Publications by authors named "Marco Rossi"

323 Publications

Negative motor responses to direct electrical stimulation: Behavioral assessment hides different effects on muscles.

Cortex 2021 Jan 29;137:194-204. Epub 2021 Jan 29.

Laboratory of Motor Control, Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Humanitas Research Hospital IRCSS, Rozzano, Milano, Italy. Electronic address:

A negative motor response (NMR) is defined as the inability to continue voluntary movements without losing consciousness when direct electrical stimulation (DES) is applied during awake neurosurgery. While visual inspection is most commonly used to define an NMR, the actual effect of stimulation on muscle activity has been neglected by recent neurosurgical literature. We show that behavioral assessment of NMRs hides different site-dependent effects on muscles as revealed by electromyography (EMG), describing ten cases of brain tumor patients undergoing awake neurosurgery while performing a hand-object manipulation task. DES-induced NMRs were assessed behaviorally and related to the underlying electromyographic recording. Quantitative analysis of motor unit recruitment and regularity between phasic muscle contractions was computed. We show that similar NMRs classified based on behavioral criteria can be associated with suppression, increased recruitment or mixed effects on ongoing hand muscles. In some cases, suppression of hand muscle activity is associated with involuntary recruitment of muscles not involved in the task. Interestingly, stimulation of behaviorally defined "negative areas" across the frontal and parietal lobes elicits different electromyographic patterns, depending on the stimulation site. This study provides novel preliminary background as to the heterogeneous profile of muscle activity during NMRs. In fact, EMG monitoring paired with behavioral assessment can distinguish between NMRs that, despite similarity on behavioral inspection, are different in their related EMG, possibly underlying different neural substrates. The identification of different circuits hidden in similar NMRs may become relevant when planning the extension of resection.
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http://dx.doi.org/10.1016/j.cortex.2021.01.005DOI Listing
January 2021

Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia.

J Immunother Cancer 2021 02;9(2)

Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Catanzaro, Italy

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a poor cure rate for relapsed/resistant patients. Due to the lack of T-cell restricted targetable antigens, effective immune-therapeutics are not presently available and the treatment of chemo-refractory T-ALL is still an unmet clinical need. To develop novel immune-therapy for T-ALL, we generated an afucosylated monoclonal antibody (mAb) (ahuUMG1) and two different bispecific T-cell engagers (BTCEs) against UMG1, a unique CD43-epitope highly and selectively expressed by T-ALL cells from pediatric and adult patients.

Methods: UMG1 expression was assessed by immunohistochemistry (IHC) on a wide panel of normal tissue microarrays (TMAs), and by flow cytometry on healthy peripheral blood/bone marrow-derived cells, on 10 different T-ALL cell lines, and on 110 T-ALL primary patient-derived cells. CD43-UMG1 binding site was defined through a peptide microarray scanning. ahuUMG1 was generated by Genetic Glyco-Engineering technology from a novel humanized mAb directed against UMG1 (huUMG1). BTCEs were generated as IgG1-(scFv) constructs with bivalent (2+2) or monovalent (2+1) CD3ε arms. Antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) and redirected T-cell cytotoxicity assays were analysed by flow cytometry. In vivo antitumor activity of ahUMG1 and UMG1-BTCEs was investigated in NSG mice against subcutaneous and orthotopic xenografts of human T-ALL.

Results: Among 110 T-ALL patient-derived samples, 53 (48.1%) stained positive (24% of TI/TII, 82% of TIII and 42.8% of TIV). Importantly, no expression of UMG1-epitope was found in normal tissues/cells, excluding cortical thymocytes and a minority (<5%) of peripheral blood T lymphocytes. ahUMG1 induced strong ADCC and ADCP on T-ALL cells in vitro, which translated in antitumor activity in vivo and significantly extended survival of treated mice. Both UMG1-BTCEs demonstrated highly effective killing activity against T-ALL cells in vitro. We demonstrated that this effect was specifically exerted by engaged activated T cells. Moreover, UMG1-BTCEs effectively antagonized tumor growth at concentrations >2 log lower as compared with ahuUMG1, with significant mice survival advantage in different T-ALL models in vivo.

