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Background Positron Emission Tomography (PET) imaging with Prostate-Specific Membrane Antigen (PSMA) and Fluorodeoxyglucose (FDG) represent promising biomarkers for risk-stratification of Prostate Cancer (PCa). We verified whether the expression of genes encoding for PSMA and enzymes regulating FDG cellular uptake are independent and additive prognosticators in PCa. Methods mRNA expression of genes involved in glucose metabolism and PSMA regulation obtained from primary PCa specimens were retrieved from open-source databases and analyzed using an integrative bioinformatics approach. Machine Learning (ML) techniques were used to create predictive Progression-Free Survival (PFS) models. Cellular models of primary PCa with different aggressiveness were used to compare [18F]F-PSMA-1007 and [18F]F-FDG uptake kinetics in vitro. Confocal microscopy, immunofluorescence staining, and quantification analyses were performed to assess the intracellular and cellular membrane PSMA expression. Results ML analyses identified a predictive functional network involving four glucose metabolism-related genes: ALDOB, CTH, PARP2, and SLC2A4. By contrast, FOLH1 expression (encoding for PSMA) did not provide any additive predictive value to the model. At a cellular level, the increase in proliferation rate and migratory potential by primary PCa cells was associated with enhanced FDG uptake and decreased PSMA retention (paralleled by the preferential intracellular localization). Conclusions The overexpression of a functional network involving four glucose metabolism-related genes identifies a higher risk of disease progression since the earliest phases of PCa, in agreement with the acknowledged prognostic value of FDG PET imaging. By contrast, the prognostic value of PSMA PET imaging is independent of the expression of its encoding gene FOLH1. Instead, it is influenced by the protein docking to the cell membrane, regulating its accessibility to tracer binding.

Defining immune mechanisms leading to multiple sclerosis (MS) is difficult, due to the great inter-individual difference in immune system responses. The anti-CD52 antibody alemtuzumab transiently abolishes differences in immune parameters among individuals, allowing analysis of subsequent immune cell repopulation patterns, and their possible role in MS.To evaluate the correlation between innate and adaptive immune cell subsets and disease activity in MS in the context of treatment with alemtuzumab.A two-center observational cohort of patients treated with alemtuzumab underwent immune profiling of T, B, and natural killer (NK) cells, biomarker, clinical and radiological follow-up.After treatment, the percentage of NK and B cells increased; NK, T- and B-cell populations underwent a profound rearrangement. Within the effector T-cell compartment, treatment led to a transient decrease, followed by an increase, of T-helper 1 cells, and to a transient decrease of T-helper 17 cells. Within the T-regulatory compartment, naïve T-regulatory cells increased. Within the B-cell compartment, memory B cells and mature B cells decreased, whereas transitional B cells increased. Within the NK cell compartment, CD56The results of this study provide novel evidence that NK cells influence reconstitution of adaptive immune cells upon alemtuzumab and that patients with a successful response to alemtuzumab have an early immune reconstitution dominated by NK cells.

The use of low-cost immersive virtual reality systems is rapidly expanding. Several studies started to analyse the accuracy of virtual reality tracking systems, but they did not consider in depth the effects of external interferences in the working area. In line with that, this study aimed at exploring the static-positional accuracy and the robustness to occlusions inside the capture volume of the SteamVR (1.0) tracking system. To do so, we ran 3 different tests in which we acquired the position of HTC Vive PRO Trackers (2018 version) on specific points of a grid drawn on the floor, in regular tracking conditions and with partial and total occlusions. The tracking system showed a high inter- and intra-rater reliability and detected a tilted surface with respect to the floor plane. Every acquisition was characterised by an initial random offset. We estimated an average accuracy of 0.5 ± 0.2 cm across the entire grid (XY-plane), noticing that the central points were more accurate (0.4 ± 0.1 cm) than the outer ones (0.6 ± 0.1 cm). For the Z-axis, the measurements showed greater variability and the accuracy was equal to 1.7 ± 1.2 cm. Occlusion response was tested using nonparametric Bland–Altman statistics, which highlighted the robustness of the tracking system. In conclusion, our results promote the SteamVR system for static measures in the clinical field. The computed error can be considered clinically irrelevant for exercises aimed at the rehabilitation of functional movements, whose several motor outcomes are generally measured on the scale of metres.

