Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment naive advanced TC. They received ramucirumab, carboplatin and paclitaxel for 6 cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was ORR according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were PFS, OS and safety. Centralized radiologic review was performed. RESULTS: From 11/2018 to 06/2023, 52 patients were screened, 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. ECOG PS was 0 in 68.5%, 1 in 31.4% patients. At the present analysis carried out some months later the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95%CI 63.1-91.6]. At the centralized radiological review of 33/35 evaluable patients, ORR was 57.6% [95%CI 39.2-74.5]. After a median follow-up of 31.6 months, median PFS was 18.1 [95%CI 10.8-52.3] and median OS 43.8 [95%CI 31.9-NR] months. Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE≥G3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO).

BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

Unraveling the complexity of anti-doping analysis: reassessing meldonium detection and doping verdicts in a case study.

BACKGROUND: The precision and accuracy of mass spectrometry (MS) made it a fundamental tool in anti-doping analysis. High-resolution (HR) mass spectrometers significantly improved compound identification. This study systematically analyzes data from an athlete (Subject 1) who tested positive for meldonium and compares it with data from a healthy volunteer (Subject 2) to examine the correctness of the doping verdict. CASE PRESENTATION: The documentation related to Subject 1 was thoroughly processed and analyzed. A study involving a volunteer (Subject 2) replicated Subject 1 regimen and urine sample collection for data alignment with anti-doping results, with Subject 2 reporting not using meldonium. The anti-doping agency's analysis of Subject 1 showed the presence of meldonium at a concentration close to the established cut-off level. However, a closer examination revealed that one specific ion, crucial for meldonium identification, was absent from the mass spectra. Analyzing Subject 2 data, using the same methodology, the absence of the specific ion was confirmed, even though the volunteer did not consume meldonium. The European directive and the method that was validated and cited by the anti-doping agency identified meldonium on at least four specific ions, whereas the anti-doping analysis used only three ions. This discrepancy compromises the specificity of meldonium identification. CONCLUSIONS: To enhance the analytical methodology, two strategic interventions are suggested: adjusting the meldonium cut-off value and expanding the analysis to include meldonium metabolites. By addressing these avenues, the precision of meldonium detection and doping verdicts can be improved. In conclusion, this study challenges the anti-doping agency's verdict and prompts a reevaluation of meldonium detection methodologies in anti-doping measures.

PEOPLE (NCT03447678), a first-line phase II pembrolizumab trial, in negative and low PD-L1 advanced NSCLC: clinical outcomes and association with circulating immune biomarkers.

BACKGROUND: The PEOPLE trial aimed to identify new immune biomarkers in negative and low programmed death-ligand 1 (PD-L1) (0%-49%) advanced non-small-cell lung cancer (aNSCLC) patients treated with first-line pembrolizumab. Here we report the main outcomes and the circulating immune biomarkers analysis. PATIENTS AND METHODS: The primary endpoint of this phase II trial was the identification of immune biomarkers associated with progression-free survival (PFS). Overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety were secondary endpoints. Absolute cell counts for 36 subsets belonging to innate and adaptive immunity were determined by multiparametric flow cytometry in peripheral blood at baseline and at first radiologic evaluation. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyze immune variables and their correlation with clinical endpoints. RESULTS: From May 2018 to October 2020, 65 patients were enrolled. After a median follow-up of 26.4 months, the median PFS was 2.9 months [95% confidence interval (CI) 1.8-5.6 months] and median OS was 12.1 months (95% CI 8.7-17.1 months). The ORR was 21.5%, DCR was 47.7% and median DoR was 14.5 months (95% CI 6.4-24.9 months). Drug-related grade 3-4 adverse events were 9.2%. Higher T cell and natural killer (NK) cell count at baseline and at the first radiologic evaluation were associated with improved PFS, DCR and OS. On the contrary, higher myeloid cell count at baseline or at the first radiologic evaluation was significantly associated with worse OS and DCR. CONCLUSIONS: Circulating immune biomarkers can contribute to predict outcomes in negative and low PD-L1 aNSCLC patients treated with first-line single-agent pembrolizumab.