Conclusion: Altogether our findings, including the safe UMG1-epitope expression profile, provide a framework for the clinical development of these innovative immune-therapeutics for this still orphan disease.
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http://dx.doi.org/10.1136/jitc-2020-002026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893666PMC
February 2021

Place your bets: pediatric pain is no longer a game for gamblers.

Minerva Anestesiol 2021 Feb 16. Epub 2021 Feb 16.

Department of Anesthesia and Intensive Care, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Catholic University of the Sacred Heart, Rome, Italy.

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http://dx.doi.org/10.23736/S0375-9393.21.15443-4DOI Listing
February 2021

Clinical Pearls and Methods for Intraoperative Motor Mapping.

Neurosurgery 2021 02;88(3):457-467

Neurosurgery , Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milano, Italy.

Resection of brain tumors involving motor areas and pathways requires the identification and preservation of various cortical and subcortical structures involved in motor control at the time of the procedure, in order to maintain the patient's full motor capacities. The use of brain mapping techniques has now been integrated into clinical practice for many years, as they help the surgeon to identify the neural structures involved in motor functions. A common definition of motor function, as well as knowledge of its neural organization, has been continuously evolving, underlining the need for implementing intraoperative strategies at the time of the procedure. Similarly, mapping strategies have been subjected to continuous changes, enhancing the likelihood of preservation of full motor capacities. As a general rule, the motor mapping strategy should be as flexible as possible and adapted strictly to the individual patient and clinical context of the tumor. In this work, we present an overview of current knowledge of motor organization, indications for motor mapping, available motor mapping, and monitoring strategies, as well as their advantages and limitations. The use of motor mapping improves resection and outcomes in patients harboring tumors involving motor areas and pathways, and should be considered the gold standard in the resection of this type of tumor.
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http://dx.doi.org/10.1093/neuros/nyaa359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884143PMC
February 2021

Case Report: A Case Report of Stereotactic Ventricular Arrhythmia Radioablation (STAR) on Large Cardiac Target Volume by Highly Personalized Inter- and Intra-fractional Image Guidance.

Front Cardiovasc Med 2020 23;7:565471. Epub 2020 Nov 23.

Dipartimento di Scienze Cardiovascolari, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Although catheter ablation is the current gold standard treatment for refractory ventricular arrhythmias, sometimes its efficacy is not optimal and it's associated with high risks of procedural complication and death. Stereotactic arrhythmia radioablation (STAR) is increasingly being adopted for such clinical presentation, considering its efficacy and safety. We do report our experience managing a case of high volume of left ventricle for refractory ventricular tachycardia in advanced heart failure patient, by delivering a single fraction of STAR through an highly personalization of dose delivery applying repeated inter- and continuous intra-fraction image guidance. According to the literature reports, we recommend considering increasing as much as possible the personalization features and safety technical procedure as long as that is not significantly affecting the STAR duration. Moreover, the duration in itself shouldn't be the main parameter, but balanced into the frame of possibly obtainable outcome improvement. At best of our knowledge, this is the first report applying such specific technology onto this clinical setting. Future studies will clarify these issues.
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http://dx.doi.org/10.3389/fcvm.2020.565471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719630PMC
November 2020

Raman Spectroscopic Stratification of Multiple Myeloma Patients Based on Exosome Profiling.

ACS Omega 2020 Dec 18;5(47):30436-30443. Epub 2020 Nov 18.

BioNEM (Bio and Nano Engineering for Medicine) Laboratory, Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia, 88100 Catanzaro, Italy.

Multiple myeloma (MM) is a hematological malignancy characterized by abnormal plasma cell proliferation within the bone marrow which leads to progressive bone marrow failure, skeletal osteolytic lesions, and renal insufficiency, thus severely affecting the quality of life. MM is always preceded by monoclonal gammopathy of uncertain significance (MGUS), which progresses to asymptomatic-MM (aMM) or symptomatic-MM (sMM) at a rate of 1% per year. Despite impressive progress in the therapy of the disease, MM remains incurable. Based on these premises, the identification of biomarkers of MGUS progression to MM is a crucial issue in disease management. In this regard, exosomes (EXs) and their precious biomolecular cargo could play a pivotal role in MM detection, stratification, and follow-up. Raman spectroscopy, a label- and manipulation-free technique, and its enhanced version, surface-enhanced Raman spectroscopy (SERS), have been used for characterizing MGUS, aMM, and sMM patient-derived EXs. Here, we have demonstrated the capability of Raman spectroscopy for discriminating EXs along the progression from MGUS to aMM and sMM, thus providing useful clinical indications for patient care. The used SERS devices, based on random nanostructures, have shown good potential in terms of sensitivity, but further developments are needed for achieving reproducible and quantitative SERS results.
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http://dx.doi.org/10.1021/acsomega.0c03813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711702PMC
December 2020

Advancing Imaging to Enhance Surgery: From Image to Information Guidance.

