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Stefania Benini,1 Gabriella Gamberi,1,2 Stefania Cocchi,1 Jessica Garbetta,1 Laurent Alberti,3 Alberto Righi,1 Marco Gambarotti,1 Piero Picci,1 Stefano Ferrari4 1Department of Pathology, Rizzoli Institute, Bologna, 2Department of Biomedical and Neuromotor Science, University of Bologna, Bologna, Italy; 3Department of Pathology, Centre Léon Bérard, Lyon, France; 4Department of Chemotherapy, Rizzoli Institute, Bologna, Italy Background: Circulating tumor cells (CTCs) analysis is a promising new diagnostic field to estimate risk and monitor treatment efficacy, metastatic relapse, and progression in cancer patients. The study aim was to isolate and characterize CTCs in blood samples of Ewing sarcoma (ES) patients exploiting two main characteristics: CD99 expression and presence of chromosomal translocations.Materials and methods: The method isolated CTCs from peripheral blood (PB) of ES patients. Cell-surface CD99 was a useful marker for CTCs determined using immunomagnetic separation with microbeads and CD99 monoclonal antibody. We tested sensitivity and specificity by detecting CTCs in blood collected from healthy donors and randomly during therapy from 18 ES patients. Evidence of CTCs was confirmed by detection of specific molecular markers using quantitative and digital reverse transcription-polymerase chain reaction targeting EWSR1/FLI1 type 1 and type 2 or EWSR1/ETS-related gene transcripts type 1 and type 9e.Results: Feasibility of finding CTCs in PB of ES patients by immunoseparation with CD99 antibody and magnetic microbeads was demonstrated for the first time. At molecular analysis, three PB specimens tested positive for chimeric EWSR1/FLI1 type 2 and one PB for chimeric EWSR1/FLI1 type 2. CTCs detection was found above a limit of detection of 1 cell/mL of PB.Conclusion: CTCs in PB of ES patients can be identified by this method and in ES CTCs analysis can be used as a liquid biopsy approach for prognostic and predictive purposes. The potential clinical implications of CTCs in PB samples detected by the platform for CTC isolation with molecular confirmation during therapy require further evaluation. Keywords: circulating tumor cells, anti-CD99 antibody, magnetic beads, Ewing sarcoma, immunoseparation, liquid biopsy

Numerous investigations have characterized the oscillatory dynamics serving working memory in adults, but few have probed its relationship with chronological age in developing youth. We recorded magnetoencephalography during a modified Sternberg verbal working memory task in 82 youth participants aged 6–14 years old. Significant oscillatory responses were identified and imaged using a beamforming approach and the resulting whole-brain maps were probed for developmental effects during the encoding and maintenance phases. Our results indicated robust oscillatory responses in the theta (4–7 Hz) and alpha (8–14 Hz) range, with older participants exhibiting stronger alpha oscillations in left-hemispheric language regions. Older participants also had greater occipital theta power during encoding. Interestingly, there were sex-by-age interaction effects in cerebellar cortices during encoding and in the right superior temporal region during maintenance. These results extend the existing literature on working memory development by showing strong associations between age and oscillatory dynamics across a distributed network. To our knowledge, these findings are the first to link chronological age to alpha and theta oscillatory responses serving working memory encoding and maintenance, both across and between male and female youth; they reveal robust developmental effects in crucial brain regions serving higher order functions.

The lack of adequate regulation in the art market, combined with the frequent complexities in verifying the exact provenance and authenticity of artworks and antiquities, intensifies with alarming frequency a long series of risk factors associated with cultural heritage, from illicit excavation and looting to forgeries and unlawful imports that originate from the artistically and archaeologically richest countries, reaching – following numerous cross-border passages – up to Western markets. The article analyzes the main criminological characteristics of this phenomenon, assessing how some market operators usually play the role of interfaces between the legal and illegal domains. Providing criminal networks free access to the sale of illicitly stolen goods, contributing to attributing them a false origin and, consequently, high profitability, these actors can foster fraudulent schemes disguised as sales operations.