Unifying Frequency Combs in Active and Passive Cavities: Temporal Solitons in Externally Driven Ring Lasers.

Frequency combs have become a prominent research area in optics. Of particular interest as integrated comb technology are chip-scale sources, such as semiconductor lasers and microresonators, which consist of resonators embedding a nonlinear medium either with or without population inversion. Such active and passive cavities were so far treated distinctly. Here we propose a formal unification by introducing a general equation that describes both types of cavities. The equation also captures the physics of a hybrid device-a semiconductor ring laser with an external optical drive-in which we show the existence of temporal solitons, previously identified only in microresonators, thanks to symmetry breaking and self-localization phenomena typical of spatially extended dissipative systems.

Sex-biased impact of endocrine disrupting chemicals on behavioral development and vulnerability to disease: Of mice and children.

Sex is a fundamental biological characteristic that influences many aspects of an organism's phenotype, including neurobiological functions and behavior as a result of species-specific evolutionary pressures. Sex differences have strong implications for vulnerability to disease and susceptibility to environmental perturbations. Endocrine disrupting chemicals (EDCs) have the potential to interfere with sex hormones functioning and influence development in a sex specific manner. Here we present an updated descriptive review of findings from animal models and human studies regarding the current evidence for altered sex-differences in behavioral development in response to early exposure to EDCs, with a focus on bisphenol A and phthalates. Overall, we show that animal and human studies have a good degree of consistency and that there is strong evidence demonstrating that EDCs exposure during critical periods of development affect sex differences in emotional and cognitive behaviors. Results are more heterogeneous when social, sexual and parental behaviors are considered. In order to pinpoint sex differences in environmentally-driven disease vulnerabilities, researchers need to consider sex-biased developmental effects of EDCs.

Conversion factors for effective dose and organ doses with the air kerma area product in patients undergoing percutaneous transhepatic biliary drainage and trans arterial chemoembolization.

Conversion factors used to estimate effective (E) and organ doses (HT) from air Kerma area product (KAP) are required to estimate population doses in percutaneous transhepatic biliary drainage (PTBD) and trans arterial chemoembolization (TACE) interventional procedures. In this study, E and HT for ten critical organs/tissues, were derived in 64 PTBD and 48 TACE procedures and in 14,540 irradiation events from dosimetric, technical and geometrical information included in the radiation dose structured report using the PCXMC Monte Carlo model, and the ICRP 103 organ weighting factors. Conversion factors of: 0.13; 0.19; 0.26 and 0.32 mSv Gy-1 cm-2 were established for irradiation events characterized by a Cu filtration of 0.0; 0.1; 0.4 and 0.9 mm, respectively. While a single coefficient of conversion is not able to provide estimates of E with enough accuracy, a high agreement is obtained between E estimated through Monte Carlo methods and E estimated through E/KAP conversion factors accounting separately for the different modes of fluoroscopy and the fluorography component of the procedures. An algorithm for the estimation of effective and organ doses from KAP has been established in biliary procedures which considers the Cu filtration in the X-ray irradiation events. A similar algorithm could be easily extended to other interventional procedures and incorporated in radiation dose monitoring systems to provide dosimetric estimates automatically with enough accuracy to assess population doses.

Clinical outcomes to pemetrexed-based versus non-pemetrexed-based platinum doublets in patients with KRAS-mutant advanced non-squamous non-small cell lung cancer.

