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Combined NMDA Inhibitor Use in a Patient With Multisubstance-induced Psychotic Disorder

This document is an Accepted Manuscript reprinted from Journal of Addiction Medicine, Vol. 12 (3): 247-251, May 2018, with permission of Kluwer Law International. Under embargo until 1 May 2019. The Version of Record is available online at DOI: https://doi.org/10.1097/ADM.0000000000000390: Novel psychoactive substance use is a major social concern. Their use may elicit or uncover unpredictably as yet undescribed clinical pictures. We aimed to illustrate a multisubstance use case indistinguishable from paranoid schizophrenia, so to alert clinicians on possibly misdiagnosing substance-induced psychotic disorders. CASE REPORT: We describe a case of a 32-year-old man who started at 18 years with cannabinoids and ketamine, and is currently using N-methyl-D-aspartate (NMDA) antagonists. At age 23, he developed social withdrawal after being assaulted by a stranger, but did not consult psychiatrists until age 26; during this period, he was using internet-purchased methoxetamine and ketamine, and was persecutory, irritable, suspicious, and insomniac and discontinued all received medical prescriptions. He added dextromethorphan to his list of used substances. At age 31, while using phencyclidine, and, for the first time, methoxphenidine, he developed a religious delusion, involving God calling him to reach Him, and the near-death experiences ensured by NMDA antagonists backed his purpose. He received Diagnostic and Statistical Manual of Mental Disorders, 5th Edition diagnosis of multisubstance-induced psychotic disorder and was hospitalized 8 times, 6 of which after visiting the emergency room due to the development of extreme anguish, verbal and physical aggression, and paranoia. He reportedly used methoxphenidine, methoxyphencyclidine, ethylnorketamine, norketamine, and deschlorketamine, to achieve near-death experiences, and eventually to reach God in heavens. CONCLUSIONS: This case points to the need for better control of drugs sold on the internet. It also illustrates that people using NMDA antagonists may present clinical pictures indistinguishable from those of major psychoses and are likely to be misdiagnosed.Peer reviewe

Prognostic features of gastro-entero-pancreatic neuroendocrine neoplasms in primary and metastatic sites: Grade, mesenteric tumour deposits and emerging novelties

Updates in classification of gastro-entero-pancreatic neuroendocrine neoplasms better reflect the biological characteristics of these tumours. In the present study, we analysed the characteristics of neuroendocrine tumours that could aid in a more precise stratification of risk groups. In addition, we have highlighted the importance of grade (re)assessment based on investigation of secondary tumour lesions. Two hundred and sixty-four cases of neuroendocrine tumours of gastro-entero-pancreatic origin from three centres were included in the study. Tumour morphology, mitotic count and Ki67 labelling index were evaluated in specimens of primary tumours, lymph node metastases and distant metastases. These variables were correlated with overall survival (OS) and relapse-free survival (RFS). Tumour stage, number of affected lymph nodes, presence of tumour deposits and synchronous/metachronous metastases were tested as possible prognostic features. Mitotic count, Ki-67 labelling index, primary tumour site, tumour stage, presence of tumour deposits and two or more affected lymph nodes were significant predictors of OS and RFS. At the same time, mitotic count and Ki-67 labelling index can be addressed as continuous variables determining prognosis. We observed a very high correlation between the measures of proliferative activity in primary and secondary tumour foci. The presence of isolated tumour deposits was identified as an important determinant of both RFS and OS for pancreatic (hazard ratio [HR] = 7.61, 95% confidence interval [CI] = 3.96-14.6, P < 0.0001 for RFS; HR = 3.28, 95% CI = 1.56-6.87, P = 0.0017 for OS) and ileal/jejunal neuroendocrine tumours (HR = 1.98, 95% CI = 1.25-3.13, P = 0.0036 for RFS and HR 2.59, 95% CI = 1.27-5.26, P = 0.009 for OS). The present study identifies the presence of mesenterial tumour deposits as an important prognostic factor for gastro-entero-pancreatic neuroendocrine tumours, provides evidence that proliferative parameters need to be treated as continuous variables and further supports the importance of grade determination in all available tumour foci

Addressing the Role of Angiogenesis in Patients with Advanced Pancreatic Neuroendocrine Tumors Treated with Everolimus: A Biological Prospective Analysis of Soluble Biomarkers and Clinical Outcomes

