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Background : Nowadays, thanks to the introduction of the VI-RADS scoring system, mpMRI has shown promising results in pre-TURBT assessment of muscular invasiveness of BCa, even if its application in everyday practice is still limited. This might be due to a lack in the literature about the learning curve of radiologists and about the characteristics of the exam. With the aim to reduce scan time and patient discomfort while maintaining diagnostic accuracy, bpMRI has been introduced as a possible alternative to mpMRI in this group of patients. This study reports a single-center experience using mpMRI and the VI-RADS scoring system to differentiate NMIBC from MIBC. The primary aim of the study is to assess diagnostic accuracy of mpMRI using the VI-RADS scoring system. The secondary aim is to evaluate the learning curve of an experienced mpMRI radiologist. Additionally, we perform a retrospective assessment of the same group of patients evaluating only DWIs and T2-weighted images, as they underwent bpMRI, to compare the performance of mpMRI and bpMRI. Materials and Methods: From 11/2021 to 11/2023, patients with suspected newly diagnosed BCa were enrolled in this prospective study. All patients underwent mpMRI prior to TURBT in a highly specialized radiology center for MRI. According to VI-RADS, a cutoff of ≥3 was assumed to define MIBC. Histological TURBT reports were compared with preoperative VI-RADS scores to assess the accuracy of mpMRI in discriminating between NMIBC and MIBC. Furthermore, to assess the learning curve of the reading radiologist we analyzed the rate of patients correctly classified as MIBC at MRI. Finally, we evaluated the performance of a hypothetic biparametric MRI in classifying our cohort according to VI-RADS score and compared it with mpMRI performance by using DeLong's test. Data analysis was performed using Jamovi software v.2.3 and R software v.4.2.1. Results: A total of 133 patients were enrolled. mpMRI showed sensitivity and specificity of 86% (95% confidence interval [CI]: 64-97) and 95% (95% CI: 89-98), respectively. The learning curve analysis of the reading radiologist showed that the rate of patients correctly classified as MIBC rapidly increases reaching its plateau after 40 cases. The hypothetic bpMRI showed a sensitivity of 76% (95% CI: 53-92) and a specificity of 93% (95% CI: 86-97), with no significant difference with mpMRI performance ( p = 0.10). Conclusions: Our study confirms the effectiveness of MRI, particularly with the VI-RADS scoring system, in differentiating NMIBC from MIBC. The learning curve analysis underscores the importance of radiologist training in optimizing diagnostic accuracy. Future research should focus on enhancing the sensitivity of bpMRI and further validating these findings in larger and multicentric studies.

Background: For many tumors, radiomics provided a relevant prognostic contribution. This study tested whether the computed tomography (CT)-based textural features of intrahepatic cholangiocarcinoma (ICC) and peritumoral tissue improve the prediction of survival after resection compared with the standard clinical indices., Methods: All consecutive patients affected by ICC who underwent hepatectomy at six high-volume centers (2009-2019) were considered for the study. The arterial and portal phases of CT performed fewer than 60 days before surgery were analyzed. A manual segmentation of the tumor was performed (Tumor-VOI). A 5-mm volume expansion then was applied to identify the peritumoral tissue (Margin-VOI)., Results: The study enrolled 215 patients. After a median follow-up period of 28 months, the overall survival (OS) rate was 57.0%, and the progression-free survival (PFS) rate was 34.9% at 3 years. The clinical predictive model of OS had a C-index of 0.681. The addition of radiomic features led to a progressive improvement of performances (C-index of 0.71, including the portal Tumor-VOI, C-index of 0.752 including the portal Tumor- and Margin-VOI, C-index of 0.764, including all VOIs of the portal and arterial phases). The latter model combined clinical variables (CA19-9 and tumor pattern), tumor indices (density, homogeneity), margin data (kurtosis, compacity, shape), and GLRLM indices. The model had performance equivalent to that of the postoperative clinical model including the pathology data (C-index of 0.765). The same results were observed for PFS., Conclusions: The radiomics of ICC and peritumoral tissue extracted from preoperative CT improves the prediction of survival. Both the portal and arterial phases should be considered. Radiomic and clinical data are complementary and achieve a preoperative estimation of prognosis equivalent to that achieved in the postoperative setting., (© 2024. Society of Surgical Oncology.)

Apical hypertrophic cardiomyopathy (ApHCM) is an HCM variant, affecting frequently males in midlife. It is characterized by apical obliteration and persistent diastolic contraction, often resulting in microvascular ischaemia. We report five cases of ApHCM, with evidence of intramyocardial calcification on echocardiogram. On cardiac magnetic imaging (MRI), a hypointense component at early gadolinium enhancement (EGE) sequences, compatible with calcium, and a deep layer, with hyperintensity at late gadolinium enhancement (LGE) sequences, referable to fibrosis, suggest an endomyocardial fibrosis (EMF) diagnosis. EMF pathologic hallmark is endocardium and myocardium scarring, evolving to dystrophic calcification. It is found only in few ApHCM patients. Our series is the largest one described until now. Analysing patients' history, coexistent inflammatory triggers were evident in all of them, so their co-morbidities could represent a further cause of small vessel disease, in the context of ischaemic microvascular stress due to hypertrophy, leading to fibrosis and dystrophic calcification. This series could demonstrate the relation between apical fibrosis/calcification and microvascular ischaemia due to hypertrophy and inflammatory triggers., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Recurrence, even after years from the last treatment, characterizes lymphoproliferative disorders. Therefore, patients in complete remission from the disease should be followed up with periodic clinical checks. There is not a consensus on the role of imaging for this aim, because the radiological techniques used at the time of diagnosis expose patients to a risk of ionizing radiation damage. Whole-body magnetic resonance imaging with diffusion-weighted imaging (WB-MRI-DWI) has given similar results to gold standard techniques in detecting lymphoma in the involved sites without ionizing radiation. In this retrospective real-life study, we aimed to assess the accuracy of WB-MRI-DWI during follow-ups of lymphoma patients in terms of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Methods : Lymphoma patients who were subject to at least one WB-MRI-DWI during follow-up between February 2010 and February 2022 were enrolled. Results : Based on our investigation, the calculated sensitivity of WB-MRI-DWI was 100% (95% CI: 99.4-100.0), the specificity was 98.6% (95% CI: 97.4-99.3), PPV was 79% (95% CI: 75.9-81.9), and NPV was 100% (95% CI: 99.4-100.0). Conclusions : Despite the possibility of poor patient compliance and the identification of false positives, WB-MRI-DWI examination demonstrated an excellent sensitivity in ruling out the disease relapse.

Designed peptides are promising biomaterials for biomedical applications. The amphiphilic cationic antimicrobial peptide (AMP), A 9 K, can self-assemble into nano-rod structures and has shown cancer cell selectivity and could therefore be a promising candidate for therapeutic delivery into cancer cells. In this paper, we investigate the selectivity of A 9 K for cancer cell models, examining its effect on two human cancer cell lines, A431 and HCT-116. Little or no activity was observed on the control, human dermal fibroblasts (HDFs). In the cancer cell lines the peptide inhibited cellular growth through changes in mitochondrial morphology and membrane potential while remaining harmless towards HDFs. In addition, the peptide can bind to and protect nucleic acids while transporting them into both 2D cultures and 3D spheroids of cancer cells. A 9 K showed high efficiency in delivering siRNA molecules into the centre of the spheroids. A 9 K was also explored in vivo, using a zebrafish (Danio rerio) development toxicity assay, showing that the peptide is safe at low doses. Finally, a high-content imaging screen, using RNA interference (RNAi) targeted towards cellular uptake, in HCT-116 cells was carried out. Our findings suggest that active cellular uptake is involved in peptide internalisation, mediated through clathrin-mediated endocytosis. These new discoveries make A 9 K attractive for future developments in clinical and biotechnological applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Open partial horizontal laryngectomies (OPHLs) represent a valuable therapeutic option for tumors of the intermediate T-category and, in selected cases, for locally advanced tumors with low-volume extra-laryngeal extension. The eligibility of patients treated with this type of surgery has increased with the introduction of the modular approach to OPHL planning. This strategy follows the introduction of the classification proposed by the European Laryngological Society, based on the extent of horizontal resection. Optimization of the selection is the result of a meticulous work-up process involving close cooperation between experienced surgeons and radiologists, followed by final quality control by pathologists. Computed tomography and magnetic resonance imaging are study methods whose pearls and pitfalls are well known, especially when performed at a high level of expertise. In this paper, based on the experience of two high-volume centers, a checklist of 20 questions addressed by the surgeon to the radiologist before planning an OPHL was proposed. Considerations regarding case selection are reported for each of the questioned parameters. A very simple question-and-answer process is easy to understand and mainly addressed by less experienced colleagues who wish to increase their knowledge and skills in performing this type of surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RS declared a past collaboration with the author CP to the handling editor., (Copyright © 2024 Crosetti, Succo, Sapino, Bertotto, Cirillo, Petracchini, Fondello, Arrigoni, Tascone, Piazza, Farina and Ravanelli.)