Summary: Background: Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance. Methods: Fresh frozen samples of MPNSTs (n = 94) and benign neurofibromas (n = 28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival. Findings: MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. “Immune active” MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P = 0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P = 0.003). “Immune deficient” MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P

The neural and cognitive processes underlying the flexible allocation of attention undergo a protracted developmental course with changes occurring throughout adolescence. Despite documented age-related improvements in attentional reorienting throughout childhood and adolescence, the neural correlates underlying such changes in reorienting remain unclear. Herein, we used magnetoencephalography (MEG) to examine neural dynamics during a Posner attention-reorienting task in 80 healthy youth (6–14 years old). The MEG data were examined in the time-frequency domain and significant oscillatory responses were imaged in anatomical space. During the reorienting of attention, youth recruited a distributed network of regions in the fronto-parietal network, along with higher-order visual regions within the theta (3–7 Hz) and alpha-beta (10–24 Hz) spectral windows. Beyond the expected developmental improvements in behavioral performance, we found stronger theta oscillatory activity as a function of age across a network of prefrontal brain regions irrespective of condition, as well as more limited age- and validity-related effects for alpha-beta responses. Distinct brain-behavior associations between theta oscillations and attention-related symptomology were also uncovered across a network of brain regions. Taken together, these data are the first to demonstrate developmental effects in the spectrally-specific neural oscillations serving the flexible allocation of attention.

Abstract Background Giant cell tumour of bone (GCTB) is an expansile osteolytic tumour which contains numerous osteoclast-like giant cells. GCTB frequently recurs and can produce metastatic lesions in the lungs. Bisphosphonates are anti-resorptive drugs which act mainly on osteoclasts. Method In this study, we have examined clinical and radiological outcomes of treatment with aminobisphosphonates on 25 cases of aggressive primary, recurrent and metastatic GCTB derived from four European centres. We also analysed in vitro the inhibitory effect of zoledronic acid on osteoclasts isolated from GCTBs. Results Treatment protocols differed with several different aminobisphosphonates being employed, but stabilisation of disease was achieved in most of these cases which were refractory to conventional treatment. Most inoperable sacral/pelvic tumours did not increase in size and no further recurrence was seen in GCTBs that had repeatedly recurred in bone and soft tissues. Lung metastases did not increase in size or number following treatment. Zoledronic acid markedly inhibited lacunar resorption by GCTB-derived osteoclasts in vitro. Conclusion Our findings suggest that bisphosphonates may be useful in controlling disease progression in GCTB and that these agents directly inhibit GCTB - derived osteoclast resorption. These studies highlight the need for the establishment of standardised protocols to assess the efficacy of bisphosphonate treatment of GCTB.

Abstract Background Pulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone. Results Using parallel oligonucleotide array platforms, shared orthologues between species were identified and normalized. The osteosarcoma expression signatures could not distinguish the canine and human diseases by hierarchical clustering. Cross-species target mining identified two genes, interleukin-8 (IL-8) and solute carrier family 1 (glial high affinity glutamate transporter), member 3 (SLC1A3), which were uniformly expressed in dog but not in all pediatric osteosarcoma patient samples. Expression of these genes in an independent population of pediatric osteosarcoma patients was associated with poor outcome (p = 0.020 and p = 0.026, respectively). Validation of IL-8 and SLC1A3 protein expression in pediatric osteosarcoma tissues further supported the potential value of these novel targets. Ongoing evaluation will validate the biological significance of these targets and their associated pathways. Conclusions Collectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapies.

Abstract Background Osteosarcoma (OS) is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory. Results We investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM) as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006) in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice. Conclusion In conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.