Neurosurg Clin N Am 2021 Jan 5;32(1):31-46. Epub 2020 Nov 5.

IRCCS Istituto Ortopedico Galeazzi, U.O. Neurochirurgia Oncologica, Milan, Italy; Department of Oncology and Hemato-Oncology, Via Festa del Perdono 7, Milan 20122, Italy.

Conventional magnetic resonance imaging (cMRI) has an established role as a crucial disease parameter in the multidisciplinary management of glioblastoma, guiding diagnosis, treatment planning, assessment, and follow-up. Yet, cMRI cannot provide adequate information regarding tissue heterogeneity and the infiltrative extent beyond the contrast enhancement. Advanced magnetic resonance imaging and PET and newer analytical methods are transforming images into data (radiomics) and providing noninvasive biomarkers of molecular features (radiogenomics), conveying enhanced information for improving decision making in surgery. This review analyzes the shift from image guidance to information guidance that is relevant for the surgical treatment of glioblastoma.
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http://dx.doi.org/10.1016/j.nec.2020.08.003DOI Listing
January 2021

Surgery for Glioblastoma in Elderly Patients.

Neurosurg Clin N Am 2021 Jan 5;32(1):137-148. Epub 2020 Nov 5.

IRCCS Istituto Ortopedico Galeazzi, Neurochirurgia Oncologica, Milan, Italy; Department of Medical Biotechnology and Translational Medicine, Universita` degli Studi di Milano, Via Festa del Perdono 7, Milan 20122, Italy.

The management of glioblastoma in the elderly population represents a field of growing interest owing a longer life expectancy. In this age group, more than in the young adult, biological age is much more important than chronologic one. The date of birth should not exclude a priori access of treatments. Maximal safe resection is proved to be the first option when performance status and general health is good. Adjuvant therapy and decision about management of recurrence should be choose in a multidisciplinary group according to performance of the patients and O-methylguanine-DNA methyl-transferase methylation.
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http://dx.doi.org/10.1016/j.nec.2020.08.008DOI Listing
January 2021

Effectiveness of anesthetic solutions for pain control in lower third molar extraction surgeries: a systematic review of randomized clinical trials with network meta-analysis.

Clin Oral Investig 2021 Jan 8;25(1):1-22. Epub 2020 Nov 8.

Postgraduate Program in Dentistry, Faculdade São Leopoldo Mandic, Campinas, Brazil.

Objective: To assess the effectiveness of different anesthetic solutions for pain control immediately after the extraction of lower third molars.

Methods: Nine databases were used to identify randomized clinical trials, without restriction of language or year of publication. The "JBI Critical Appraisal Tools for Systematic Reviews" was used to assess the risk of bias in the studies. The network meta-analysis was performed to compare the effectiveness of different anesthetics to control the pain immediately after the surgery of lower third molars, using the standardized mean difference (SMD) as the effect estimate. The GRADE approach was used to assess the certainty of evidence.

Results: The search presented 13,739 initial results, from which 45 met the eligibility criteria and presented low to moderate risk of bias. Thirteen studies were included in the meta-analysis. The 2% lidocaine + clonidine presented the lowest pain scores (SMD = - 1.44; - 2.72 to - 0.16) compared to 4% articaine + adrenaline, followed by 0.5% bupivacaine + adrenaline (SMD = - 1.36; - 2.13 to - 0.59). The certainty of evidence varied between very low to moderate.

Conclusion: 2% lidocaine + clonidine and 0.5% bupivacaine + adrenaline were the anesthetics with the highest probability for pain control immediately after the surgical procedure of removing impacted lower third molars.

Clinical Significance: The use of an adequate anesthetic with effective pain control can contribute to a more comfortable postoperative period.
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http://dx.doi.org/10.1007/s00784-020-03675-wDOI Listing
January 2021

A proteomics approach to further highlight the altered inflammatory condition in Rett syndrome.