Standard imaging cannot assess the pathology details of intrahepatic cholangiocarcinoma (ICC). We investigated whether CT-based radiomics may improve the prediction of tumor characteristics. All consecutive patients undergoing liver resection for ICC (2009-2019) in six high-volume centers were evaluated for inclusion. On the preoperative CT, we segmented the ICC (Tumor-VOI, i.e., volume-of-interest) and a 5-mm parenchyma rim around the tumor (Margin-VOI). We considered two types of pathology data: tumor grading (G) and microvascular invasion (MVI). The predictive models were internally validated. Overall, 244 patients were analyzed: 82 (34%) had G3 tumors and 139 (57%) had MVI. For G3 prediction, the clinical model had an AUC = 0.69 and an Accuracy = 0.68 at internal cross-validation. The addition of radiomic features extracted from the portal phase of CT improved the model performance (Clinical data+Tumor-VOI: AUC = 0.73/Accuracy = 0.72; +Tumor-/Margin-VOI: AUC = 0.77/Accuracy = 0.77). Also for MVI prediction, the addition of portal phase radiomics improved the model performance (Clinical data: AUC = 0.75/Accuracy = 0.70; +Tumor-VOI: AUC = 0.82/Accuracy = 0.73; +Tumor-/Margin-VOI: AUC = 0.82/Accuracy = 0.75). The permutation tests confirmed that a combined clinical-radiomic model outperforms a purely clinical one ( p < 0.05). The addition of the textural features extracted from the arterial phase had no impact. In conclusion, the radiomic features of the tumor and peritumoral tissue extracted from the portal phase of preoperative CT improve the prediction of ICC grading and MVI.

Background: Arthrogryposis multiplex congenita is a rare condition that mainly involves the lower limbs, characterized by severe joint deformity and contracture, muscular atrophy, and functional impairment. Its clinical manifestations are heterogenous and may involve the maxillofacial district as well., Case Presentation: This case report describes a 20-year-old patient with arthrogryposis multiplex congenita with skeletal crossbite, facial asymmetry, reduced mouth opening and absence of lateral mandibular movement on the left side. After clinical evaluation, the following exams were required: postero-anterior cephalometric tracing, head and neck electromyography, computerized axiography, computed tomography scan, and maxillofacial magnetic resonance imaging. Orthognathodontic evaluation indicated skeletal asymmetry, reduced condylar movements on the left side and abnormally low electromyography activity of the masticatory muscles on the left side. Computed tomography and magnetic resonance imaging revealed unilateral left mandibular hypoplasia, hypotrophy, and fatty infiltration of masticatory muscles on the left side, as well as immobility of the left condyle during mouth opening, and hypoplasia of the left articular disk, which was however not displaced. Surgery was not indicated and conservative orthognathodontic treatment with function generating bite was suggested to balance the occlusal plane, as well as stretching exercises., Conclusions: A rare case of arthrogryposis multiplex congenita with maxillofacial involvement illustrates that a patient-centred, multidisciplinary approach with accurate diagnosis is required to formulate the best treatment plan. Because of the considerable damage to the masticatory muscles, conservative orthognathodontic therapy may be the best treatment option., (© 2023. The Author(s).)

Task-based functional MRI (tb-fMRI) represents an extremely valuable approach for the identification of language eloquent regions for presurgical mapping in patients with brain tumors. However, its routinely application is limited by patient-related factors, such as cognitive disability and difficulty in coping with long-time acquisitions, and by technical factors, such as lack of equipment availability for stimuli delivery. Resting-state fMRI (rs-fMRI) instead, allows the identification of distinct language networks in a 10-min acquisition without the need of performing active tasks and using specific equipment. Therefore, to test the feasibility of rs-fMRI as a preoperative mapping tool, we reconstructed a lexico-semantic intrinsic connectivity network (ICN) in healthy controls (HC) and in a case series of patients with gliomas and compared the organization of this language network with the one derived from tb-fMRI in the patient's group. We studied three patients with extra-frontal gliomas who underwent functional mapping with auditory verb-generation (AVG) task and rs-fMRI with a seed in the left inferior frontal gyrus (IFG). First, we identified the functional connected areas to the IFG in HC. We qualitatively compared these areas with those that showed functional activation in AVG task derived from Neurosynth meta-analysis. Last, in each patient we performed single-subject analyses both for rs- and tb-fMRI, and we evaluated the spatial overlap between the two approaches. In HC, the IFG-ICN network showed a predominant left fronto-temporal functional connectivity in regions overlapping with the AVG network derived from a meta-analysis. In two patients, rs- and tb-fMRI showed comparable patterns of activation in left fronto-temporal regions, with different levels of contralateral activations. The third patient could not accomplish the AVG task and thus it was not possible to make any comparison with the ICN. However, in this patient, task-free approach disclosed a consistent network of fronto-temporal regions as in HC, and additional parietal regions. Our preliminary findings support the value of rs-fMRI approach for presurgical mapping, particularly for identifying left fronto-temporal core language-related areas in glioma patients. In a preoperative setting, rs-fMRI approach could represent a powerful tool for the identification of eloquent language areas, especially in patients with language or cognitive impairments., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Modeling discussions on social networks is a challenging task, especially if we consider sensitive topics, such as politics or healthcare. However, the knowledge hidden in these debates helps to investigate trends and opinions and to identify the cohesion of users when they deal with a specific topic. To this end, we propose a general multilayer network approach to investigate discussions on a social network. In order to prove the validity of our model, we apply it on a Twitter dataset containing tweets concerning opinions on COVID-19 vaccines. We extract a set of relevant hashtags (i.e., gold-standard hashtags) for each line of thought (i.e., pro-vaxxer, neutral, and anti-vaxxer). Then, thanks to our multilayer network model, we figure out that the anti-vaxxers tend to have ego networks denser (+14.39%) and more cohesive (+64.2%) than the ones of pro-vaxxer, which leads to a higher number of interactions among anti-vaxxers than pro-vaxxers (+393.89%). Finally, we report a comparison between our approach and one based on single networks analysis. We prove the effectiveness of our model to extract influencers having ego networks with more nodes (+40.46%), edges (+39.36%), and interactions with their neighbors (+28.56%) with respect to the other approach. As a result, these influential users are much more important to analyze and can provide more valuable information., (© 2022 Elsevier Ltd. All rights reserved.)

Objective: To investigate the diagnostic accuracy of the PI-RADS v2.1 multiparametric magnetic resonance imaging (mpMRI) features in predicting extraprostatic extension (mEPE) of prostate cancer (PCa), as well as to develop and validate a comprehensive mpMRI-derived score (mEPE-score)., Methods: We retrospectively reviewed all consecutive patients admitted to two institutions for radical prostatectomy for PCa with available records of mpMRI performed between January 2015 and December 2020. Data from one institution was used for investigating diagnostic performance of each mEPE feature using radical prostatectomy specimens as benchmark. The results were implemented in a mEPE-score as follows: no mEPE features: 1; capsular abutment: 2; irregular or spiculated margin: 3; bulging prostatic contour, or asymmetry of the neurovascular bundles, or tumor-capsule interface > 1.0 cm: 4; ≥ 2 of the previous three parameters or measurable extraprostatic disease: 5. The performance of mEPE features was evaluated using the five diagnostic parameters and ROC curve analysis., Results: Two-hundred patients were enrolled at site 1 and 76 at site 2. mEPE features had poor sensitivities ranging from 0.08 (0.00-0.15) to 0.71 (0.59-0.83), whereas specificity ranged from 0.68 (0.58-0.79) to 1.00. mEPE-score showed excellent discriminating ability (AUC > 0.8) and sensitivity = 0.82 and specificity = 0.77 with a threshold of 3. mEPE-score had AUC comparable to ESUR-score (p = 0.59 internal validation; p = 0.82 external validation), higher than or comparable to mEPE-grade (p = 0.04 internal validation; p = 0.58 external validation), and higher than early-and-late-EPE (p < 0.0001 internal and external validation). There were no significant differences between readers having different expertise with EPE-score (p = 0.32) or mEPE-grade (p = 0.45), but there were significant differences for ESUR-score (p = 0.02) and early-versus-late-EPE (p = 0.03)., Conclusions: The individual mEPE features have low sensitivity and high specificity. The use of mEPE-score allows for consistent and reliable assessment for pathologic EPE., Key Points: • Individual PI-RADS v2.1 mpMRI features had poor sensitivities ranging from 0.08 (0.00-0.15) to 0.71 (0.59-0.83), whereas Sp ranged from 0.68 (0.58-0.79) to 1.00. • mEPE-score is an all-inclusive score for the assessment of pEPE with excellent discriminating ability (i.e., AUC > 0.8) and Se = 0.82, Sp = 0.77, PPV = 0.74, and NPV = 0.84 with a threshold of 3. • The diagnostic performance of the expert reader and beginner reader with pEPE-score was comparable (p = 0.32)., (© 2022. The Author(s).)

