that the three variables interacted in predicting both heartbeat and muscular activity. Specifically, valence influenced activation for lower levels of arousal. This pattern was further modulated by concreteness: the lower the word concreteness, the larger affective-variable impact. Taken together, our results provide evidence for bodily responses during word comprehension. Crucially, such responses were found not only for voluntary muscles, but also for the heartbeat, providing evidence to the idea of a common emotional motor system. The higher impact of affective properties for abstract words supports proposals suggesting that emotions play a central role in the grounding of abstract concepts.

In visual search, the presence of a salient, yet task-irrelevant, distractor in the stimulus array interferes with target selection and slows down performance. Neuroimaging data point to a key role of the frontoparietal dorsal attention network in dealing with visual distractors; however, the respective roles of different nodes within the network and their hemispheric specialization are still unresolved. Here, we used transcranial magnetic stimulation (TMS) to evaluate the causal role of two key regions of the dorsal attention network in resisting attentional capture by a salient singleton distractor: the frontal eye field (FEF) and the cortex within the intraparietal sulcus (IPS). The task of the participants (male/female human volunteers) was to discriminate the pointing direction of a target arrow while ignoring a task-irrelevant salient distractor. Immediately after stimulus onset, triple-pulse 10 Hz TMS was delivered either to IPS or FEF on either side of the brain. Results indicated that TMS over the right FEF significantly reduced the behavioral cost engendered by the salient distractor relative to left FEF stimulation. No such effect was obtained with stimulation of IPS on either side of brain. Interestingly, this FEF-dependent reduction in distractor interference interacted with the contingent trial history, being maximal when no distractor was present on the previous trial relative to when there was one. Our results provide direct causal evidence that the right FEF houses key mechanisms for distractor filtering, pointing to a pivotal role of the frontal cortex of the right hemisphere in limiting interference from an irrelevant but attention-grabbing stimulus.SIGNIFICANCE STATEMENT Visually conspicuous stimuli attract our attention automatically and interfere with performance by diverting resources away from the main task. Here, we applied transcranial magnetic stimulation over four frontoparietal cortex locations (frontal eye field and intraparietal sulcus in each hemisphere) to identify regions of the dorsal attention network that help limit interference from task-irrelevant, salient distractors. Results indicate that the right FEF participates in distractor-filtering mechanisms that are recruited when a distracting stimulus is encountered. Moreover, right FEF implements adjustments in distraction-filtering mechanisms following recent encounters with distractors. Together, these findings indicate a different hemispheric contribution of the left versus right dorsal frontal cortex to distraction filtering. This study expands our understanding of how our brains select relevant targets in the face of task-irrelevant, salient distractors.

Background: Sickle cell disease (SCD) is a chronic multisystem disorder requiring comprehensive care that includes newborn screening (NBS) as the first step of care. Italy still lacks a national SCD NBS program and policy on blood disorders. Pilot single-center screening programs and a regional targeted screening have been implemented so far, but more evidence is needed in order to impact health policies. Population and methods: NBS was offered to parents of newborns in gynecology clinics in Padova and Monza, tertiary care university hospitals in northern Italy. High-performance liquid chromatography (HPLC) was performed as the first test on samples collected on Guthrie cards. Molecular analysis of the beta-globin gene was performed on positive samples. Results: A total of 5466 newborns were enrolled; for 5439, informed consents were obtained. A similar family origin was seen in the two centers (65% Italians, 9% mixed couples, 26% immigrants). Compared with SCD NBS programs in the United States and Europe, our results show a similar incidence of SCD patients and carriers. All SCD patients had a Sub-Saharan family background; HbS carriers were 15% Caucasians (Italian, Albanians) and 10% from other areas (North Africa–India–South America); carriers of other hemoglobin variants were mainly (47%) from other areas. Conclusions: Our results demonstrate the feasibility of a multicentric NBS program for SCD, give information on HbS epidemiology in two Northern Italian Areas, and support previous European recommendation for a universal NBS program for SCD in Italy: a high incidence of patients and carriers has been detected, with a high percentage of Caucasian carriers, impossible to identify in a targeted NBS.