Arch Biochem Biophys 2020 12 5;696:108660. Epub 2020 Nov 5.

Plants for Human Health Institute, Animal Science Dept., NC Research Campus, NC State University, 600 Laureate Way, Kannapolis, NC, 28081, USA; Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Ferrara, Italy; Kyung Hee University, Department of Food and Nutrition, Seoul, South Korea. Electronic address:

Rett syndrome (RTT) is a progressive neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. RTT patients show multisystem disturbances associated with perturbed redox homeostasis and inflammation, which appear as possible key factors in RTT pathogenesis. In this study, using primary dermal fibroblasts from control and RTT subjects, we performed a proteomic analysis that, together with data mining approaches, allowed us to carry out a comprehensive characterization of RTT cellular proteome. Functional and pathway enrichment analyses showed that differentially expressed proteins in RTT were mainly enriched in biological processes related to immune/inflammatory responses. Overall, by using proteomic data mining as supportive approach, our results provide a detailed insight into the molecular pathways involved in RTT immune dysfunction that, causing tissue and organ damage, can increase the vulnerability of affected patients to unknown endogenous factors or infections.
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http://dx.doi.org/10.1016/j.abb.2020.108660DOI Listing
December 2020

Association of Supratotal Resection with Progression-Free Survival, Malignant Transformation, and Overall Survival in Lower-Grade Gliomas.

Neuro Oncol 2020 Oct 13. Epub 2020 Oct 13.

Neurosurgical Oncology Unit, Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Istituto Ortopedico Galeazzi, IRCCS, Milano, Italy.

Background: supratotal resection is advocated in lower-grade-gliomas (LGGs) based on theoretical advantages, but with limited verification of functional risk and data on oncological outcomes. We assessed the association of supratotal resection in molecular-defined LGGs with oncological outcomes.

Methods: 460 presumptive LGGs included; 404 resected; 347 were LGGs, 319 IDH-mutated, 28 wildtype. All patients had clinical, imaging, molecular data. Resection aimed at supratotal resection without any patient or tumor a-priori selection. The association of Extent-of-Resection (EOR), categorized on volumetric-FLAIR-images as residual-tumor-volume, along with post-surgical-management with Progression-free-survival (PFS), malignant-progression-free-survival (MPFS), and Overall-Survival (OS) assessed by univariate, multivariate, propensity-score-analysis. The study mainly focused on IDH-mutated-LGGs, the "typical LGGs".

Results: Median follow-up:6.8 years(IQR:5-8). Out of 319 IDH-mutated-LGGs, 190 (59.6%) progressed, median PFS:4.7 years(95%CI:4-5.3). Total and supratotal resection obtained in 39% and 35% of patients of IDH1-mutated tumors. In IDH-mutated, most patients in partial/subtotal group progressed, 82.4% in total, only 6 (5.4%) in supratotal. Median PFS was 29 months(95%CI:25-36) in subtotal, 46 months(95%CI:38-48) in total, while at 92 months, PFS in supratotal was 94.0%. There was no association with molecular-subtypes and grade. At random-forest-analysis, PFS strongly associated with EOR,RT, previous treatment. In the propensity-score analysis, EOR associated with PFS (HR,0.03;95%CI,0.01-0.13). MPFS occurred in 32.1% of subtotal-total groups; 1 event in supratotal. EOR, grade-III, previous treatment correlated to MPFS. At random-forest analysis, OS associated with EOR as well.

Conclusions: Supratotal resection strongly associated with PFS, MPFS and OS in LGGs, regardless of molecular subtypes and grade, right from the beginning of clinical presentation.
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http://dx.doi.org/10.1093/neuonc/noaa225DOI Listing
October 2020

Preserving Visual Functions During Gliomas Resection: Feasibility and Efficacy of a Novel Intraoperative Task for Awake Brain Surgery.

Front Oncol 2020 2;10:1485. Epub 2020 Sep 2.

Neurosurgical Oncological Unit, Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milano, Italy.