Background: Pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer (LARC) is achieved in 15-30% of cases. Our aim was to implement and externally validate a magnetic resonance imaging (MRI)-based radiomics pipeline to predict response to treatment and to investigate the impact of manual and automatic segmentations on the radiomics models., Methods: Ninety-five patients with stage II/III LARC who underwent multiparametric MRI before chemoradiotherapy and surgical treatment were enrolled from three institutions. Patients were classified as responders if tumour regression grade was 1 or 2 and nonresponders otherwise. Sixty-seven patients composed the construction dataset, while 28 the external validation. Tumour volumes were manually and automatically segmented using a U-net algorithm. Three approaches for feature selection were tested and combined with four machine learning classifiers., Results: Using manual segmentation, the best result reached an accuracy of 68% on the validation set, with sensitivity 60%, specificity 77%, negative predictive value (NPV) 63%, and positive predictive value (PPV) 75%. The automatic segmentation achieved an accuracy of 75% on the validation set, with sensitivity 80%, specificity 69%, and both NPV and PPV 75%. Sensitivity and NPV on the validation set were significantly higher (p = 0.047) for the automatic versus manual segmentation., Conclusion: Our study showed that radiomics models can pave the way to help clinicians in the prediction of tumour response to chemoradiotherapy of LARC and to personalise per-patient treatment. The results from the external validation dataset are promising for further research into radiomics approaches using both manual and automatic segmentations., (© 2022. The Author(s) under exclusive licence to European Society of Radiology.)

Background and Objectives: Chemotherapy in locally advanced rectal cancer (LARC) is shifting from an adjuvant setting to a total neoadjuvant therapy (TNT) strategy, that relies on distant metastases (DM) risk prediction. This study aims to assess the accuracy of magnetic resonance imaging-detected extramural vascular invasion (mrEMVI) as predictive factor for DM in LARC, compared with other MRI-detected and pathologic factors., Methods: This retrospective single-center study analyzed data extracted from a series of consecutive patients curatively resected for rectal cancer at Mauriziano Hospital in Turin (Italy) from January 2013 to December 2018., Results: Data from 69 patients were analyzed. MrEMVI was detected in 31 (44.9%) cases. Median follow-up was 39.9 months. DM and local recurrence occurred in 19 (27.5%) and 4 (5.8%) patients. One- and 3-year cumulative incidence of DM were 32.3% (95% confidence interval [CI]: 0.17-0.49) and 56.8% (95% CI: 0.35-0.74) in the mrEMVI-positive group and 5.4% (95% CI: 0.01-0.16) and 14.0% (95% CI: 0.05-0.27) in the mrEMVI-negative group (log-rank test, p < 0.001). In the multivariate analysis of MRI factors, mrEMVI was the only independent predictor of DM (HR: 3.59, CI: 1.21-10.69, p = 0.02)., Conclusions: This study confirmed that mrEMVI is a powerful predictor of DM in LARC. It should be routinely reported and considered during multidisciplinary care strategy planning., (© 2022 Wiley Periodicals LLC.)

Epithelial cells migrate across wounds to repair injured tissue. Leader cells at the front of migrating sheets often drive this process. However, it is unclear how leaders emerge from an apparently homogeneous epithelial cell population. We characterized leaders emerging from epithelial monolayers in cell culture and found that they activated the stress sensor p53, which was sufficient to initiate leader cell behavior. p53 activated the cell cycle inhibitor p21 WAF1/CIP1 , which in turn induced leader behavior through inhibition of cyclin-dependent kinase activity. p53 also induced crowding hypersensitivity in leader cells such that, upon epithelial closure, they were eliminated by cell competition. Thus, mechanically induced p53 directs emergence of a transient population of leader cells that drive migration and ensures their clearance upon epithelial repair.

Introduction: Recently, the Food and Drug Administration authorized the marketing of IQOS Tobacco Heating System as a Modified Risk Tobacco Product based on an electronic heat-not-burn technology that purports to reduce the risk., Methods: Sprague-Dawley rats were exposed in a whole-body mode to IQOS aerosol for 4 weeks. We performed the chemical characterization of IQOS mainstream and we studied the ultrastructural changes in trachea and lung parenchyma of rats exposed to IQOS stick mainstream and tissue pro-inflammatory markers. We investigated the reactive oxygen species amount along with the markers of tissue and DNA oxidative damage. Moreover, we tested the putative genotoxicity of IQOS mainstream through Ames and alkaline Comet mutagenicity assays., Results: Here, we identified irritating and carcinogenic compounds including aldehydes and polycyclic aromatic hydrocarbons in the IQOS mainstream as sign of incomplete combustion and degradation of tobacco, that lead to severe remodelling of smaller and largest rat airways. We demonstrated that IQOS mainstream induces lung enzymes that activate carcinogens, increases tissue reactive radical concentration; promotes oxidative DNA breaks and gene level DNA damage; and stimulates mitogen activated protein kinase pathway which is involved in the conventional tobacco smoke-induced cancer progression., Conclusions: Collectively, our findings reveal that IQOS causes grave lung damage and promotes factors that increase cancer risk., Implications: IQOS has been proposed as a safer alternative to conventional cigarettes, due to depressed concentration of various harmful constituents typical of traditional tobacco smoke. However, its lower health risks to consumers have yet to be determined. Our findings confirm that IQOS mainstream contains pyrolysis and thermogenic degradation by-products, the same harmful constituents of traditional cigarette smoke, and, for the first time, we show that it causes grave lung damage and promotes factors that increase cancer risk in the animal model., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Antimicrobial/anticancer peptides (AMPs/ACPs) have shown promising results as new therapeutic agents in cancer thearpy. Among them, the designed amphiphilic α-helical peptide G(IIKK) 3 I-NH 2 (G3) displayed great affinity and specificity in targeting cancer cells. Here, we report new insights on how G3 penetrates cancer cells. G3 showed high specificity to HCT-116 colon cancer cells compared to the HDFs (human neonatal primary dermal fibroblasts) control. With high concentrations of peptide, a clear cancer cell membrane disruption was observed through SEM. Gene knockdown of the endocytic pathways demonstrated that an energy-dependent endocytic pathway is required for the uptake of the peptide. In addition, G3 can protect and selectively deliver siRNAs into cancer cells and successfully modulated their gene expression. Gene delivery was also tested in 3D cancer spheroids and showed deep penetration delivery into the cancer spheroids. Finally, the in vivo toxicity of G3 was evaluated on zebrafish embryos, showing an increasing toxicity effect with concentration. However, the toxicity of the peptide was attenuated when complexed with siRNA. In addition, negligible toxicity was observed at the concentration range for efficient gene delivery. The current results demonstrate that G3 is promising as an excellent agent for cancer therapy.

Objectives: To build a machine learning (ML) model to detect extraprostatic extension (EPE) of prostate cancer (PCa), based on radiomics features extracted from prostate MRI index lesions., Methods: Consecutive MRI exams of patients undergoing radical prostatectomy for PCa were retrospectively collected from three institutions. Axial T2-weighted and apparent diffusion coefficient map images were annotated to obtain index lesion volumes of interest for radiomics feature extraction. Data from one institution was used for training, feature selection (using reproducibility, variance and pairwise correlation analyses, and a correlation-based subset evaluator), and tuning of a support vector machine (SVM) algorithm, with stratified 10-fold cross-validation. The model was tested on the two remaining institutions' data and compared with a baseline reference and expert radiologist assessment of EPE., Results: In total, 193 patients were included. From an initial dataset of 2436 features, 2287 were excluded due to either poor stability, low variance, or high collinearity. Among the remaining, 14 features were used to train the ML model, which reached an overall accuracy of 83% in the training set. In the two external test sets, the SVM achieved an accuracy of 79% and 74% respectively, not statistically different from that of the radiologist (81-83%, p = 0.39-1) and outperforming the baseline reference (p = 0.001-0.02)., Conclusions: A ML model solely based on radiomics features demonstrated high accuracy for EPE detection and good generalizability in a multicenter setting. Paired to qualitative EPE assessment, this approach could aid radiologists in this challenging task., Key Points: • Predicting the presence of EPE in prostate cancer patients is a challenging task for radiologists. • A support vector machine algorithm achieved high diagnostic accuracy for EPE detection, with good generalizability when tested on multiple external datasets. • The performance of the algorithm was not significantly different from that of an experienced radiologist., (© 2021. The Author(s).)