Simple Summary Despite the approval of new targeted therapies for pancreatic neuroendocrine tumors (PanNETs) over the past decades, the early identification of resistant tumors remains the major challenge, mainly because clear signs of tumor shrinkage are rarely achieved by imaging assessment. Starting from the hypothesis that angiogenesis can be implicated in the resistance to mTOR inhibitors, we evaluated a specific angiogenesis panel (through the measurement of soluble biomarkers for angiogenesis turnover, circulating endothelial cells, and circulating progenitors) as possible predictors of resistance to everolimus or everolimus efficacy in PanNETs. Our study showed that none of the investigated categories of biomarkers had a predictive value for everolimus resistance or efficacy. However, we suggest that circulating endothelial progenitors might be surrogate biomarkers for angiogenesis activity in PanNETs during everolimus treatment, and their baseline levels might correlate with survival outcomes. These data have never been reported before for NETs. Background: The success of targeted therapies in the treatment of pancreatic neuroendocrine tumors has emphasized the strategy of targeting angiogenesis and the PI3K/AKT/mTOR pathway. However, the major challenge in the targeted era remains the early identification of resistant tumors especially when the efficacy is rarely associated to a clear tumor shrinkage at by imaging assessment. Methods: In this prospective study (NCT02305810) we investigated the predictive and prognostic role of soluble biomarkers of angiogenesis turnover (VEGF, bFGF, VEGFR2, TSP-1) circulating endothelial cells and progenitors, in 43 patients with metastatic panNET receiving everolimus. Results: Among all tested biomarkers, we found a specific subpopulation of circulating cells, CD31+CD140b-, with a significantly increased tumor progression hazard for values less or equal to the first quartile. Conclusion: Our study suggested the evidence that circulating cells might be surrogate biomarkers of angiogenesis activity in patients treated with everolimus and their baseline levels can be correlated with survival. However, further studies are now needed to validate the role of these cells as surrogate markers for the selection of patients to be candidates for antiangiogenic treatments

Use of benzylglycinamide by a HIV-seropositive polysubstance user: : the changing pattern of novel psychoactive substance use among youths

This document is the Accepted Manuscript of the following article: Matteo Caloro, et al, ‘Use of benzylglycinamide by a HIV-seropositive polysubstance user: The changing pattern of novel psychoactive substance use among youths’, Addictive Behaviors, Vol. 60, pp. 53-57, September 2016. The Version of Record is available online at doi: https://doi.org/10.1016/j.addbeh.2016.03.032. © 2016 Elsevier Ltd. All rights reserved.A 24-year old woman with multisubstance use since the age of 13, including opioids and cocaine, and long-standing HIV/HCV seropositivity status, presented with psychosis, agitation, and insomnia at the emergency department of a university hospital. She had been abusive and physically aggressive frequently without specific reasons and was involved in criminal legal cases. She was hospitalized twice. During her first hospital stay she experienced a brief episode of detachment from her environment, similar to episodes reportedly suffered at home. Psychosis had developed following heavy polysubstance abuse. Her mother provided sachets containing benzylglycinamide, a substance with no known psychotropic effects, which were also present in the patient's urine. She was occasionally positive for cannabinoids. She used to buy various novel psychoactive substances (NPSs) from the internet and used experimentally various substances freely made available to her by drug suppliers/dealers. She was unable to explain clearly why she was taking any of the identified NPS. She stated she was taking benzylglycinamide to calm her when smoking synthetic cannabinoids. While it appears that benzylglycinamide is not likely to constitute a novel drug of abuse, her polysubstance use exemplifies trends in NPS use patterns among the youths in the Western world and should alert mental health workers as to the possible dangers of such behavior and its reflection on social behavior and psychopathology.Peer reviewedFinal Accepted Versio

Risk-taking and reasons for living in non-clinical Italian university students.

The associations between risk-taking, hopelessness, and reasons for living were explored in a sample of 312 Italian students. Respondents completed the Physical Risk Assessment Inventory, the Physical Risk-Taking Behavior Inventory, the Beck Hopelessness Scale, and the Reasons for Living Inventory. Students with lower scores on the Reasons for Living Inventory and higher scores on the Beck Hopelessness Scale rated the risky activities as less risky and engaged in them more often. Women obtained higher scores on risk assessment, lower scores on personal risk-taking and higher scores on the Reasons for Living Inventory and most of its subscales. Men in general and people who take risks and perceive lower risk are more hopeless and relatively weak in reasons for living

Correlations between cortical gyrification and schizophrenia symptoms with and without comorbid hostility symptoms

Introduction: Interest in identifying the clinical implications of the neuropathophysiological background of schizophrenia is rising, including changes in cortical gyrification that may be due to neurodevelopmental abnormalities. Inpatients with schizophrenia can show abnormal gyrification of cortical regions correlated with the symptom severity. Methods: Our study included 36 patients that suffered an acute episode of schizophrenia and have undergone structural magnetic resonance imaging (MRI) to calculate the local gyrification index (LGI). Results: In the whole sample, the severity of symptoms significantly correlated with higher LGI in different cortical areas, including bilateral frontal, cingulate, parietal, temporal cortices, and right occipital cortex. Among these areas, patients with low hostility symptoms (LHS) compared to patients with high hostility symptoms (HHS) showed significantly lower LGI related to the severity of symptoms in bilateral frontal and temporal lobes. Discussion: The severity of psychopathology correlated with higher LGI in large portions of the cerebral cortex, possibly expressing abnormal neural development in schizophrenia. These findings could pave the way for further studies and future tailored diagnostic and therapeutic strategies