PURPOSE: KRAS mutation has been associated with enhanced dependency on the folate metabolism in preclinical studies. However, whether KRAS mutation correlates to increased sensitivity to pemetrexed in patients with advanced NSCLC is unknown. METHODS: Patients with advanced non-squamous NSCLC who had a documented EGFR and ALK WT genotype with simultaneous KRAS mutation assessment were evaluated for clinical outcome to pemetrexed- and non-pemetrexed-based first-line platinum doublet according to KRAS mutation status. RESULTS: Of 356 patients identified, 138 harbored a KRAS mutation. Among KRAS-mutant NSCLCs, those treated with platinum/pemetrexed (81/138) had significantly lower ORR (30.9% versus 47.4%, P = 0.05), DCR (51.8% versus 71.9%, P = 0.02) and shorter median progression-free survival [mPFS 4.1 versus 7.1 months, HR 1.48 (95% CI 1.03-2.12), P = 0.03] and median overall survival [mOS 9.7 versus 26.9 months, HR 1.93 (95% CI 1.27-2.94), P = 0.002] compared to those who received a non-pemetrexed-based platinum doublet (57/138). No difference in ORR, DCR, mPFS and mOS was observed between KRAS WT patients who received a pemetrexed-based (124/218) versus non-pemetrexed base platinum doublets (94/218). After adjusting for performance status, age and the presence of brain metastasis at baseline, treatment with pemetrexed-based platinum doublet was associated with an increased risk of death [HR 2.27 (95% CI 1.12-4.63), P = 0.02] among KRAS-mutant patients in multivariate analysis. CONCLUSION: Patients with KRAS-mutant lung adenocarcinoma have a poorer outcome on pemetrexed-based first-line chemotherapy. Whether KRAS-mutant NSCLCs should be excluded from pemetrexed-containing regimens should be assessed prospectively.

Positive self-perception and corticospinal excitability: Recalling positive behavior expands peripersonal space boundaries.

Converging evidence suggests that peripersonal space has dynamic properties, that can be influenced by motor and cognitive factors. Here, we investigated whether changes in self-perception may impact upon peripersonal representation. Specifically, employing non-invasive brain stimulation, we tested whether corticospinal excitability elicited by objects placed in the vertical peripersonal vs extrapersonal space can be influenced by changes in self-perception after recalling a personal experience inducing the feeling of high power (vs. positivity vs. low power). In a preliminary study (Study 1, N = 39) participants were presented with an object, whose position was manipulated in the horizontal vs vertical space. We assessed corticospinal excitability by measuring Motor Evoked Potentials (MEPs) using Transcranial Magnetic Stimulation with Electromyography co-registration (TMS-EMG). In the horizontal condition, we replicated the well-known motor facilitation induced by objects falling in the peri vs extrapersonal space, while in the vertical dimension MEPs were higher in the extrapersonal space. In the main experiment (Study 2), participants (N = 55) were randomly assigned to feel high power, low power, or a general positive emotion and were asked to observe the same object positioned either in the peripersonal or in the extrapersonal vertical space. Results showed that in the low power condition MEPs were higher in the extrapersonal vs peripersonal, as in Study 1, while in high power and positive conditions MEPs were not influenced by distance. Taken together, our findings suggest a dissociable pattern of motor facilitation underlying vertical vs horizontal space perception and, crucially, that changes in self-perception can influence such a representation.

[Secondary labiaplasty: Retrospective study about 44 cases. Annual report SOFCPRE 2019]. / Nymphoplastie secondaire : étude rétrospective à propos de 44 cas. Rapport annuel de la SOFCPRE 2019.