Background: Endovascular aneurysm sealing (EVAS) is an innovative alternative to conventional endovascular aneurysm repair (EVAR). EVAS relies on sac anchoring without proximal fixation to achieve sealing and should have allowed for the treatment of a broader range of anatomic features compared with standard EVAR. Despite the encouraging early reports, the mid- and long-term follow-up data have shown increased rates of failure. To address the issue, the manufacturer introduced revised instructions for use (IFU) in 2016. The present study reports the outcomes of this system after a median follow-up of 45 months., Methods: Data for all patients electively treated with EVAS at our institution were retrospectively collected. The patients were retrospectively reclassified according to the 2016 revised IFU of the device. All patients in the present series had undergone EVAS for the treatment of infrarenal abdominal aortic aneurysms (AAAs). The primary end point was therapeutic failure: graft migration >5 mm, sac expansion >5 mm, type IA endoleak (Is2 and Is3 using the Van den Ham classification), type Ib endoleak, and secondary rupture. The overall mortality, aortic-related mortality, and reintervention rates were also analyzed., Results: A total of 101 patients had undergone elective treatment by EVAS from 2013 to 2018 for infrarenal AAAs. The median follow-up was 3.75 years. Therapeutic failure was observed in 31 of the 101 patients (30.7%), with no significant difference between the in-IFU and off-IFU 2016 subgroups. Failure occurred at a median interval of 34 months from the index procedure. Of the 101 patients, 6.9% had presented with secondary rupture. Freedom from aneurysm-related mortality was 96.9% at 1 and 2 years and 89.9% at 5 years. Freedom from reintervention decreased over time: 94.7% at 1 year, 77% at 4 years, and 52.1% at 6 years. Of the 101 patients, 14 (13.9%) had undergone emergent or elective graft explantation., Conclusions: EVAS performed worse than conventional endografts for several critical end points, regardless of any preoperative anatomic parameters. The incidence of therapeutic failures tended to increase over time, especially 4 years after the index procedure., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Along-tract statistics analysis enables the extraction of quantitative diffusion metrics along specific white matter fiber tracts. Besides quantitative metrics derived from classical diffusion tensor imaging (DTI), such as fractional anisotropy and diffusivities, new parameters reflecting the relative contribution of different diffusion compartments in the tissue can be estimated through advanced diffusion MRI methods as neurite orientation dispersion and density imaging (NODDI), leading to a more specific microstructural characterization. In this study, we extracted both DTI- and NODDI-derived quantitative microstructural diffusion metrics along the most eloquent fiber tracts in 15 healthy subjects and in 22 patients with brain tumors. We obtained a robust intraprotocol reference database of normative along-tract microstructural metrics, and their corresponding plots, from healthy fiber tracts. Each diffusion metric of individual patient's fiber tract was then plotted and statistically compared to the normative profile of the corresponding metric from the healthy fiber tracts. NODDI-derived metrics appeared to account for the pathological microstructural changes of the peritumoral tissue more accurately than DTI-derived ones. This approach may be useful for future studies that may compare healthy subjects to patients diagnosed with other pathological conditions., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has rapidly spread throughout the world since December 2019 to become a global public health emergency for the elevated deaths and hospitalizations in Intensive Care Units. The severity spectrum of SARS-CoV-2 pneumonia ranges from mild to severe clinical conditions. The clinical course of SARS-CoV-2 disease is correlated with multiple factors including host characteristics (genetics, immune status, age, and general health), viral load and, above all, the host distribution of the airways and lungs of the viral receptor cells. In this review, we will briefly summarize the current knowledge of the characteristics and management of coronavirus disease 2019-pneumonia. However, other studies are needed to better understand the pathogenetic mechanisms induced by SARS-Cov-2 infection, and to evaluate the long-term consequences of the virus on the lungs., (© 2020 Wiley Periodicals LLC.)

Peripheral immune regulation is critical for the maintenance of self-tolerance. Here we have investigated signaling processes that distinguish T cells with regulatory capability from effector T cells. The murine Tg4 T cell receptor recognizes a peptide derived from the self-antigen myelin basic protein. T cells from Tg4 T cell receptor transgenic mice can be used to generate effector T cells and three types of T cells with regulatory capability, inducible regulatory T cells, T cells tolerized by repeated in vivo antigenic peptide exposure or T cells treated with the tolerogenic drug UCB9608 (a phosphatidylinositol 4 kinase IIIβ inhibitor). We comparatively studied signaling in all of these T cells by activating them with the same antigen presenting cells presenting the same myelin basic protein peptide. Supramolecular signaling structures, as efficiently detected by large-scale live cell imaging, are critical mediators of T cell activation. The formation of a supramolecular signaling complex anchored by the adaptor protein linker for activation of T cells (LAT) was consistently terminated more rapidly in Tg4 T cells with regulatory capability. Such termination could be partially reversed by blocking the inhibitory receptors CTLA-4 and PD-1. Our work suggests that attenuation of proximal signaling may favor regulatory over effector function in T cells.

Preterm birth can affect cognitive functions, such as attention or more generally executive control mechanisms, with severity in impairments proportional to prematurity. The functional cross-talk between the Default Mode (DMN) and Executive Control (ECN) networks mirrors the integrity of cognitive processing and is directly related to brain development. In this study, a cohort of 20 preterm-born infants was investigated using rs-fMRI. First, we addressed biological maturity of the DMN per se and its interplay with the ECN in terms of patterns of increased functional connectivity. Second, we assessed the impact of the degree of prematurity on the DMN-ECN functional interplay development in relation to cognitive outcome at six months. Our results highlighted the emergence of DMN in preterm neonates, with connectivity strength and synchronization between the anterior DMN hub and frontal areas increasing as a function of biological maturity. Further, cognitive scores at 6 months were predicted by mPFC-ECN connectivity strength with degree of prematurity impacting on mPFC-ECN connectivity and triggering differential patterns of functional maturation of the ECN for very early/early and moderate/late preterm neonates. Our findings suggest that the prematurity window allows to observe precursors of functional plasticity that may underlie different developmental trajectories in preterm children., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Evaluation of clinical and radiological effects of the therapeutic outcome of CT-guided pulsed radiofrequency (PRF) treatment adjacent to the lumbar dorsal root ganglion (DRG) for patients with chronic intractable lumbosacral radicular pain in a single-center prospective longitudinal study in order to evaluate predictive factors of safety and therapeutic success., Materials and Methods: Thirty patients, from 2016 to 2018, were enrolled (age: 42-80 aa, 66.7% men and 33.3% females) with low back pain, lumbosciatalgia and/or lumbocruralgia, resistant to previous medical and physical treatments for a period not < 3 months, failure of surgical and chemiodiscolysis with ozone oxygen therapy. Each patient was subjected to a clinical evaluation (antalgic walking, sensitive deficit, interviews with specific questionnaires: ODI, RDQ,VAS) and to a radiological evaluation with MRI examination, before and 30 days after the CT-guided PRF treatment. Measurements of the thickness of the involved and not involved DRG were taken using common postprocessing software of MRI examinations in order to have measurement parameters for comparison. We analyzed the clinical course using the paired samples T test in order to evaluate modification for each clinical and radiological parameter (statistical significance p < 0.05)., Results: Significant improvements of the clinical outcomes with a good resolution of the pain symptoms (VAS evaluation: The score fell from 68.47 to 39.17 with a difference of 29.3 and a reduction of the 42.79% in the perceived pain, p = 0.00000152). The thickness of DRG falls from an average media of 0.586-0.448 cm (p = 0.000085), with a difference of 0.138 cm and a percentage reduction of 22.30%., Conclusions: PRF treatment of the DRG may be considered for patients with chronic severe lumbosacral radicular pain refractory to conventional medical management when other noninvasive or surgical procedures fail. It is minimally invasive, inexpensive and simple to perform with no complications.