Automated Analysis of Proliferating Cells Spatial Organisation Predicts Prognosis in Lung Neuroendocrine Neoplasms

SIMPLE SUMMARY: Lung neuroendocrine neoplasms (lung NENs) are categorised by morphology, defining a classification sometimes unable to reflect ultimate clinical outcome, particularly for the intermediate domains of adenocarcinomas and large-cell neuroendocrine carcinomas. Moreover, subjectivity and poor reproducibility characterise diagnosis and prognosis assessment of all NENs. The aim of this study was to design and evaluate an objective and reproducible approach to the grading of lung NENs, potentially extendable to other NENs, by exploring a completely new perspective of interpreting the well-recognised proliferation marker Ki-67. We designed an automated pipeline to harvest quantitative information from the spatial distribution of Ki-67-positive cells, analysing its heterogeneity in the entire extent of tumour tissue—which currently represents the main weakness of Ki-67—and employed machine learning techniques to predict prognosis based on this information. Demonstrating the efficacy of the proposed framework would hint at a possible path for the future of grading and classification of NENs. ABSTRACT: Lung neuroendocrine neoplasms (lung NENs) are categorised by morphology, defining a classification sometimes unable to reflect ultimate clinical outcome. Subjectivity and poor reproducibility characterise diagnosis and prognosis assessment of all NENs. Here, we propose a machine learning framework for tumour prognosis assessment based on a quantitative, automated and repeatable evaluation of the spatial distribution of cells immunohistochemically positive for the proliferation marker Ki-67, performed on the entire extent of high-resolution whole slide images. Combining features from the fields of graph theory, fractality analysis, stochastic geometry and information theory, we describe the topology of replicating cells and predict prognosis in a histology-independent way. We demonstrate how our approach outperforms the well-recognised prognostic role of Ki-67 Labelling Index on a multi-centre dataset comprising the most controversial lung NENs. Moreover, we show that our system identifies arrangement patterns in the cells positive for Ki-67 that appear independently of tumour subtyping. Strikingly, the subset of these features whose presence is also independent of the value of the Labelling Index and the density of Ki-67-positive cells prove to be especially relevant in discerning prognostic classes. These findings disclose a possible path for the future of grading and classification of NENs

Studio immunoistochimico e molecolare di parametri biologici correlati con la resistenza al trastuzumab nei pazienti affetti da carcinoma mammario metastatico HER-2/neu positivo

Il nostro studio prospettico ha lo scopo di identificare dei parametri biomolecolari (EGFR, PTEN, p-Akt, HER3, c-Met, IGF1R) la cui espressione, nei carcinomi mammari metastatici HER-2/neu positivi, possa predire la risposta al trastuzumab, considerando che la percentuale di non progressione ad un anno dall’inizio del trattamento è del 40% circa. Materiali e Metodi: Sono state valutate l’espressione immunoistochimica di EGFR, PTEN, pAkt, HER, c-Met e IGF1R e l’amplificazione del gene EGFR tramite FISH in 101 carcinomi mammari metastatici HER-2/neu positivi trattati con trastuzumab. Le pazienti, con follow-up noto, sono state controllate fino al decesso o a settembre 2009. Le pazienti sono state distribuite (“modalità di risposta”) nei gruppi di resistenza, di refrattarietà o di risposta al trastuzumab. Sono stati considerati 13,0 mesi come cut-off per considerare una paziente come rispondente o non rispondente al trattamento. Risultati: Nella casistica, la percentuale di risposta al trastuzumab è del 40,2%. Lo stato recettoriale ha mostrato una correlazione statisticamente significativa diretta con PTEN (P=0,021 e P=0,005 per recettori estrogenici e progestinici) ed inversa con EGFR (P=0,006 per recettori estrogenici) e pAkt (P=0,031 per recettori progestinici). E’ stata evidenziata una correlazione bassa e inversa tra PTEN e pAkt (P<0,001). Esistono correlazioni statisticamente significative tra il parametro “modalità di risposta” e pAkt ed EGFR. L’analisi discriminante ha selezionato i parametri EGFR e pAkt con sensibilità del 57,6%, specificità del 73,8%, accuratezza del 64,4%, valore predittivo positivo del 75,5% e predittivo negativo del 55,4%. Conclusioni: La paziente, in virtù del suo profilo d’espressione, se assegnata al gruppo di predizione dei rispondenti, avrà una probabilità del 75,5% di rispondere al trastuzumab. Ciò va oltre quel 40% di risposta globale che non considera lo specifico profilo molecolare della neoplasia