INTRODUCTION: Labiaplasty is a surgery currently booming. The number of publications on this subject is also increasing significantly. With the increase of the operated cases, we see more and more consultations for revisions after a labiaplasty, called secondary labiaplasty. The author reports here his experience with secondary labiaplasties in 44 cases. MATERIAL AND METHOD: The study carried out by the author reports 44 cases divided into two categories of secondary labiaplasties. The first category is characterized by a wound dehiscence, including those following the author's lambda laser procedures, which are easily repaired under local anesthesia after border cutting and suture. The second category is characterized by over-resections or real amputations or even remains of atypical flaps. DISCUSSION: The over-resection is a technical fault. In this case, the technique used to improve the aesthetic, functional and psychological aspect is the use of the remains of labia minora in the form of a flap to avoid a dog-ear appearance at the anterior and posterior part. The use of lipofilling of the labia majora is to mask the area and improve the function. The future of this surgery is probably the reconstruction of the labia minora by local flaps. CONCLUSION: The conclusion of the study is that it is imperative that surgeons performing labiaplasties be trained in both anatomy and labiaplasty techniques and avoid as much as possible over-resections and amputations, mending being often difficult.

Evidence for swine and human papillomavirus in pig slurry in Italy.

AIMS: The diversity and the geographical distribution of swine papillomaviruses (PVs) are virtually unknown. The occurrence and the diversity of swine PV were therefore investigated in pig slurry collected in Italy, to contribute towards filling this gap in knowledge. METHODS AND RESULTS: Twenty-two slurry samples underwent analysis by nested PCR and DNA sequencing using published and newly designed specific primer pairs for Sus scrofa papillomavirus (SsPV) type 1 and 2 (SsPV1 and 2), along with degenerate PV-specific primers targeting the major coat protein L1 and the helicase protein E1. Overall, three samples (13·6%) were positive for SsPV1 by specific primers, and nucleotide (nt) sequences showed 99-100% nt identity with SsPV1 variant a (EF395818), while SsPV2 was not found in any sample. Using generic primers, eight samples (36·4%) were tested positive for human papillomavirus (HPV), and were characterized as follows: ß1-HPV8, ß1-HPV14, ß1-HPV206, ß2-HPV113, ß2-HPV120 and γ1-HPV173. Moreover, one unclassified γ-type was detected. CONCLUSIONS: Both swine and human PVs were detected in pig slurry in this study. The unexpected presence of HPV in pig waste could be explained as the result of an improper use of the sewage collection pits and/or with improper procedures of the operators. SIGNIFICANCE AND IMPACT OF THE STUDY: This study reports the first detection of SsPV1 in Italy, along with the first detection of HPVs in pig slurry samples in Italy, and expands our knowledge about PV diversity and geographic distribution.

Variability of the discrepancy between manufacturer and measured CTDI100 values by scanner type, acquisition parameters and phantom size.

According to the EU directive 2013/59, the computed tomography (CT) equipments shall be able to inform the practitioner of parameters for assessing the patient dose. The aim of this study was to measure the accuracy of the CTDI100 with respect to the values stipulated in the manufacturer manual for different manufacturers/models of CT and to assess the impact of acquisition parameters on CTDI100 accuracy. Ten CT from 4 different manufacturers were included in the study. The discrepancy with the manufacturer value CTDI100 was checked with a dosimeter with traceable calibration. Manufacturer values for the CTDI100 were derived from the equipment's manual. The impact of the kVp, CT model, primary collimation and phantom size on the discrepancy of the CTDI100, was assessed by a four-way ANOVA. All the factors had a statistically significant impact on CTDI100 discrepancy (P < 0.05). In a head to head comparison, the greater discrepancies were found on average for 80 kV (15.4 ±â€¯10.7%), sixteen channels CT (10.3 ±â€¯5.1%) and for thick collimations (13.2 ±â€¯6.8%), whilst no significant differences were found between head and body phantoms. For sixteen channels CT and acquisition protocols involving the use of low kV or thick primary collimation, the discrepancies with the manufacturer value CTDI100 can be higher than 20%, which is the suspension level indicated in the EC RP N.162 Publication. This suggests the need of individual calibration of CT X-ray tubes by the manufacturers and the necessity of including this check in the quality control programs for CT.

Dynamics of a broad-band quantum cascade laser: from chaos to coherent dynamics and mode-locking.