Abstract Background Ewing sarcoma family of tumors (ESFT), characterized by t(11;22)(q24;q12), is one of the most common tumors of bone in children and young adults. In addition to EWS/FLI1 gene fusion, copy number changes are known to be significant for the underlying neoplastic development of ESFT and for patient outcome. Our genome-wide high-resolution analysis aspired to pinpoint genomic regions of highest interest and possible target genes in these areas. Methods Array comparative genomic hybridization (CGH) and expression arrays were used to screen for copy number alterations and expression changes in ESFT patient samples. A total of 31 ESFT samples were analyzed by aCGH and in 16 patients DNA and RNA level data, created by expression arrays, was integrated. Time of the follow-up of these patients was 5–192 months. Clinical outcome was statistically evaluated by Kaplan-Meier/Logrank methods and RT-PCR was applied on 42 patient samples to study the gene of the highest interest. Results Copy number changes were detected in 87% of the cases. The most recurrent copy number changes were gains at 1q, 2, 8, and 12, and losses at 9p and 16q. Cumulative event free survival (ESFT) and overall survival (OS) were significantly better (P < 0.05) for primary tumors with three or less copy number changes than for tumors with higher number of copy number aberrations. In three samples copy number imbalances were detected in chromosomes 11 and 22 affecting the FLI1 and EWSR1 loci, suggesting that an unbalanced t(11;22) and subsequent duplication of the derivative chromosome harboring fusion gene is a common event in ESFT. Further, amplifications on chromosomes 20 and 22 seen in one patient sample suggest a novel translocation type between EWSR1 and an unidentified fusion partner at 20q. In total 20 novel ESFT associated putative oncogenes and tumor suppressor genes were found in the integration analysis of array CGH and expression data. Quantitative RT-PCR to study the expression levels of the most interesting gene, HDGF, confirmed that its expression was higher than in control samples. However, no association between HDGF expression and patient survival was observed. Conclusion We conclude that array CGH and integration analysis proved to be effective methods to identify chromosome regions and novel target genes involved in the tumorigenesis of ESFT.

Abstract Osteosarcoma is a primary malignant tumour of the skeleton characterised by the direct formation of immature bone or osteoid tissue by the tumour cells. The classic osteosarcoma is a rare (0.2% of all malignant tumours) highly malignant tumour, with an estimated incidence of 3 cases/million population/year. Osteosarcoma arises predominantly in the long bones and rarely in the soft tissues. The age at presentation ranges from 10 to 25 years of age. Plain radiographs, computed tomography, magnetic resonance imaging, angiography and dynamic bone scintigraphy are used for diagnosis, evaluation the extent of tumour involvement and decision of the type of operation and, if necessary, the type of reconstruction. Years ago, all patients with osteosarcoma were treated by amputation but the cure rate was under 10% and almost all patients died within a year from diagnosis. Today, for localised osteosarcoma at onset (80% of cases) treated in specialized bone tumour centres with pre- and postoperative chemotherapy associated with surgery, the percentage of patients cured varies between 60% and 70%. Surgery is conservative (limb salvage) in more than 90% of patients. Prognosis is more severe (cure rate about 30%) for tumours located in the axial skeleton and in patients with metastasis at onset.

The optimization of the brake systems is crucial for vehicle performance and safety of Formula SAE (FSAE) race cars. This study introduces a specialized brake test bench designed to enhance the understanding and testing of these systems. The bench integrates a rotating mechanical system mounting a brake disc-caliper group, which is driven by an electric motor, a pneumatic brake pedal assembly to simulate real braking conditions, and a comprehensive array of sensors that facilitate the measurement of critical parameters, such as rotation speed, braking torque, oil pressure, and disc temperature. Its structure, sensor integration, and control electronics are fully described, demonstrating the capability to replicate on-track scenarios in a controlled environment. The results underscore the utility of the bench in providing precise and consistent testing conditions essential for analyzing the efficiency, durability, and safety of the braking systems of FSAE race cars.

Recent investigations have studied the development of motor-related oscillatory responses to delineate maturational changes from childhood to young adulthood. While these studies included youth during the pubertal transition period, none have probed the impact of testosterone levels on motor cortical dynamics and performance. We collected salivary testosterone samples and recorded magnetoencephalography during a complex motor sequencing task in 58 youth aged 9–15 years old. The relationships between testosterone, age, task behavior, and beta (15–23 Hz) oscillatory dynamics were examined using multiple mediation modeling. We found that testosterone mediated the effect of age on movement-related beta activity. We also found that the effect of age on movement duration was mediated by testosterone and reaction time. Interestingly, the relationships between testosterone and motor performance were not mediated by beta activity in the left primary motor cortex, which may indicate the importance of higher-order motor regions. Overall, our results suggest that testosterone has unique associations with neural and behavioral indices of complex motor performance, beyond those already characterized in the literature. These findings are the first to link developmental changes in testosterone levels to maturation of beta oscillatory dynamics serving complex motor planning and execution, and specific measures of motor performance.