Background Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era. Methods We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups. Results Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32–0.60, p p = 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 (p = 0.038) and associated with a longer OS for the first three prognostic groups (p p = 0.54). Conclusions Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score.

To analyse the course of multiple sclerosis (MS) after fingolimod withdrawal in a multicentre cohort. Patients who discontinued fingolimod were included. Relapses, Expanded Disability Status Scale (EDSS), and new/gadolinium-enhancing lesions on magnetic resonance imaging (MRI) were assessed during the last year on fingolimod, and in the year after discontinuation. Wilcoxon test was used to analyse the difference in EDSS and relapses between the two periods, and to compare lymphocyte counts at discontinuation and 3 months later. Demographic and clinical variables were evaluated using univariable and multivariable logistic regression analyses. Patients were 230 (females 66.1%; mean age 38 years; median EDSS 3). Fingolimod was discontinued due to inefficacy in 57%, and 87.4% started another treatment. Relapse was observed in 33% of the patients in the year after discontinuation. Severe reactivation was observed in 15%. During the first 6 months after discontinuation, new/enhancing lesions were seen in 62/116 patients. Higher age at the fingolimod discontinuation was found to be associated with a lower probability of inflammatory activity (p = 0.001) and severe reactivation (p = 0.007) during the year after discontinuation. Lower lymphocyte count was a risk factor for clinical, radiological, and severe activity (p = 0.02, p = 0.002, p = 0.01, respectively). The main reason for the discontinuation of fingolimod was inefficacy. One-third of the patients had a relapse during the year after discontinuation, 15% experienced a severe reactivation, and approximately 50% of patients with available MRI scan had new/enhancing lesions. The risk factors for disease activity after discontinuation were low lymphocyte count and younger age.

Introduction Available evidence from observational studies and meta-analyses has highlighted an increased mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections (BSI) compared with their carbapenem-susceptible (CSKP) counterparts, but the exact reasons for this outcome difference are still to be determined. Methods We updated the search of a previous meta-analysis through four databases up to April 2018. A two-stage individual-patient data (IPD) meta-analysis was conducted, building an adjusting model to account for age, comorbidities and activity of empirical and targeted antimicrobial therapy. The protocol was registered on PROSPERO (identifier: CRD42018104256). Results IPD data were obtained from 14 out of 28 eligible observational studies. A total of 1952 patients were investigated: 1093 in the CRKP group and 859 in the CSKP group. Patients with CRKP-BSI had a twofold risk of death compared with CSKP-infected patients [adjusted odds ratio (aOR) 2.17; 95% confidence interval (CI) 1.56–3.04; I2 = 44.1%]. Mortality was higher in patients with CRKP BSI, in both the subgroup of absent/inactive (aOR 1.75; 95% CI 1.24–2.47; I2 = 0) and of active initial therapy (aOR 2.66; 95% CI 1.70–4.16; I2 = 16%) as well as in case of active targeted therapy (aOR 2.21; 95% CI 1.36–3.59; I2 = 58%). Conclusion Resistance to carbapenem is associated with worse outcome in patients with BSI by Klebsiella pneumoniae even adjusting for comorbidities and treatment appropriateness according to in vitro activity of empirical and targeted therapy. This applies to a scenario dominated by colistin-based therapies for CRKP. Further studies are needed to compare the mortality difference between CRKP and CSKP cases in the light of new anti-CRKP antimicrobials. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00408-8.