The dynamics of a multimode quantum cascade laser, are studied in a model based on effective semiconductor Maxwell-Bloch equations, encompassing key features for the radiation-medium interaction such as an asymmetric frequency dependent gain and refractive index as well as the phase-amplitude coupling provided by the linewidth enhancement factor. By considering its role and that of the free spectral range, we find the conditions in which the traveling wave emitted by the laser at the threshold can be destabilized by adjacent modes, thus leading the laser emission towards chaotic or regular multimode dynamics. In the latter case our simulations show that the field oscillations are associated to self-confined structures which travel along the laser cavity, bridging mode-locking and solitary wave propagation. In addition, we show how a RF modulation of the bias current leads to active mode-locking yielding high-contrast, picosecond pulses. Our results compare well with recent experiments on broad-band THz-QCLs and may help in the understanding of the conditions for the generation of ultrashort pulses and comb operation in mid-IR and THz spectral regions.

Conversion factors of effective and equivalent organ doses with the air kerma area product in patients undergoing coronary angiography and percutaneous coronary interventions.

To derive effective dose (E), organ dose (HT) and conversion factors with the air kerma area product (KAP) in coronary angiography (CA) and percutaneous coronary intervention (PCI) by the radial route, using the ICRP 103 tissue weighting factors. The study included 34 patients referred for CA and 31 for PCI. E and HT were derived from in-the-field KAP measurements using Montecarlo methods. Median KAP of 23.2 and 56.8Gycm2 and E of 6.9 and 20.0mSv were found for CA and PCI, respectively. Mean KAP and E were significantly higher in males than in females (52.4±40.0 vs 32.3±16.6Gycm2; p=0.02) and (16.8±13.6 vs 10.7±5.8mSv; p=0.04). KAP (r=0.39; p=0.001) and E (r=0.34; p=0.005) showed a significant correlation with the patient's weight. Conversion factors between KAP and E (E/KAP) were 0.30±0.04mSvGy-1cm-2 for CA and 0.33±0.05mSvGy-1cm-2 for PCI. No significant differences in the E/KAP between males and females were found (0.31±0.05 vs 0.33±0.05; p=0.08). Again, no significant correlation was found between E/KAP and patient's weight (r=0.23; p=0.07). The correlation between E and KAP was excellent for CA (r=0.99) and PCI (r=0.96). The correlation between HT and KAP ranged from r=0.87 to r=1 and from r=0.71 to r=0.98 for CA and PCI, respectively. A single factor, the total KAP, could be used for a specific acquisition protocol to reliably estimate E and HT without the need of a patient's specific analysis. Conversion factors might be installation, X-ray beam quality or protocol dependent.

Nutrition in the first 1000 days and respiratory health: A descriptive review of the last five years’ literature

The aim of this paper is to discuss the current evidence regarding short and long-term health respiratory effects of nutrients and dietary patterns during the first 1000 days from conception. Population of interest included children from birth to two years and their mothers (during pregnancy and lactation). Studies were searched on MEDLINE(R) and Cochrane database, inserting individually and using the Boolean ANDs and ORs, ‘nutrients’, ‘micronutrients’, ‘LC-PUFA’, ‘Mediterranean Diet’, ‘human milk’, ‘complementary food’, ‘pregnancy’, ‘respiratory disease’, ‘pulmonary disease’, ‘asthma’, ‘epigenetics’, ‘first 1000 days’, ‘maternal diet’ and ‘respiratory health’. All sources were retrieved between 01-09-2015 and 07-12-2016. While unhealthy maternal dietary patterns (high fat intake) during pregnancy can result in alteration of foetal lung development, with increased risk of respiratory disorders, Mediterranean diet has been associated with a lower risk of allergic sensitisation and allergic rhinitis. Breastfeeding has beneficial effects on respiratory infections while evidences about its protective effect on allergic disorders are unclear. During complementary feeding there is no evidence to avoid or encourage exposition to ‘highly allergenic’ foods to have modification of tolerance development. In children from birth to two years of age, Mediterranean diet has been associated with a lower risk of atopy, wheezing and asthma. Micronutrients, antioxidant and LCPUFA supplementation is not recommended and a whole food approach should be preferred, except for Vitamin D (AU)

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Nutrition in the first 1000 days and respiratory health: A descriptive review of the last five years' literature.