The intraoperative identification and preservation of optic radiations (OR) during tumor resection requires the patient to be awake. Different tasks are used. However, they do not grant the maintenance of foveal vision during all testing, limiting the ability to constantly monitor the peripheral vision and to inform about the portion of the peripheral field that is encountered. Although hemianopia can be prevented, quadrantanopia cannot be properly avoided. To overcome these limitations, we developed an intra-operative Visual field Task (iVT) to monitor the foveal vision, alerting about the likelihood of injuring the OR during task administration, and to inform about the portion of the peripheral field that is explored. Data on feasibility and efficacy in preventing visual field deficits are reported, comparing the outcome with the standard available task (Double-Picture-Naming-Task, DPNT). Patients with a temporal and/or parietal lobe tumor in close morphological relationship with the OR, or where the resection can involve the OR at any extent, without pre-operative visual-field deficits (Humphrey) were enrolled. Fifty-four patients were submitted to iVT, 38 to DPNT during awake surgery with brain mapping neurophysiological techniques. Feasibility was assessed as ease of administration, training and mapping time, and ability to alert about the loss of foveal vision. Type and location of evoked interferences were registered. Functional outcome was evaluated by manual and Humphrey test; extent of resection was recorded. Tractography was performed in a sample of patients to compare patient anatomy with intraoperative stimulation site(s). The test was easy to administer and detected the loss of foveal vision in all cases. Stimulation induced visual-field interferences, detected in all patients, classified as detection or discrimination errors. Detection was mostly observed in temporal tumors, discrimination in temporo-parietal ones. Immediate visual disturbances in DPNT group were registered in 84 vs. 24% of iVT group. At 1-month Humphrey evaluation, 26% of iVT vs. 63% of DPNT had quadrantanopia (32% symptomatic); 10% of DPNT had hemianopia. EOR was similar. Detection errors were induced for stimulation of OR; discrimination also for other visual processing tract (ILF). iVT was feasible and sensitive to preserve the functional integrity of the OR.
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http://dx.doi.org/10.3389/fonc.2020.01485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492569PMC
September 2020

A New Model of Chronic Lung Infection in Immunocompetent Mice.

Int J Mol Sci 2020 Sep 9;21(18). Epub 2020 Sep 9.

Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.

Pulmonary infections caused by (MA) have increased over recent decades, affecting individuals with underlying pathologies such as chronic obstructive pulmonary disease, bronchiectasis and, especially, cystic fibrosis. The lack of a representative and standardized model of chronic infection in mice has limited steps forward in the field of pulmonary infection. To overcome this challenge, we refined the method of agar beads to establish chronic infection in immunocompetent mice. We evaluated bacterial count, lung pathology and markers of inflammation and we performed longitudinal studies with magnetic resonance imaging (MRI) up to three months after infection. In this model, was able to establish a persistent lung infection for up to two months and with minimal systemic spread. Lung histopathological analysis revealed granulomatous inflammation around bronchi characterized by the presence of lymphocytes, aggregates of vacuolated histiocytes and a few neutrophils, mimicking the damage observed in humans. Furthermore, lung lesions were successfully monitored for the first time by MRI. The availability of this murine model and the introduction of the successfully longitudinal monitoring of the murine lung lesions with MRI pave the way for further investigations on the impact of pathogenesis and the efficacy of novel treatments.
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http://dx.doi.org/10.3390/ijms21186590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554715PMC
September 2020

Non-Coding RNAs in Multiple Myeloma Bone Disease Pathophysiology.

Noncoding RNA 2020 Sep 9;6(3). Epub 2020 Sep 9.

Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy.

Bone remodeling is uncoupled in the multiple myeloma (MM) bone marrow niche, resulting in enhanced osteoclastogenesis responsible of MM-related bone disease (MMBD). Several studies have disclosed the mechanisms underlying increased osteoclast formation and activity triggered by the various cellular components of the MM bone marrow microenvironment, leading to the identification of novel targets for therapeutic intervention. In this regard, recent attention has been given to non-coding RNA (ncRNA) molecules, that finely tune gene expression programs involved in bone homeostasis both in physiological and pathological settings. In this review, we will analyze major signaling pathways involved in MMBD pathophysiology, and report emerging evidence of their regulation by different classes of ncRNAs.
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http://dx.doi.org/10.3390/ncrna6030037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549375PMC
September 2020

Granisetron transdermal system and dexamethasone for the prevention of nausea and vomiting in multiple myeloma patients receiving chemo-mobilization: An observational real-world study of effectiveness and safety.