The default mode network (DMN) plays a crucial role in internal self-processing, rumination, and social functions. Disruptions to DMN connectivity have been linked with early adversity and the emergence of psychopathology in adolescence and early adulthood. Herein, we investigate how subclinical psychiatric symptoms can impact DMN functional connectivity during the pubertal transition. Resting-state fMRI data were collected annually from 190 typically-developing youth (9–15 years-old) at three timepoints and within-network DMN connectivity was computed. We used latent growth curve modeling to determine how self-reported depressive and posttraumatic stress symptoms predicted rates of change in DMN connectivity over the three-year period. In the baseline model without predictors, we found no systematic changes in DMN connectivity over time. However, significant modulation emerged after adding psychopathology predictors; greater depressive symptomatology was associated with significant decreases in connectivity over time, whereas posttraumatic stress symptoms were associated with significant increases in connectivity over time. Follow-up analyses revealed that these effects were driven by connectivity changes involving the dorsal medial prefrontal cortex subnetwork. In conclusion, these data suggest that subclinical depressive and posttraumatic symptoms alter the trajectory of DMN connectivity, which may indicate that this network is a nexus of clinical significance in mental health disorders.

Elevated plasma lipoprotein(a) [Lp(a)] is a relatively common and highly heritable trait conferring individuals time-dependent risk of developing atherosclerotic cardiovascular disease (CVD). Following its first description, Lp(a) triggered enormous scientific interest in the late 1980s, subsequently dampened in the mid-1990s by controversial findings of some prospective studies. It was only in the last decade that a large body of evidence has provided strong arguments for a causal and independent association between elevated Lp(a) levels and CVD, causing renewed interest in this lipoprotein as an emerging risk factor with a likely contribution to cardiovascular residual risk. Accordingly, the 2022 consensus statement of the European Atherosclerosis Society has suggested inclusion of Lp(a) measurement in global risk estimation. The development of highly effective Lp(a)-lowering drugs (e.g., antisense oligonucleotides and small interfering RNA, both blocking LPA gene expression) which are still under assessment in phase 3 trials, will provide a unique opportunity to reduce “residual cardiovascular risk” in high-risk populations, including patients with arterial hypertension. The current evidence in support of a specific role of Lp(a) in hypertension is somehow controversial and this narrative review aims to overview the general mechanisms relating Lp(a) to blood pressure regulation and hypertension-related cardiovascular and renal damage.

BackgroundAmong sarcomas, which are rare cancers with an incidence of 24 months. Nine patients had at least one grade 3/4 adverse event, mostly being bone marrow toxicity (n=6).ConclusionsTrabectedin has some anti-tumor activity in some ultra-rare and other rare sarcomas, particularly translocation-related sarcomas, with the well-known manageable safety profile.

Children show substantial variation in the rate of physical, cognitive, and social maturation as they traverse adolescence and enter adulthood. Differences in developmental paths are thought to underlie individual differences in later life outcomes, however, there remains a lack of consensus on the normative trajectory of cognitive maturation in adolescence. To address this problem, we derive a Cognitive Maturity Index (CMI), to estimate the difference between chronological and cognitive age predicted with latent factor estimates of inhibitory control, risky decision-making and emotional processing measured with standard neuropsychological instruments. One hundred and forty-one children from the Adolescent Development Study (ADS) were followed longitudinally across three time points from ages 11–14, 13–16, and 14–18. Age prediction with latent factor estimates of cognitive skills approximated age within ±10 months (r = 0.71). Males in advanced puberty displayed lower cognitive maturity relative to peers of the same age; manifesting as weaker inhibitory control, greater risk-taking, desensitization to negative affect, and poor recognition of positive affect.