The aim of this paper is to discuss the current evidence regarding short and long-term health respiratory effects of nutrients and dietary patterns during the first 1000 days from conception. Population of interest included children from birth to two years and their mothers (during pregnancy and lactation). Studies were searched on MEDLINE® and Cochrane database, inserting individually and using the Boolean ANDs and ORs, 'nutrients', 'micronutrients', 'LC-PUFA', 'Mediterranean Diet', 'human milk', 'complementary food', 'pregnancy', 'respiratory disease', 'pulmonary disease', 'asthma', 'epigenetics', 'first 1000 days', 'maternal diet' and 'respiratory health'. All sources were retrieved between 01-09-2015 and 07-12-2016. While unhealthy maternal dietary patterns (high fat intake) during pregnancy can result in alteration of foetal lung development, with increased risk of respiratory disorders, Mediterranean diet has been associated with a lower risk of allergic sensitisation and allergic rhinitis. Breastfeeding has beneficial effects on respiratory infections while evidences about its protective effect on allergic disorders are unclear. During complementary feeding there is no evidence to avoid or encourage exposition to 'highly allergenic' foods to have modification of tolerance development. In children from birth to two years of age, Mediterranean diet has been associated with a lower risk of atopy, wheezing and asthma. Micronutrients, antioxidant and LCPUFA supplementation is not recommended and a whole food approach should be preferred, except for Vitamin D.

Modulating risky decision-making in Parkinson's disease by transcranial direct current stimulation.

BACKGROUND AND PURPOSE: Performance on gambling tasks in Parkinson's disease (PD) is of particular interest, as pathological gambling is often associated with dopamine replacement therapy in these patients. We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC) in modulating gambling behaviour in PD. METHODS: We assessed the effects of cathodal tDCS over the right DLPFC during the Iowa Gambling Task in 20 patients with PD, compared with sham stimulation. We then conducted a second experimental design, assessing the effects of anodal tDCS over the right DLPFC. RESULTS: We observed that cathodal tDCS over the right DLPFC increased Iowa Gambling Task scores compared with sham stimulation. In the second experimental design, we did not find significant differences between anodal and sham tDCS. CONCLUSIONS: Cathodal tDCS over the right DLPFC possibly reduces the pathological overdrive in frontostriatal networks in patients with PD on dopaminergic medication, thus modulating impulsive and risky decision-making.

Hepatitis E Virus (Genotype 3) in Slurry Samples from Swine Farming Activities in Italy.

Hepatitis E virus (HEV) is an emergent causative agent of acute hepatitis, transmitted by fecal-oral route. Infection with HEV is a global cause for morbidity and mortality throughout the world: it mainly causes large outbreaks in endemic areas and sporadic autochthonous cases in industrialized countries where HEV infections seem to be an emergent zoonotic disease. Infection of porcine livestock and its relationship with the human cases have been demonstrated. The present study describes an investigation on the prevalence and diversity of HEV in pig slurry in Italy. Slurry samples (24) were collected from ten farms located in North Italy during 2015 and analyzed for HEV, using four broad-range nested PCR assays targeting ORF1 (MTase), ORF2 (capsid) genes, and ORF2/3 regions. Overall, 18 samples (75%) were positive for HEV RNA, and characterized as genotype 3. Nine samples could be subtyped by ORF2 sequencing: Eight belonged to subtype 3f, while one sequence could not be characterized by blast analysis and phylogenetic analysis and may actually represent a new subtype. Furthermore, similarity of 99% was found between 3f Italian HEV sequences of human and swine origins. Real-Time PCR assay was also performed, in order to obtain quantitative data on positive samples. Two swine slurry samples were positive, containing 600 and 1000 UI per mL of sewage. The results of this study show that HEV strains belonging to zoonotic genotype 3 are widely present in swine excreta, and have high degree of identity with strains detected in autochthonous HEV cases. Improving swine farming operations safety and increasing operators' awareness of the zoonotic potential connected with the handling of swine effluents turn out to be key points in order to reduce the environmental and sanitary problem represented by the possible dissemination of HEV to water bodies.