Objectives To verify the incidence of calcified brain metastases (CBM), illustrating the different presentation patterns and histology of primary tumor. Methods A series of 1002 consecutive brain computed tomography (CT) scans of patients with known primary tumors was retrospectively assessed. CBM were defined by the presence of calcification within intra-axial-enhancing lesions; identification of CBM was based on visual examination and ROI analysis (> 85 Hounsfield units). Also, calcifications in the primary tumor of all patients with brain metastases were evaluated. In CBM patients, we investigated the type of calcifications (punctate, nodular, cluster, ring, coarse), the histology of primary tumor, and if a previous RT was performed. Results Among 190 (18.9%) patients with brain metastatic disease, 34 presented with CBM (17.9%). Sixteen patients were previously treated with RT, while 18 presented calcifications ab initio (9.5% of all brain metastases). The majority of patients with CBM had a primitive lung adenocarcinoma (56%), followed by breast ductal invasive carcinoma (20%) and small cell lung carcinoma (11.8%). CBM were single in 44.1% of patients and multiple in 55.9%. With regard to the type of calcifications, the majority of CBM were punctate, without specific correlations between calcification type and histology of primary tumor. No patients with ab initio CBM had calcifications in primary tumor. Conclusion In conclusion, our data show that CBM are more common than usually thought, showing an incidence of 9.5% ab initio in patients with brain metastases. This study underlines that neuroradiologists should not overlook intraparenchymal brain calcifications, especially in oncologic patients. Key Points • Among the differential diagnosis of brain intraparenchymal calcifications, metastases are considered uncommon and found predominantly in patients treated with radiotherapy (RT). • Our data show that CBM are more common than usually thought, showing an incidence of 9.5% ab initio in patients with brain metastases. • A proportion of intraparenchymal brain calcifications, especially in oncologic patients, might represent evolving lesions and neuroradiologists should not overlook them to avoid a delay in diagnosis and treatment.

To retrospectively evaluate the different performances of T1-SE and T1-GE sequences in detecting hypointense lesions in multiple sclerosis (MS), to quantify the degree of microstructural damage within lesions and to correlate them with patient clinical status. Sixty clinically isolated syndrome (CIS) and MS patients underwent brain magnetic resonance imaging (MRI) on 1.5-T and 3-T scanners. We identified T2 fluid-attenuated inversion recovery hyperintense lesions with no hypointense signal on T1-SE/T1-GE (a), hypointense lesions only on T1-GE (b), and hypointense lesions on both T1-SE and T1-GE sequences (c). We compared mean lesion number (LN) and volume (LV) identified on T1-SE and T1-GE sequences, correlating them with Expanded Disability Status Scale (EDSS); fractional anisotropy (FA) and mean diffusivity (MD) values inside each lesion type were extracted and normal-appearing white matter (NAWM). Thirty-five patients were female. Mean age was 39.2 (± 7.8); median EDSS was 3 (± 2). There were 23 CIS, 21 relapsing–remitting (RR), and 16 progressive MS. T1-GE and T1-SE LN and LV were significantly different (p