Patients with essential thrombocythemia (ET) often suffer from neurological symptoms (NS) not ever resulting from previous thrombotic cerebral events (TCE). We reported NS occurred in 282 patients, in order to identify the factors influencing ET-related NS in the absence of TCE, and the response to therapy. Overall, 116 of 282 patients (41%) presented NS; 101 of them (87%) reported subjective transient and fluctuating NS, without concurrent TCE, which we defined as ET-related NS, by frequency: cephalalgia, chronic paresthesias, dizziness or hypotension, visual disturbances, and tinnitus. In univariate analysis, ET-related NS resulted more frequently in young people (P=0.017) and in females (P=0.025). We found a higher prevalence of JAK2V617F mutation in ET-related NS patients (P=0.021). In multivariate analysis, gender (P=0.024) and JAK2V617F mutation (P=0.041) remained significantly associated with the development of ET-related NS, with a risk of about four times higher for JAK2V617F-mutated patients (OR=3.75). Ninety-seven of 101 patients with ET-related NS received an antiplatelet (AP) agent at the time of NS, whereas only selected high-risk ET-related NS patients were treated with a cytoreductive drug, according to the published guidelines and similarly to patients without NS. We observed that only 32 of 97 (33%) patients with ET-related NS achieved a complete response after AP treatment. Among the 65 non-responder patients, 36 (55.4%) improved NS after the introduction of cytoreductive therapy; therefore, the addition of cytoreductive treatment should be considered in this setting.

Background: Dyslipidemia is an established risk factor for many diseases, but its effect on colorectal cancer risk is less clear. We investigated the association of colorectal cancer risk with plasma triglycerides, total, HDL, and LDL cholesterol in four Italian EPIC centers. Methods: We conducted a case-cohort study on participants recruited to four Italian EPIC centers (Turin, Varese, Naples, and Ragusa; 34,148 subjects). A random subcohort of 850 subjects was obtained and 286 colorectal cancer cases were diagnosed. Triglycerides, total and HDL cholesterol were determined in plasma samples obtained at baseline and stored at -196 degrees C; LDL cholesterol was calculated. Hazard ratios (HR) with 95% confidence intervals (CI), adjusted for potential confounders, were estimated by Cox regression models using the Prentice method. Results: The highest tertiles of total (HR 1.66, 95% CI 1.12-2.45) and LDL cholesterol (HR 1.87, 95% CI 1.27-2.76) were associated with increased colorectal cancer risk compared to lowest tertiles. Risks were greater for men than women, and for postmenopausal than premenopausal women. Highest tertiles of total and LDL cholesterol were also significantly associated with increased risks of colon cancer, distal colon cancer, and rectal cancer, but not proximal colon cancer. Conclusions: Our findings suggest that high levels of total and LDL cholesterol increase colorectal cancer risk, particularly in men and postmenopausal women. However additional studies are needed to clarify the role of plasma lipids in these cancers, particularly in view of the conflicting findings of previous studies. (C) 2014 Elsevier Ltd. All rights reserved.

International audience; It is well known that specific components of motor programs are automatically activated when they are afforded by object related pragmatic features. Among these features the handle appears to be particularly salient for interacting with an object. The aim of this study was to test the modulation of the motor system when object features, particularly relevant for the action, like the object's handle, are violated. In order to address this issue a TMS paradigm was used in which familiar objects with a whole or broken handle, positioned to the right or to the left, were centrally presented. A control condition was also included in which a symbol ('#' character) was shown in the right or in the left visual field. Participants had to watch stimuli carefully. The left hemisphere hand motor area was magnetically stimulated 200 ms after stimulus presentation. Results showed that MEP areas were larger when the handle was located to the right side consistent with the visuomotor role of this feature, but only when the handle was complete. The present data (1) suggest a more active role of the dorsal stream in building up object knowledge and (2) allow one to rule out the role of any asymmetrical aspect of an object in motor coding.

International audience; Embodiment theory proposes that neural systems for perception and action are also engaged during language comprehension. Previous neuroimaging and neurophysiological studies have only been able to demonstrate modulation of action systems during comprehension of concrete language. We provide neurophysiological evidence for modulation of motor system activity during the comprehension of both concrete and abstract language. In Experiment 1, when the described direction of object transfer or information transfer (e.g., away from the reader to another) matched the literal direction of a hand movement used to make a response, speed of responding was faster than when the two directions mismatched (an action-sentence compatibility effect). In Experiment 2, we used single-pulse transcranial magnetic stimulation to study changes in the corticospinal motor pathways to hand muscles while reading the same sentences. Relative to sentences that do not describe transfer, there is greater modulation of activity in the hand muscles when reading sentences describing transfer of both concrete objects and abstract information. These findings are discussed in relation to the human mirror neuron system.