Quality of life in patients treated by adjuvant radiotherapy for endometrial and cervical cancers: correlation with dose-volume parameters

Introduction: Modern multidisciplinary cancer treatments aim at obtaining minimal influence on patients’ quality of life (QoL). The purpose of this study was to assess QoL and correlate it with dose-volume parameters of organ at risks (OARs) in patients who received adjuvant radiotherapy for endometrial and cervical cancers. Materials and methods: We administered the EORTC QLQ-C30 and EN24 or CX24 questionnaires to 124 patients, 100 with endometrial cancer and 24 with cervical cancer treated with postoperative radiotherapy ± chemotherapy in regular follow-up. Bladder function, fecal incontinence or urgency and sexual functioning were investigated and correlated with dose-volume parameters of OAR by multiple linear regression analysis. This correlation was assessed by R2 value. Results: QoL was very high in the majority of patients (82.3 % of patients). Few patients referred urinary incontinence (3.2 %) or abdominal discomfort of high grade (4.0 %). We found a significant correlation between bladder V40, i.e., absolute percentage of bladder volume that received a dose of 40 Gy, and global health status (p < 0.05, R 2 = 0.17), urinary urgency (p < 0.05, R 2 = 0.24), urinary incontinence (p < 0.05, R 2 = 0.23) and dyspareunia (p < 0.05, R 2 = 0.04). We found also a correlation between global health status and mean dose to vagina (p < 0.05, R 2 = 0.17) and between maximum dose to lumbo-sacral plexus and abdominal pain (p < 0.05, R 2 = 0.07). Conclusions: Women treated with surgery and adjuvant radiotherapy for endometrial and cervical cancers have good QoL with minimal limitations of daily activities. QoL was correlated with dose-volume parameters such as bladder V40, mean dose to vagina, maximum dose to trigone and LSP

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Human skin-derived fibroblasts used as a 'Trojan horse' for drug delivery.

BACKGROUND: Drug toxicity currently represents the main challenge of tumour chemotherapy. Our group recently developed a new method for drug delivery inspired by the 'Trojan Horse' concept. Human mesenchymal stem cells (hMSCs) have been shown to play the role of new 'horses' in delivering anti-tumour agents, without involving any genetic manipulation. As human stromal dermal fibroblasts (hSDFs) represent an interesting alternative to hMSCs, being easy to isolate, they could be an ideal candidate for this kind of procedure. AIM: To investigate whether hSDFs can take up and deliver paclitaxel (PTX) in sufficient concentrations to inhibit a very aggressive melanoma tumour (IgR39) in vitro. METHODS: hSDFs were primed with high doses of PTX, and then the effect of drug delivery on IgR39 melanoma proliferation in vitro was evaluated using several assays (antiproliferation, transwell cocultures, rosette assays and colony growth assays). Furthermore, the cell cycle and PTX uptake/release mechanism of hSDFs were studied both under both normal and hypoxic conditions. RESULTS: hSDFs incorporated PTX and then released it with unaffected pharmacological activity, inhibiting human IgR39 melanoma growth in vitro. The hypoxic conditions did not induce changes in cell cycle pattern and the uptake-release mechanism with PTX was not affected. CONCLUSIONS: hSDFs can be used as a Trojan horse, as the released drug was functionally active. These results indicated that these cells could be used for clinical treatment as the drug was released into the cellular environment and the primed cells underwent apoptosis.