The killing of tumor cells by CD8 + T cells is suppressed by the tumor microenvironment, and increased expression of inhibitory receptors, including programmed cell death protein-1 (PD-1), is associated with tumor-mediated suppression of T cells. To find cellular defects triggered by tumor exposure and associated PD-1 signaling, we established an ex vivo imaging approach to investigate the response of antigen-specific, activated effector CD8 + tumor-infiltrating lymphocytes (TILs) after interaction with target tumor cells. Although TIL-tumor cell couples readily formed, couple stability deteriorated within minutes. This was associated with impaired F-actin clearing from the center of the cellular interface, reduced Ca 2+ signaling, increased TIL locomotion, and impaired tumor cell killing. The interaction of CD8 + T lymphocytes with tumor cell spheroids in vitro induced a similar phenotype, supporting a critical role of direct T cell-tumor cell contact. Diminished engagement of PD-1 within the tumor, but not acute ex vivo blockade, partially restored cell couple maintenance and killing. PD-1 thus contributes to the suppression of TIL function by inducing a state of impaired subcellular organization., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: To compare morphologic findings in MRI and skeletal divergence of a group of patients with temporomandibular joint disorders (TMD) subdivided into condylar symmetric and asymmetric., Methods: Fifty-nine adults (26.7 years old) with TMD were retrospectively recruited. Condylar height symmetry was evaluated by orthopantomography (Habets's method) and used to divide patients into Symmetric and Asymmetric groups; skeletal divergence was assessed on lateral cephalograms. MRI was used to evaluate the condylar long axis' angle, the glenoid fossa morphology, and the degree of disc displacement., Results: Asymmetric subjects showed a hyperdivergent skeletal pattern ( p  = 0.036), asymmetric condylar long axis ( p  = 0.018), and deeper ( p  = 0.025) and asymmetric ( p  = 0.001) glenoid fossa compared to symmetric subjects., Conclusion: Patients with TMD and condylar asymmetry diagnosed with orthopantomography are more likely to show hyperdivergent skull in cephalometry, condylar asymmetry of both height and major axis, and a steeper glenoid fossa in MRI.

Trans-bronchial needle aspiration allows lymph node sampling in several thoracic conditions; the ability of Rapid On-Site Evaluation (ROSE) to predict the final diagnosis in this setting has not been well characterized. We performed a retrospective study to establish the utility of ROSE in the diagnosis of thoracic diseases with mediastinal lymph node involvement. We retrospectively reviewed 297 patients with hilar-mediastinal lymph node enlargement detected at CT scan from January 2013 to April 2016. 201 patients underwent conventional TBNA; in 96 patients, TBNA procedure was performed by on-site presence of a team of pathologists and research morphologists. Lung neoplasms, sarcoidosis, infections and lymphoma were the most common diseases diagnosed with TBNA samples. TBNA simultaneously performed in combination with ROSE produced an increase in percentage of appropriate samples compared to single cTBNA (adequate samples cTBNA vs ROSE-TBNA: 73% vs 81%; p<0.05). Our observations indicate an increase in adequacy of fine needle aspirations and increased diagnostic yield in the ROSE group. In conclusions, ROSE may serve to reduce procedure time and enhance sample triaging therefore limiting the need for further invasive diagnostic testing.

Background: MR Tractography enables non-invasive preoperative depiction of language subcortical tracts, which is crucial for the presurgical work-up of brain tumors; however, it cannot evaluate the exact function of the fibers., Purpose: A systematic pipeline was developed to combine tractography reconstruction of language fiber bundles, based on anatomical landmarks (Anatomical-T), with language fMRI cortical activations. A fMRI-targeted Tractography (fMRI-T) was thus obtained, depicting the subsets of the anatomical tracts whose endpoints are located inside a fMRI activation. We hypothesized that fMRI-T could provide additional functional information regarding the subcortical structures, better reflecting the eloquent white matter structures identified intraoperatively., Methods: Both Anatomical-T and fMRI-T of language fiber tracts were performed on 16 controls and preoperatively on 16 patients with left-hemisphere brain tumors, using a q -ball residual bootstrap algorithm based on High Angular Resolution Diffusion Imaging (HARDI) datasets ( b = 3000 s/mm 2 ; 60 directions); fMRI ROIs were obtained using picture naming, verbal fluency, and auditory verb generation tasks. In healthy controls, normalized MNI atlases of fMRI-T and Anatomical-T were obtained. In patients, the surgical resection of the tumor was pursued by identifying eloquent structures with intraoperative direct electrical stimulation mapping and extending surgery to the functional boundaries. Post-surgical MRI allowed to identify Anatomical-T and fMRI-T non-eloquent portions removed during the procedure., Results: MNI Atlases showed that fMRI-T is a subset of Anatomical-T, and that different task-specific fMRI-T involve both shared subsets and task-specific subsets - e.g., verbal fluency fMRI-T strongly involves dorsal frontal tracts, consistently with the phonogical-articulatory features of this task. A quantitative analysis in patients revealed that Anatomical-T removed portions of AF-SLF and IFOF were significantly greater than verbal fluency fMRI-T ones, suggesting that fMRI-T is a more specific approach. In addition, qualitative analyses showed that fMRI-T AF-SLF and IFOF predict the exact functional limits of resection with increased specificity when compared to Anatomical-T counterparts, especially the superior frontal portion of IFOF, in a subcohort of patients., Conclusion: These results suggest that performing fMRI-T in addition to the 'classic' Anatomical-T may be useful in a preoperative setting to identify the 'high-risk subsets' that should be spared during the surgical procedure., (Copyright © 2020 Sanvito, Caverzasi, Riva, Jordan, Blasi, Scifo, Iadanza, Crespi, Cirillo, Casarotti, Leonetti, Puglisi, Grimaldi, Bello, Gorno-Tempini, Henry, Falini and Castellano.)

Hypophysitis (HP) is a rare acute or chronic inflammatory condition of the pituitary gland. The greatest challenge in the management of HP is establishing a diagnosis through clinical criteria and non-invasive methods and predicting the patients' clinical outcome. The aim of this review is to describe the neuroradiological findings of this rare disease, providing some information regarding the possible differential diagnosis in order to avoid unnecessary surgery. Gadolinium-enhanced pituitary magnetic resonance imaging (MRI) is considered the neuroradiological investigation of choice. The features suggestive for HP include an enlarged triangular- or dumbbell-shaped gland with a thickened and not obviously deviated stalk, further supported by the absence of posterior pituitary bright spot on T1weighted images, particularly in patients presenting with diabetes insipidus. Contrast enhancement pattern is quite variable; dural enhancement has been reported in some cases after intravenous contrast administration. The characterization of the unusual sellar mass is not straightforward and generally results in a wide differential. HP should be primarily differentiated from pituitary adenomas (including pituitary apoplexy), from pituitary metastases, and from other sellar and parasellar tumors, e.g., craniopharyngiomas, germinomas, gliomas, lymphomas, meningiomas, pituicytomas, chordomas, teratomas, dermoids and epidermoids, Rathke's cleft cysts, and abscesses. In patients suspected for secondary forms related to systemic pathology, additional imaging is helpful in identifying other involved sites. Neuroradiologists need to know MRI appearance of this rare disease, as well as its typical symptoms and serological markers. A strict collaboration with endocrinologists and neurosurgeons is mandatory in order to reach a definitive diagnosis, allowing to promptly initiating an appropriate treatment.