Transfus Apher Sci 2020 Dec 24;59(6):102911. Epub 2020 Aug 24.

CNR-IFC, Research Unit of Reggio Calabria, Reggio Calabria, Italy.

Purpose: Cyclophosphamide (CY) in a dose of 2-4 g/m is widely used for hemopoietic progenitor stem cells mobilization. CY administration is associated with several adverse effects, including chemotherapy-induced nausea and vomiting (CINV). This study aimed to evaluate the efficacy and tolerability of granisetron transdermal system (GTDS) plus dexamethasone in the management of CINV in MM patients undergoing chemo-mobilization with CY.

Methods: In this single-center, prospective, observational, real world study, GTDS plus dexamethasone was administered to MM patients receiving chemo-mobilization based on CY 2 g/m2 plus G-CSF in an outpatient setting. The rate of complete response was evaluated as the main outcome. Other outcomes were rate of complete control of CINV, incidence of nausea/vomiting of any grade and safety.

Results: A total of 88 patients were enrolled. A complete response was achieved in 45.5 % of patients; among them, 39.77 % attained complete control of CINV. Nausea and vomiting never occurred in 34.1 % and 45.5 % of patients, respectively. No episodes of grade 3-4 nausea and/or vomiting were documented. GTDS was safe and well tolerated.

Conclusion: In real world, GTDS provided an innovative, effective, and well-tolerated control of CINV in MM patients after chemo-mobilization with CY. The study found out effectiveness of a non-invasive delivery system of antiemetic.
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http://dx.doi.org/10.1016/j.transci.2020.102911DOI Listing
December 2020

Mycosis fungoides and gastric T-cell lymphoma: A case report.

Mol Clin Oncol 2020 Sep 6;13(3):15. Epub 2020 Jul 6.

Department of Health Sciences, University 'Magna Græcia' of Catanzaro, Catanzaro I-88100, Italy.

Mycosis fungoides (MF) is a cutaneous malignant lymphoma with an extended clinical course. MF presents in series of dermatological manifestations, beginning with patches and plaques of the skin, and eventually evolving into tumours. Often MF can occur for extended periods without worsening of external symptoms, while the disease advances internally in organs such as lymph nodes, liver, spleen, lung, bone marrow, gastrointestinal tract, pancreas and kidney. The present report presents a clinical case in which gastrointestinal symptomatology occurred a decade after the first dermatological manifestation. Immunohistochemical analysis of the skin, along with small bowel biopsies revealed evidence of gastric T-cell lymphoma. To the best of our knowledge, the present study is the first to describe such a case in the literature.
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http://dx.doi.org/10.3892/mco.2020.2085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391825PMC
September 2020

COVID-19 Sepsis and Microcirculation Dysfunction.

Front Physiol 2020 26;11:747. Epub 2020 Jun 26.

Department of Science for Health Promotion and Mother to Child Care, University of Palermo, Palermo, Italy.

The spreading of Coronavirus (SARS-CoV-2) pandemic, known as COVID-19, has caused a great number of fatalities all around the World. Up to date (2020 May 6) in Italy we had more than 28,000 deaths, while there were more than 205.000 infected. The majority of patients affected by COVID-19 complained only slight symptoms: fatigue, myalgia or cough, but more than 15% of Chinese patients progressed into severe complications, with acute respiratory distress syndrome (ARDS), needing intensive treatment. We tried to summarize data reported in the last months from several Countries, highlighting that COVID-19 was characterized by cytokine storm (CS) and endothelial dysfunction in severely ill patients, where the progression of the disease was fast and fatal. Endothelial dysfunction was the fundamental mechanism triggering a pro-coagulant state, finally evolving into intravascular disseminated coagulation, causing embolization of several organs and consequent multiorgan failure (MOF). The Italian Society of Clinical Hemorheology and Microcirculation was aimed to highlight the role of microcirculatory dysfunction in the pathogenetic mechanisms of COVID-19 during the spreading of the biggest challenges to the World Health.
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http://dx.doi.org/10.3389/fphys.2020.00747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333313PMC
June 2020

miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma.

Leukemia 2021 Mar 6;35(3):823-834. Epub 2020 Jul 6.

Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.