Dehydroepiandrosterone (DHEA) production is closely associated with the first pubertal hormonal event, adrenarche. Few studies have documented the relationships between DHEA and functional brain development, with even fewer examining the associations between DHEA and spontaneous cortical activity during the resting-state. Thus, whether DHEA levels are associated with the known developmental shifts in the brain’s idling cortical rhythms remains poorly understood. Herein, we examined spontaneous cortical activity in 71 typically-developing youth (9–16 years; 32 male) using magnetoencephalography (MEG). MEG data were source imaged and the power within five canonical frequency bands (delta, theta, alpha, beta, gamma) was computed to identify spatially- and spectrally-specific effects of salivary DHEA and DHEA-by-sex interactions using vertex-wise ANCOVAs. Our results indicated robust increases in power with increasing DHEA within parieto-occipital cortices in all frequency bands except alpha, which decreased with increasing DHEA. In the delta band, DHEA and sex interacted within frontal and temporal cortices such that with increasing DHEA, males exhibited increasing power while females showed decreasing power. These data suggest that spontaneous cortical activity changes with endogenous DHEA levels during the transition from childhood to adolescence, particularly in sensory and attentional processing regions. Sexually-divergent trajectories were only observed in later-developing frontal cortical areas.

Background Trait dissociation has not been examined from a structural human brain mapping perspective in healthy adults or children. Non-pathological dissociation shares some features with daydreaming and mind-wandering, but also involves subtle disruptions in affect and autobiographical memory. Aims To identify neurostructural biomarkers of trait dissociation in healthy children. Method Typically developing 9- to 15-year-olds (n = 180) without psychological or behavioural disorders were enrolled in the Developmental Chronnecto-Genomics (DevCoG) study of healthy brain development and completed psychological assessments of trauma exposure and dissociation, along with a structural T1-weighted magnetic resonance imaging. We conducted univariate ANCOVA generalised linear models for each region of the default mode network examining the effects of trait dissociation, including scanner site, age, gender and trauma as covariates and correcting for multiple comparison. Results We found that the precuneus was significantly larger in children with higher levels of trait dissociation but this was not related to trauma exposure. The inferior parietal volume was smaller in children with higher levels of trauma but was not related to dissociation. No other regions of interest, including frontal and limbic structures, were significantly related to trait dissociation even before multiple comparison correction. Conclusions Trait dissociation reflects subtle cognitive disruptions worthy of study in healthy people and warrants study as a potential risk factor for psychopathology. This neurostructural study of trait dissociation in healthy children identified the precuneus as an essential brain region to consider in future dissociation research.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including alpha-linolenic acid (ALA) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are “essential” fatty acids mainly obtained from diet sources comprising plant oils, marine blue fish, and commercially available fish oil supplements. Many epidemiological and retrospective studies suggested that ω-3 PUFA consumption decreases the risk of cardiovascular disease, but results of early intervention trials have not consistently confirmed this effect. In recent years, some large-scale randomized controlled trials have shed new light on the potential role of ω-3 PUFAs, particularly high-dose EPA-only formulations, in cardiovascular prevention, making them an attractive tool for the treatment of “residual” cardiovascular risk. ω-3 PUFAs' beneficial effects on cardiovascular outcomes go far beyond the reduction in triglyceride levels and are thought to be mediated by their broadly documented “pleiotropic” actions, most of which are directed to vascular protection. A considerable number of clinical studies and meta-analyses suggest the beneficial effects of ω-3 PUFAs in the regulation of blood pressure in hypertensive and normotensive subjects. These effects occur mostly through regulation of the vascular tone that could be mediated by both endothelium-dependent and independent mechanisms. In this narrative review, we summarize the results of both experimental and clinical studies that evaluated the effect of ω-3 PUFAs on blood pressure, highlighting the mechanisms of their action on the vascular system and their possible impact on hypertension, hypertension-related vascular damage, and, ultimately, cardiovascular outcomes.