Electronic cigarette (e-cigarette; e-cig) use has grown exponentially in recent years despite their unknown health effects. E-cig aerosols are now known to contain hazardous chemical compounds, including carbonyls and reactive oxygen species (ROS), and these compounds are directly inhaled by consumers during e-cig use. Both carbonyls and ROS are formed when the liquid comes into contact with a heating element that is housed within an e-cig's atomizer. In the present study, the effect of coil resistance (1.5 Ω and 0.25 Ω coils, to obtain a total wattage of 8 ± 2 W and 40 ± 5 W, respectively) on the generation of carbonyls (formaldehyde, acetaldehyde, acrolein) and ROS was investigated. The effect of the aerosols generated by different coils on the viability of H1299 human lung carcinoma cells was also evaluated. Our results show a significant (p < 0.05) correlation between the low resistance coils and the generation of higher concentrations of the selected carbonyls and ROS in e-cig aerosols. Moreover, exposure to e-cig vapor reduced the viability of H1299 cells by up to 45.8%, and this effect was inversely related to coil resistance. Although further studies are needed to better elucidate the potential toxicity of e-cig emissions, our results suggest that these devices may expose users to hazardous compounds which, in turn, may promote chronic respiratory diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cerebral plasticity is the ability of the central nervous system to reorganize itself in response to different injuries. The reshaping of functional areas is a crucial mechanism to compensate for damaged function. It is acknowledged that functional remodeling of cortical areas may occur also in glioma patients. Principal limits of previous investigations on cortical plasticity of motor and language functions included scarce reports of longitudinal evaluations and limited sample sizes. This systematic review is aimed at elucidating cortical brain plasticity for motor and language functions, in adult glioma patients, by means of preoperative and intraoperative mapping techniques. We systematically reviewed the literature for prospective studies, assessing cortical plasticity of motor and language functions in low-grade and high-grade gliomas. Eight longitudinal studies investigated cortical plasticity, evaluated by motor and language task-based functional MRI (fMRI), motor navigated transcranial magnetic stimulation (n-TMS), and intraoperative mapping with cortical direct electrocortical stimulation (DES) of language and motor function. Motor function reorganization appeared relatively limited and mostly characterized by intrahemispheric functional changes, including secondary motor cortices. On the other hand, a high level of functional reshaping was found for language function in DES studies. Occurrence of cortical functional reorganization of language function was described focusing on the intrahemispheric recruitment of perilesional areas. However, the association between these functional patterns and recovery of motor and language deficits still remains partially clear. A number of relevant methodological issues possibly affecting the finding generalization emerged, such as the complexity of plasticity outcome measures and the lack of large longitudinal studies. Future studies are required to further confirm these evidences on cortical plasticity in larger samples, combining both functional imaging and intraoperative mapping techniques in longitudinally evaluations., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2019 S. Cirillo et al.)

Despite the knowledge gap regarding the risk-benefit ratio of the electronic cigarette (e-cig), its use has grown exponentially, even in teenagers. E-cig vapor contains carcinogenic compounds (eg, formaldehyde, acetaldehyde, and acrolein) and free radicals, especially reactive oxygen species (ROS) that cause toxicological effects, including DNA damage. The role of e-cig voltage customization on molecule generation has been reported, but the effects of the resistance on e-cig emissions and toxicity are unknown. Here, we show that the manipulation of e-cig resistance influences the carbonyls production from nonnicotine vapor and the oxidative and inflammatory status in a rat model. Fixing the voltage at the conventional 3.5 V, we observed that the amount of the selected aldehydes increased as the resistance decreased from 1.5 to 0.25 Ω. Under these conditions, we exposed Sprague Dawley rats to e-cig aerosol for 28 days, and we studied the pulmonary inflammation, oxidative stress, tissue damage, and blood homeostasis. We found a perturbation of the antioxidant and phase II enzymes, probably related to the increased ROS levels due to the enhanced xanthine oxidase and P450-linked monooxygenases. Furthermore, frames from scanning electron microscope showed a disorganization of alveolar and bronchial epithelium in 0.25 Ω group. Overall, various toxicological outcomes, widely recognized as smoke-related injuries, can potentially occur in e-cig consumers who use low-voltage and resistance device. Our study suggests that certain "tips for vaping safety" cannot be established, and encourages further independent investigations to help public health agencies in regulating the e-cig use., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Primary hyperparathyroidism (PHPT) is a frequent endocrine pathology that has surgical treatment as its only decisive measure. High-Resolution Neck Ultrasonography with color-Doppler (CDHR-NUS) and 99m Technetium-SestaMIBI Parathyroid Scintigraphy ( 99m Tc-MIBI PS) are the two instrumental exams more commonly used in the preoperatory localization of pathologic parathyroids. The aim of this observational study was to outline-in accordance with the latest scientific literature-the precise role of CDHR-NUS in the environment of PHPT, comparing it with that of Parathyroid Scintigraphy., Methods: 136 patients operated on for PHPT and underwent CDHR-NUS and 99m Tc-MIBI PS preoperatively. The CDHR-NUS was carried out by an expert medical sonographer. The results of the two methods were compared between each other and with the results of the operative act for the evaluation of accordance and diagnostic performances., Results: PHPT is prevalently due to monoglandular pathology (SGD). The parallel use of CDHR-NUS and of 99m Tc-MIBI PS does not determine a significant increase in diagnostic accuracy. The preoperative accordance evaluation between the two methods does not exclude the presence of multiglandular pathology (MGD) with certainty., Conclusions: CDHR-NUS is an accurate as well as cost-effective method; its role as a main and eventual unique preoperative localization method in patients affected by PHPT is confirmed. In the presence of expert medical sonographers, the sequential use of the two methods is retained correct and their use in parallel is neither justified nor cost-effective. The preoperative accordance evaluation between the two methods is neither necessary nor indispensable.

A large number of basic researches and observational studies suggested the cancer preventive activity of vitamin E, but large-scale human intervention trials have yielded disappointing results and actually showed a higher incidence of prostate cancer although the mechanisms underlying the increased risk remain largely unknown. Here we show through in vitro and in vivo studies that vitamin E produces a marked inductive effect on carcinogen-bioactivating enzymes and a pro-oxidant status promoting both DNA damage and cell transformation frequency. First, we found that vitamin E in the human prostate epithelial RWPE-1 cell line has the remarkable ability to upregulate the expression of various phase-I activating cytochrome P450 (CYP) enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), giving rise to supraphysiological levels of reactive oxygen species. Furthermore, our rat model confirmed that vitamin E in the prostate has a powerful booster effect on CYP enzymes associated with the generation of oxidative stress, thereby favoring lipid-derived electrophile spread that covalently modifies proteins. We show that vitamin E not only causes DNA damage but also promotes cell transformation frequency induced by the PAH-prototype benzo[a]pyrene. Our findings might explain why dietary supplementation with vitamin E increases the prostate cancer risk among healthy men.

Despite the lack of knowledge of the effects of electronic cigarettes (e-cigarettes, e-cigs) on public health, they have been proposed as a part of smoking cessation efforts. Recently, several basic scientific studies have pointed out how e-cigs can generate carcinogens, such as e-cig liquid thermal degradation by-products, and how the exposure can lead to genomic damage through inhibiting DNA repair or disrupting the redox homeostasis. However, scientific studies have pointed out how e-cigs can generate carcinogens and their release could be avoided setting the device to a low-voltage regimen. To test this feasibility, we show the effects of e-cig vapour generated from a low-voltage device filled with a nicotine-free liquid on rat testicular functions. The chemical analysis revealed the presence of carbonyls, such as formaldehyde, acetaldehyde and acrolein. Rats exposed reported a lower relative testis weight and higher levels of lactate dehydrogenase (LDH) as tissue damage marker, along with an impairment of 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD) and glucose-6-phosphate dehydrogenase (G6PDH) as key enzymes in the steroidogenesis pathway. The pro-oxidative environment was confirmed by the higher amount of reactive oxygen species (ROS), the development of lipid peroxidation and protein carbonylation, as well as from the disruption of antioxidant capability. Finally, we observed a higher rate of DNA unwinding in white blood cell line and boosted lipoxygenase (LOX)-linked activity, a tumour promotion marker. Even with the device setting at weak conditions, our results if extrapolated to humans suggest that exposure to e-cig vapours might alter gonads function in male vapers., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The comet assay is a sensitive technique to detect DNA damage caused by exposure to genotoxic chemical and physical agents and is widely used in ecotoxicology. The assay has been applied in aquatic species, mainly fish and bivalves, in field biomonitoring programs and in experimental studies. The aim of the present study was to retrieve and review the published evidence to define the role of the comet assay in the assessment of genotoxic pollutants. The study focused on the application of the test in Mytilus sp, used as a sentinel organism. Twenty-one biomonitoring studies, carried out in wild and in transplanted mussels, were evaluated. An increase of the comet parameters in animals from polluted areas with respect to the controls was observed in the majority of the studies with a large variability (frequency ratio:1.2-14.5) associated with types and extent of exposure to pollutants. Three studies out of 21 reported a lack of response. Heavy metals, polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB) and pesticides were the main types of chemicals detected in sediments and/or mussel tissues from polluted areas. Twenty-nine laboratory studies were retrieved showing the sensitivity of the comet assay in detecting DNA damage in mussels exposed to the most relevant pollutants and mixtures of relevant contaminants, such as pharmaceuticals, anti-fouling agents or crude oil. The comet test also appeared to be a suitable approach to detect the genotoxic effects of nanoparticles. In some studies problems in the interpretation of data or discrepancies between the results from different laboratories were noted. Critical steps in experimental protocol and characterization of pollution, environmental variables such as temperature, salinity, food availability, physiological and pathological status of the animals are important factors which should be controlled and considered in the analysis of the results., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The aim of this retrospective study was to identify different radiological features in intermediate⁻advanced laryngeal cancer (LC) associated with arytenoid fixation, in order to differentiate cases still safely amenable to conservative treatment by partial laryngectomy or chemoradiotherapy. Methods : 29 consecutive patients who underwent open partial horizontal laryngectomies (OPHLs), induction chemotherapy followed by radiotherapy in the case of >50% response (IC + RT) or total laryngectomy were classified as: pattern I (supraglottic LC fixing the arytenoid due to weight effect), pattern II (glottic LC involving the posterior paraglottic space and spreading toward the crico-arytenoid joint and infraglottic extension <10 mm), pattern III (glottic-infraglottic LC involving the crico-arytenoid joint and infraglottic extension >10 mm) and pattern IV (transglottic and infraglottic LC with massive crico-arytenoid unit involvement, reaching the hypopharyngeal submucosa). All glottic cancers treated with surgery were studied by a cross sectional approach. Results: A substantial agreement between the work-up and the pathology results has been obtained in each of the subcategories. Three-year disease-free survivals, local control and freedom from laryngectomy were significantly better in pattern II compared to pattern III⁻IV. Conclusions : LC showing fixed arytenoid due to weight effect or posterior paraglottic space involvement with infraglottic extension <10 mm assessed at the true vocal cord midline are still safely manageable by OPHL or IC + RT.