Multiple myeloma (MM) is tightly dependent on inflammatory bone marrow microenvironment. IL-17 producing CD4+ T cells (Th17) sustain MM cells growth and osteoclasts-dependent bone damage. In turn, Th17 differentiation relies on inflammatory stimuli. Here, we investigated the role of miR-21 in Th17-mediated MM tumor growth and bone disease. We found that early inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired Th17 differentiation in vitro and abrogated Th17-mediated MM cell proliferation and osteoclasts activity. We validated these findings in NOD/SCID-g-NULL mice, intratibially injected with miR-21i-T cells and MM cells. A Pairwise RNAseq and proteome/phosphoproteome analysis in Th17 cells demonstrated that miR-21 inhibition led to upregulation of STAT-1/-5a-5b, STAT-3 impairment and redirection of Th17 to Th1/Th2 like activated/polarized cells. Our findings disclose the role of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract microenvironment dependence of MM growth and bone disease.
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http://dx.doi.org/10.1038/s41375-020-0947-1DOI Listing
March 2021

Comparison between sedation room and operating room in central venous catheter positioning in children.

J Vasc Access 2020 Jun 22:1129729820932415. Epub 2020 Jun 22.

Department of Anesthesia and Pain Therapy, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy.

Background: Placement of central venous access devices is a clinical procedure associated with some risk of adverse events and with a relevant cost. Careful choice of the device, appropriate insertion technique, and proper management of the device are well-known strategies commonly adopted to achieve an optimal clinical result. However, the environment where the procedure takes place may have an impact on the overall outcome in terms of safety and cost-effectiveness.

Methods: We carried out a retrospective analysis on pediatric patients scheduled for a major neurosurgical operation, who required a central venous access device in the perioperative period. We divided the patients in two groups: in group A the central venous access device was inserted in the operating room, while in group B the central venous access device was inserted in the sedation room of our Pediatric Intensive Care Unit. We compared the two groups in terms of safety and cost-effectiveness.

Results: We analyzed 47 central venous access devices in 42 children. There were no insertion-related complications. Only one catheter-related bloodstream infection was recorded, in group A. However, the costs related to central venous access device insertion were quite different: €330-€540 in group A versus €105-€135 in group B.

Conclusion: In the pediatric patient candidate to a major neurosurgical operation, preoperative insertion of the central venous access device in the sedation room rather than in the operating room is less expensive and equally safe.
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http://dx.doi.org/10.1177/1129729820932415DOI Listing
June 2020

Androgen Deprivation Therapy for Prostatic Cancer in Patients With Torsades de Pointes.

Front Pharmacol 2020 13;11:684. Epub 2020 May 13.

Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

Background: Men normally have shorter heart rate-corrected QT interval (QTc) than women, at least in part due to accelerating effects of testosterone on ventricular repolarization. Accumulating data suggest that androgen-deprivation therapy (ADT) used for the treatment of prostatic cancer, may increase Torsades de Pointes (TdP) risk by prolonging QTc. However, the evidence for such an association is currently limited to few case reports, in most cases deriving from the analysis of uncontrolled sources such as pharmacovigilance databases.

Objective: To better determine the clinical impact of ADT on TdP development, we examined the prevalence of this therapy in a consecutive cohort of 66 TdP patients, prospectively collected over a ~10 years period.

Methods And Results: We found and described four patients who were under ADT for prostatic cancer when TdP occurred, and in two cases degenerated to cardiac arrest. Notably, in this unselected population, ADTs unexpectedly represented the second most frequently administered QT-prolonging medication in males (4/24, 17%), after amiodarone. Moreover, in the ADT patients, a blood withdrawal was performed within 24 h from TdP/marked QTc prolongation occurrence and circulating concentration of androgens and gonadothropins were measured. As expected, all cases showed markedly reduced testosterone levels (total, free, and available).

Conclusion: We provide evidence that a significant proportion of patients developing TdP were under treatment with ADT for prostatic cancer, thus confirming the clinical relevance of previous pharmacovigilance signals. An accurate assessment of the arrhythmic risk profile should be included in the standard of care of prostatic cancer patients before starting ADT.
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http://dx.doi.org/10.3389/fphar.2020.00684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239032PMC
May 2020

Proteomic profiling reveals mitochondrial alterations in Rett syndrome.