The vast majority of individuals experience trauma within their lifetime. Yet, most people do not go on to develop clinical levels of psychopathology. Recently, studies have highlighted the potential protective effects of having larger amygdala and hippocampal volumes, such that larger volumes may promote adaptive functioning following trauma. However, research has not yet elucidated whether certain subregions of these stress-sensitive structures have specific protective effects. Herein, we examined the mediating effects of amygdala and hippocampal subregions on the relationship between traumatic exposure and concurrent or longitudinal changes in psychiatric symptom levels in typically developing youth (9–15 years of age). Using high-resolution T1-and T2-weighted structural MRI scans, we found that the volume of the right basolateral complex of the amygdala mediated associations between trauma exposure and internalizing symptoms. Specifically, greater levels of childhood trauma related to larger volumes, and larger volumes were associated with fewer internalizing symptoms. The volume of the right CA4/dentate gyrus (DG) of the hippocampus yielded similar mediation results, such that greater trauma was related to larger volumes, which in turn were associated with decreases in internalizing symptoms across time. These findings provide initial support for potentially protective effects of larger right amygdala and hippocampal subregion volumes against internalizing symptomology concurrently and longitudinally during adolescence.

Abstract Background Giant cell tumor of bone (GCTB) is a rare osteoclastogenic stromal tumor. GCTB can rarely undergo malignant transformation. This post hoc analysis evaluated and classified malignancies in patients with GCTB who received denosumab. Methods This analysis was conducted on patients with pathologically confirmed GCTB and measurable active disease treated with denosumab 120 mg subcutaneously once every 4 weeks, with loading doses on study days 8 and 15, as part of a phase 2, open-label, multicenter study. We identified potential cases of malignancy related to GCTB through an independent multidisciplinary review or medical history, associated imaging or histopathologic reports, and disease course. The findings were summarized and no statistical analysis was performed. Results Twenty of five hundred twenty-six patients (3.8%) who received at least one dose of denosumab were misdiagnosed with GCTB that was later discovered to be malignancies: five primary malignant GCTB, five secondary malignant GCTB, four sarcomatous transformations, and six patients with other malignancies (giant cell-rich osteosarcoma, undifferentiated pleomorphic sarcoma, spindle cell sarcoma, osteogenic sarcoma, phosphaturic mesenchymal tumor of mixed connective tissue type, and fibrosarcoma/malignant fibrous histiocytoma). Many malignancies were present before denosumab was initiated (8 definitive cases, 7 likely cases), excluding potential involvement of denosumab in these cases. Signs associated with potential misdiagnoses of GCTB included poor mineralization with denosumab treatment, rapid relapse in pain, or a failure of the typical dramatic improvement in pain normally observed with denosumab. Conclusions Although rare, GCTB can undergo malignant transformation, and rates in this study were consistent with previous reports. Signs of poor mineralization or lack of response to denosumab treatment may warrant close monitoring. Trial registration clinicaltrials.gov , ( NCT00680992 ). Registered May 20, 2008.

According to the 2021 World Drug Report, around 275 million people use drugs of abuse, and 36 million people suffer from addiction, fostering a thriving market for illicit substances. In Italy, 30,083 people were reported to the Judicial Authority for offenses in violation of the Italian Law D.P.R. 309/1990. These offences are sentenced after a qualitative–quantitative analysis of seized materials. Given the large quantity of seized drugs and the need to perform accurate analytical determinations, Italian forensic laboratories struggle to complete analyses in a short time, delaying the entire reporting process needed to achieve sentencing. For this purpose, an UHPLC-MS/MS-based platform was developed at the University of Milano-Bicocca to support law-enforcement authorities. Software was designed to easily manage street seizure acquisition, documentation registration, and sampling. A sensitive UHPLC-MS/MS method was fully validated for the quantification of the traditional illicit substances (cocaine, heroin, 6-MAM, morphine, amphetamine, methamphetamine, MDMA, ketamine, GHB, GBL, LSD, trans-∆9-THC, and THCA) at the ppb level. The final report is relayed to the Prefecture in 3–4 days, even within 24 h for urgent requests. The platform allows for semi-automatic data handling to minimize erroneous results for an accurate report generation by standardized procedures.