The electronic cigarettes (e-cigarettes, e-cigs) have become the most sought-after alternative to the traditional cigarettes, partly due to the widespread perception of safety. However, the high temperature reached by e-cig solutions can generate toxic compounds, some of which are listed as known human carcinogens. To evaluate the impact of e-cig aerosol on rat brain lipid profile, twenty male Sprague Dawley rats were exposed to 11 cycles/day (E-cig group), to consume 1 mL/day of e-liquid, for 5 days/week up to 8 weeks. Ten rats were sacrificed after 4 weeks (4w) and ten at the end of treatment (8w). The composition of total fatty acids, sterols and oxysterols of the lipid fraction of rat brains, was analyzed. The results of the E-cig group were compared with those of the control group (not exposed). After 8 weeks, the saturated fatty acids significantly raised up to 7.35 mg/g tissue, whereas polyunsaturated fatty acids decreased reaching 3.17 mg/g. The e-cig vaping increased both palmitic (3.43 mg/g) and stearic acids (3.82 mg/g), while a significant decrement of arachidonic (1.32 mg/g) and docosahexaenoic acids (1.00 mg/g) was found. Atherogenic (0.5) and thrombogenic (1.12) indices also increased in 8w treated animals. The e-cig aerosol significantly impacted the cholesterol homeostasis, since the latter at 8w (21.57 mg/g) was significantly lower than control (24.56 mg/g); moreover, a significant increase of 7-dehydrocholesterol (1.87 mg/g) was also denoted in e-cig group. The e-cig aerosol also reduced the oxysterol formation (19.55 μg/g) after 4 weeks of exposure, except for triol and 5α,6α-epoxycholesterol (α-EC). The principal component analysis (PCA) separated all E-cig from control groups, evidencing that oxysterols (except triol and 24(S)-hydroxycholesterol (24(S)-HC)) were inversely correlated to 7-DHC and TI. The present research revealed that e-cigs aerosol affected the lipid and cholesterol homeostasis in rat brain, which could contribute to the new occurrence of some neurodegenerative diseases., (Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Purpose: We previously showed the positive effects of the new antioxidant molecule bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC) in reducing basal hyperglycaemia and relieving glucose intolerance in a diabetes model. However, the chemical properties of IAC did not allow an efficient oral administration, thus representing the main failing of that study. Here, we tested the effect of a new oral delivery system based on solid lipid microparticles (SLMs) in a diabetes mouse model., Methods: The diabetes model was induced in C57B1/6J mice using streptozotocin and nicotinamide. Only the animals that overcame the glycaemic threshold of 180 mg/dL were enrolled in the study. Diabetic animals were then randomly assigned to 4 groups (n = 9) and treated once a day for 5 consecutive weeks with IAC (50, 100, and 150 mg/kg b.w.). The control group was composed of (n = 7) healthy mice that received only the vehicle. Glucose level was weekly monitored during the treatment period and up to 3 weeks after the suspension of the treatment. Glucose tolerance and insulin-resistance test were carried out., Results: Our results showed that SLMs maintained the IAC effect in reducing basal hyperglycaemia as well as improving the insulin sensitivity and glucose tolerance., Conclusion: The present study confirms that SLMs are promising drug carriers, which allow the oral administration of IAC ensuring its therapeutic efficacy. The concrete possibility to administer IAC per os represents a significant breakthrough in the putative consideration of this multi-radical scavenger in the diabetes therapeutic approach.

Background: The purpose of this retrospective study was to identify subcategories in cT3 to cT4a supraglottic/glottic cancers, describing their different spreading patterns, and local and locoregional recurrence modes., Methods: Four hundred eighty-nine patients who underwent open partial horizontal laryngectomies (OPHLs) were retrospectively classified as: subcategory I (anterior pT3 with normal arytenoid mobility); subcategory II (posterior pT3 with impaired/absent mobility); subcategory III (anterior pT4 with normal mobility); and subcategory IV (posterior pT4 with impaired/absent mobility)., Results: Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional, local control, freedom from laryngectomy, and laryngectomy-free survival were significantly better in anterior tumors (subcategories I and III) when compared with the corresponding posterior ones (subcategories II and IV)., Conclusion: Anterior cT3 tumors are manageable by OPHL, and this approach could also be proposed in the treatment of early anterior cT4aN0. Despite promising results, OPHLs should be considered under investigation in posterior cT3 tumors due to clinical and biological behavior similar to cT4a tumors., (© 2018 Wiley Periodicals, Inc.)

The effects of Castanea sativa Mill. have been studied in high fat diet (HFD) overweight rats. Natural Extract of Chestnut bark (Castanea sativa Mill.) (ENC®), rich in ellagitannins, has been studied in 120 male Sprague-Dawley rats, divided in four groups. Two groups were controls: regular (RD) and HDF diet. Two groups received ENC® (20 mg/kg/day): RD + ENC® and HFD + ENC®. At baseline and at 7, 14 and 21 days, weight gain, serum lipids, plasma cytokines, liver histology, microsomial enzymes and oxidation, intestinal oxidative stress and contractility were studied. HFD increased body weight, increased pro-inflammatory cytokines, induced hepatocytes microvescicular steatosis, altered microsomial, increased liver and intestinal oxidative stress, deranged intestinal contractility. In HFD-fed rats, ENC® exerted antiadipose and antioxidative activities and normalized intestinal contractility, suggesting a potential approach to overweight management associated diseases., Competing Interests: The authors have read the journal's policy and have the following conflicts: AC is affiliated with GVM Care & Research but did not receive a salary. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

The relationship between psychosocial stress at work and mental health outcome is well-known. Brain-imaging studies hypothesize morphological brain modifications connected to work-related stress. To our knowledge this is the first study describing the link between work characteristics and brain imaging in a sample of work-related psychiatric patients assessed according to standardized clinical and diagnostic criteria. The aims of the study are: (1) to evaluate hippocampal and whole brain volumes in work-related psychiatric disturbances; (2) to verify the relationship between brain changes and the anxious and/or depressive symptoms; (3) to observe the relationship between the brain changes and the degree of the bullying at workplace. The hippocampus and whole brain volumes of 23 patients with work-related adjustment-disorders were compared with 15 controls by means of MRI. MR images highlight a smaller hippocampal volume in patients compared with controls. Significant reduction in the patients' gray matter was found in three brain areas: right inferior temporal gyrus, left cuneus, left inferior occipital gyrus. The reduction of the hippocampi volumes was related to work distress and, above all, to bullying at workplace. The results confirm that the morphological brain abnormalities could be involved in work-related psychiatric disturbances.