Background. We recently reported that enhanced [18F]-fluorodeoxyglucose (FDG) uptake in skeletal muscles predicts disease aggressiveness in patients with amyotrophic lateral sclerosis (ALS). The present experimental study aimed to assess whether this predictive potential reflects the link between FDG uptake and redox stress that has been previously reported in different tissues and disease models. Methods. The study included 15 SOD1G93A mice (as experimental ALS model) and 15 wildtype mice (around 120-days-old). Mice were submitted to micro-PET imaging. Enzymatic pathways and response to oxidative stress were evaluated in harvested quadriceps and hearts by biochemical, immunohistochemical and immunofluorescence analysis. Colocalization between the endoplasmic reticulum (ER) and the fluorescent FDG analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) was performed in fresh skeletal muscle sections. Finally, mitochondrial ultrastructure and bioenergetics were evaluated in harvested quadriceps and hearts.Results. FDG retention was significantly higher in hindlimb skeletal muscles of symptomatic SOD1G93A mice with respect to control ones. This difference was not explained by any acceleration in glucose degradation through glycolysis or cytosolic pentose phosphate pathway (PPP). Similarly, it was independent of inflammatory infiltration. Rather, the high FDG retention in SOD1G93A skeletal muscle was associated with an accelerated generation of reactive oxygen species. This redox stress selectively involved the ER and the local PPP triggered by hexose-6P-dehydrogenase. ER involvement was confirmed by the colocalization of the 2-NBDG with a vital ER tracker. The oxidative damage in transgenic skeletal muscle was associated with a severe impairment in the crosstalk between ER and mitochondria combined with alterations in mitochondrial ultrastructure and fusion/fission balance. The expected respiratory damage was confirmed by a deceleration in ATP synthesis and oxygen consumption rate. These same abnormalities were represented to a markedly lower degree in the myocardium, as a sample of non-voluntary striated muscle.Conclusion. Skeletal muscle of SOD1G93A mice reproduces the increased FDG uptake observed in ALS patients. This finding reflects the selective activation of the ER-PPP in response to significant redox stress associated with alterations of mitochondrial ultrastructure, networking, and connection with the ER itself. This scenario is less severe in cardiomyocytes suggesting a relevant role for either communication with synaptic plaque or contraction dynamics.

Palliative care (PC) is an approach that improves the quality of life (QoL) of patients and their families facing the problem associated with incurable terminal disease. A number of QoL assessment tools have been validated in PC and their use described for research purposes, to support clinical practice, and as part of the quality improvement programs. There is a paucity of evidence on the implementation of a nursing intervention focused on QoL assessment in PC practice. The aim of this study is to model and determine the feasibility of a nursing complex intervention focused on QoL assessment in PC practice. The intervention will be evaluated through a quasi-experimental non-equivalent comparison group before-after study design. This project can be classified as phases 1–2, according to the Medical Research Council (MRC) framework for the development and evaluation of complex interventions. The study setting will take place in two inpatient hospice units in Italy. The study sample will be constituted of 39 multidisciplinary healthcare professionals and a sample of 46 advanced cancer patients admitted to hospices during the implementation of the intervention. This study will generate information to address the implementation of QoL measurement in palliative care practice. Findings of this study will be used to inform a phase 3 trial according to the MRC framework. ISRCTN41201864 retrospectively registered.

Background Despite the steady growth of the immigrant population in Italy, data on the health status of immigrants are scarce. Our main goals were to measure Health-Related Quality of Life (HRQoL), Self-Rated Health (SRH) and morbidity among immigrants in Genoa. We aimed to assess the relative contribution of some social, structural and behavioral determinants to “within-group” health disparities. Methods We enrolled 502 subjects by means of snowball sampling. The SF-12 questionnaire, integrated with socio-demographic and health-related items, was used. Multivariate logistic and Poisson regression models were applied in order to identify characteristics associated with poor SRH, lower SF-12 scores and prevalence of self-reported morbidities. Results Subjects showed relatively moderate levels of HRQoL (median physical and mental scores of 51.6 and 47.3, respectively) and about 15% of them rated their health as fair or poor. Lower scores in the physical dimension of HRQoL were associated with the presence of morbidities and immigration for work and religious reasons, while those who had migrated for religious and family reasons displayed a lower probability of lower scores in the mental dimension of HRQoL. Poor SRH was associated with female gender, overweight/obesity and presence of morbidities. Moreover, compared with immigrants from countries with a low human development index, immigrants from highly developed societies showed significantly lower odds of reporting poor SRH. About one-third of respondents reported at least one medical condition, while the prevalence of multi-morbidity was 10%. Females, over 45-year-olds, overweight and long-term immigrants had a higher prevalence of medical conditions. Conclusions Our study confirms the presence of health inequalities within a heterogeneous immigrant population. HRQoL, SRH and morbidity are valid, relatively rapid and cheap tools for measuring health inequalities, though they do so in different ways. These indicators should be used with caution and, if possible, simultaneously, as they could help to identify and to monitor more vulnerable subjects among immigrants.