Introduction: Neuroendocrine tumors (NETs) are rare and malignant neoplasms characterized by their potential to produce metabolically active substances with the capacity to bring about clinical syndromes. The clinical expression of serotonin-producing NETs is known as carcinoid syndrome (CS). The synthesis of serotonin in the brain is dependent on tryptophan availability. At the central level, serotonin is indispensable for mood, anxiety, and sleep regulation. In CS patients, around 60% of all tryptophan is reported to be consumed by tumor cells for the peripheral synthesis of serotonin, increasing the risk of a central deficiency and thus psychiatric disorders. Materials and methods: This manuscript reviews the existing literature about psychiatric disorders associated with NETs and addresses the safety of psychiatric drugs in these patients. A systematic search of the biomedical literature was performed using the following databases: PubMed, Embase, CINAHL (EBSCO), PsycInfo (OVID), and Cochrane CENTRAL (Wiley). The database search included articles published between January 1965 and February 2021. Relevant information were charted using a calibrated charting-form. Results: Twenty-two articles were included in the present review. The overall population size of the studies came to 3319 patients. All patients presented a confirmed diagnosis of NET. The information about the presence of CS was confirmed in 351 cases. The psychiatric symptoms reported included mood disturbances (including, depression and anxiety), psychoses, impulse control disorders and sleeping alterations. We also evaluated the presence of cognitive impairments in NET patients. Finally, we summarize the available data regarding the safety of psychiatric drugs in this setting. Conclusions: Psychiatric disorders among NET patients are poorly recognized, and therefore have received very little research attention. As a result, no standardized algorithm is presently available. Our findings support detailed psychiatric evaluation in NET patients, especially in those presenting CS and symptoms suggestive of psychiatric involvement. Not only do cognitive impairment and psychiatry symptoms negatively impact health-related quality of life in cancer patients, they can also reduce survival rates.

Parkinson’s disease (PD) is a complex pathology causing a plethora of non-motor symptoms besides classical motor impairments, including cognitive disturbances. Recent studies in the PD human brain have reported microgliosis in limbic and neocortical structures, suggesting a role for neuroinflammation in the development of cognitive decline. Yet, the mechanism underlying the cognitive pathology is under investigated, mainly for the lack of a valid preclinical neuropathological model reproducing the disease’s motor and non-motor aspects. Here, we show that the bilateral intracerebral infusion of pre-formed human alpha synuclein oligomers (H-αSynOs) within the substantia nigra pars compacta (SNpc) offers a valid model for studying the cognitive symptoms of PD, which adds to the classical motor aspects previously described in the same model. Indeed, H-αSynOs-infused rats displayed memory deficits in the two-trial recognition task in a Y maze and the novel object recognition (NOR) test performed three months after the oligomer infusion. In the anterior cingulate cortex (ACC) of H-αSynOs-infused rats the in vivo electrophysiological activity was altered and the expression of the neuron-specific immediate early gene (IEG) Npas4 (Neuronal PAS domain protein 4) and the AMPA receptor subunit GluR1 were decreased. The histological analysis of the brain of cognitively impaired rats showed a neuroinflammatory response in cognition-related regions such as the ACC and discrete subareas of the hippocampus, in the absence of any evident neuronal loss, supporting a role of neuroinflammation in cognitive decline. We found an increased GFAP reactivity and the acquisition of a proinflammatory phenotype by microglia, as indicated by the increased levels of microglial Tumor Necrosis Factor alpha (TNF-α) as compared to vehicle-infused rats. Moreover, diffused deposits of phospho-alpha synuclein (p-αSyn) and Lewy neurite-like aggregates were found in the SNpc and striatum, suggesting the spreading of toxic protein within anatomically interconnected areas. Altogether, we present a neuropathological rat model of PD that is relevant for the study of cognitive dysfunction featuring the disease. The intranigral infusion of toxic oligomeric species of alpha-synuclein (α-Syn) induced spreading and neuroinflammation in distant cognition-relevant regions, which may drive the altered neuronal activity underlying cognitive deficits.

The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.