Background: Failure of portal vein ligation (PVL) to induce hypertrophy is not uncommon. The aim of the study was to evaluate the impact of intraportal alcohol injection prior to ligation on liver regeneration., Method: Forty-two patients with colorectal liver metastases who underwent PVL between 01/2004 and 06/2014 were analyzed. Beginning in 09/2011, alcohol was injected prior to PVL. Patients treated with PVL alone (Alc- group) were compared with those treated with alcohol injection plus PVL (Alc+ group). Liver regeneration was assessed by volumetric increase (VI)., Results: Alc+ (23 patients) and Alc- (19 patients) groups were similar in terms of age, sex and pre-PVL FLRV. Alc- group had a higher risk of recanalization (12 vs. 1, p < 0.001) and cavernous transformation (7 vs. 2, p = 0.055) of the occluded portal vein. Post-PVL FLRV (43.3 ± 14.3% vs. 34.6 ± 6.4%, p = 0.013) and VI (0.44 ± 0.24 vs. 0.28 ± 0.20, p = 0.029) were higher in Alc+ group. On multivariate analysis male sex (B = -0.149) and alcohol injection (B = 0.143) significantly predicted VI., Conclusions: Alcohol injection prior to PVL may increase the regeneration of the FLRV by reducing the recanalization of the occluded portal vein., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

The presence of an acute coronary syndrome in patients with anaphylaxis is a challenging diagnostic conundrum for the cardiologist. Both Kounis syndrome and takotsubo syndrome must be taken into account. We present here the case of a 46-year-old woman suffering from ventricular fibrillation after adrenaline infusion for an anaphylactic reaction. The case report shows the important role of a clear diagnostic work-up and the role of cardiac magnetic resonance in this clinical scenario to reach the final diagnosis of reverse takotsubo cardiomyopathy.

The main purpose of this study was to compare the benefits of SSJ supplementation in obese rats with those achieved only by switching the alimentary regimen from high-fat (HFD) to the regular one (RD) in liver, ileum and prostate. Furthermore, changings in caecal chime microbiota were investigated. SSJ was administered to rats in combination with a RD (HFD-RD + SSJ). The switch from HFD to RD led to a weight loss of almost 9.8 g, and the total cholesterol was found to be significantly lower. In the HFD-RD + SSJ group, all values were improved compared with the HFD control, and the weight decrement was higher (-23.29 g) with respect to HFD-RD. HFD led to a widespread increment of oxidative stress (OS) markers in liver, ileum and prostate. SSJ has shown to improve the results achieved by the suspension of HFD and it has proven effective wherever the only switch in diet regimen failed.

The present study aimed to evaluate the impact of Raphanus sativus cv Sango sprout juice (SSJ) administration (75mg/kg b.w. SSJ/day) on the brain lipidomic profile (fatty acid, sterols, cholesterol oxidation) of rats (non-genetic model) subjected to a high-fat (34% crude fat) dietary regimen. The SSJ did not affect the lipid infiltration (7.7-9.3%) and the fatty acid composition of the rat brain, which was mainly composed by unsaturated fatty acids (∼58%); however, the high-fat diet regimen significantly halved linoleic acid (LA). The high-fat diet also decreased (21.13mg/g) the level of brain cholesterol with respect to the regular diet (4.5% crude fat) (23.83mg/g); however, when the diet was shifted from high-fat to a regular regimen with or without SSJ supplementation, the levels of cholesterol significantly (p <0.05) increased up to 30.46mg/g of brain. The main oxysterols were 24(S)-hydroxycholesterol (24(S)-HC) and β-epoxycholesterol (β-EC). The high-fat diet led to the highest cholesterol oxidation (63.1μg/g), increasing 27-hydroxycholesterol (27-HC) infiltration (0.24μg/g rat brain) through the blood-brain barrier (BBB) compared to the regular diet (0.13μg/g rat brain). On the other hand, when the diet was switched from high-fat to a regular regimen with SSJ supplementation, a significant reduction of 27-HC in the rat brain was found. Although 24-HC did not significantly change (p=0.054), an increasing trend was observed when high-fat diet was supplied. The principal component analysis (PCA) revealed that SSJ was more active in counteracting cholesterol oxidation when supplied with the high-fat diet, due to inverse correlation with 24(S)-HC and 27-HC; however, further studies are needed to better understand which is the relationship between LA and cholesterol homeostasis in rat brain., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose of Review: Advanced neuroimaging techniques such as functional MRI (fMRI) and diffusion MR tractography have been increasingly used at every stage of the surgical management of brain gliomas, as a means to improve tumor resection while preserving brain functions. This review provides an overview of the last advancements in the field of functional MRI techniques, with a particular focus on their current clinical use and reliability in the preoperative and intraoperative setting, as well as their future perspectives for personalized multimodal management of patients with gliomas., Recent Findings: fMRI and diffusion MR tractography give relevant insights on the anatomo-functional organization of eloquent cortical areas and subcortical connections near or inside a tumor. Task-based fMRI and diffusion tensor imaging (DTI) tractography have proven to be valid and highly sensitive tools for localizing the distinct eloquent cortical and subcortical areas before surgery in glioma patients; they also show good accuracy when compared with intraoperative stimulation mapping data. Resting-state fMRI functional connectivity as well as new advanced HARDI (high angular resolution diffusion imaging) tractography methods are improving and reshaping the role of functional MRI for surgery of gliomas, with potential benefit for personalized treatment strategies. Noninvasive functional MRI techniques may offer the opportunity to perform a multimodal assessment in brain tumors, to be integrated with intraoperative mapping and clinical data for improving surgical management and oncological and functional outcome in patients affected by gliomas.

Background: An approach based on multiparametric magnetic resonance imaging (mpMRI) might increase the detection rate (DR) of clinically significant prostate cancer (csPCa)., Objective: To compare an mpMRI-based pathway with the standard approach for the detection of prostate cancer (PCa) and csPCa., Design, Setting, and Participants: Between November 2014 and April 2016, 212 biopsy-naïve patients with suspected PCa (prostate specific antigen level ≤15 ng/ml and negative digital rectal examination results) were included in this randomized clinical trial. Patients were randomized into a prebiopsy mpMRI group (arm A, n=107) or a standard biopsy (SB) group (arm B, n=105)., Intervention: In arm A, patients with mpMRI evidence of lesions suspected for PCa underwent mpMRI/transrectal ultrasound fusion software-guided targeted biopsy (TB) (n=81). The remaining patients in arm A (n=26) with negative mpMRI results and patients in arm B underwent 12-core SB., Outcomes Measurements and Statistical Analysis: The primary end point was comparison of the DR of PCa and csPCa between the two arms of the study; the secondary end point was comparison of the DR between TB and SB., Results and Limitations: The overall DRs were higher in arm A versus arm B for PCa (50.5% vs 29.5%, respectively; p=0.002) and csPCa (43.9% vs 18.1%, respectively; p<0.001). Concerning the biopsy approach, that is, TB in arm A, SB in arm A, and SB in arm B, the overall DRs were significantly different for PCa (60.5% vs 19.2% vs 29.5%, respectively; p<0.001) and for csPCa (56.8% vs 3.8% vs 18.1%, respectively; p<0.001). The reproducibility of the study could have been affected by the single-center nature., Conclusions: A diagnostic pathway based on mpMRI had a higher DR than the standard pathway in both PCa and csPCa., Patient Summary: In this randomized trial, a pathway for the diagnosis of prostate cancer based on multiparametric magnetic resonance imaging (mpMRI) was compared with the standard pathway based on random biopsy. The mpMRI-based pathway had better performance than the standard pathway., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Aim: Our study aimed to investigate the role of qualitative and quantitative whole body MRI with DWI for assessment of bone marrow involvement (BMI) in newly diagnosed lymphoma using FDG PET-CT and bone marrow biopsy (BMB) as reference standard., Materials and Methods: We retrospectively evaluated 56 patients with newly diagnosed lymphoma (21 Hodgkin's lymphoma and 35 non-Hodgkin's lymphoma) who underwent random unilateral BMB, FDG PET-CT and Wb-MRI-DWI for initial staging. In a patient-based analysis, results of Wb-MRI-DWI were compared with FDG PET-CT and BMB. For quantitative analysis, mean ADC values of posterior iliac crest were correlated with BMI and bone marrow cellularity., Results: WB-MR-DWI obtained excellent concordance with FDG PET-CT both in HL (k = 1.000; 95% CI 1.000-1.000) and in DLBCL (k = 1.000; 95% CI 1.000-1.000). In other NHL, WB-MRI-DWI obtained a good correlation with BMB (k = 0.611; 95% CI 0.295-0.927) while FDG PET-CT had poor concordance (k = 0.067; 95% CI 0.372-0.505). WB-MR-DWI has no false negative errors but 4 false positive results consisting in focal lesions consensually reported by FDG PET-CT and resolved after therapy. No significant correlation between ADC mean value and BMI was found (p = 0.0586)., Conclusion: Our data suggest that Wb-MRI-DWI is a valid technique for BMI assessment in lymphoma patients, thanks to its excellent concordance with FDG PET-CT and good concordance with BMB (superior than FDG PET-CT). If further investigations will confirm our results on larger patient groups, it could become a useful tool in the clinical workup.