Free Radic Biol Med 2020 08 20;155:37-48. Epub 2020 May 20.

Plants for Human Health Institute, Animal Science Dept., NC Research Campus, NC State University, 600 Laureate Way, Kannapolis, NC, 28081, USA; Department of Biomedical and Specialist Surgical Sciences, Section of Medical Biochemistry, Molecular Biology and Genetics, University of Ferrara, Ferrara, Italy; Kyung Hee University, Department of Food and Nutrition, Seoul, South Korea. Electronic address:

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder associated with mutation in MECP2 gene. Despite a well-defined genetic cause, there is a growing consensus that a metabolic component could play a pivotal role in RTT pathophysiology. Indeed, perturbed redox homeostasis and inflammation, i.e. oxinflammation, with mitochondria dysfunction as the central hub between the two phenomena, appear as possible key contributing factors to RTT pathogenesis and its clinical features. While these RTT-related changes have been widely documented by transcriptomic profiling, proteomics studies supporting these evidences are still limited. Here, using primary dermal fibroblasts from control and patients, we perform a large-scale proteomic analysis that, together with data mining approaches, allow us to carry out the first comprehensive characterization of RTT cellular proteome, showing mainly changes in expression of proteins involved in the mitochondrial network. These findings parallel with an altered expression of key mediators of mitochondrial dynamics and mitophagy associated with abnormal mitochondrial morphology. In conclusion, our proteomic analysis confirms the pathological relevance of mitochondrial dysfunction in RTT pathogenesis and progression.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.05.014DOI Listing
August 2020

The scalp block for postoperative pain control in craniosynostosis surgery: a case control study.

Childs Nerv Syst 2020 Dec 17;36(12):3063-3070. Epub 2020 May 17.

Anesthesia and Intensive care, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy.

Purpose: Postoperative analgesia after corrective surgery of pediatric craniosynostosis is crucial in terms of short- and long-term outcomes. The objective of this observational study was to evaluate the effectiveness of an analgesic technique based on the scalp block versus traditional pharmacological approach.

Methods: Thirteen patients, aged between 3 months and 2 years, undergoing surgical correction of craniosynostosis, received scalp nerve block before awakening (scalp block group). This group of patients was compared to a second group of 13 patients, retrieved from our database, treated with the traditional pharmacological approach (control group). Pain scores, need of rescue therapy, resumption of oral nutrition, degree of parent satisfaction at discharge, and length of stay in the Pediatric Intensive Care Unit (PICU) and in the hospital were compared between the two groups.

Results: Objective Pain Score values were significantly lower in patients treated with scalp block at 30 min and at 8 h after extubation. The number of pharmacological interventions for the treatment of pain in PICU was significantly higher in Control group. Children in Scalp block group started earlier oral feeding than in Control group, both for clear fluids and milk. Length of stay in PICU was longer in Scalp block group than in Control group, though the difference between the mean data in the two groups is about 3 . This difference does not seem significant from a clinical standpoint, since it seems more related to logistic issues (e.g., availability of bed in the Pediatric Neurosurgery Unit, presence of a parent), rather than clinical problems contraindicating the discharge from PICU. Indeed, the overall hospital length of stay was similar between the two groups.

Conclusion: Scalp nerve block was effective for immediate postoperative pain control in patients younger than 2 years who underwent cranioplasty for craniosynostosis. The best pain control compared to conventional therapy allowed to limit the need for rescue analgesics in PICU and an earlier recovery time. ClinicalTrials.gov Identification: NCT04133467.
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http://dx.doi.org/10.1007/s00381-020-04661-zDOI Listing
December 2020

Evolution, Predictors, and Neurocognitive Effects of Silent Cerebral Embolism During Transcatheter Aortic Valve Replacement.

JACC Cardiovasc Interv 2020 06 13;13(11):1291-1300. Epub 2020 May 13.

Cardiac Catheterization Laboratory, Cardiothoracic and Vascular Department, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.

Objectives: The aim of this study was to assess the characteristics, predictors, evolution, and neurocognitive effects of silent cerebral ischemic lesions (SCILs).

Background: Most patients undergoing transcatheter aortic valve replacement (TAVR) develop SCILs detectable on magnetic resonance imaging (MRI). The natural history and clinical relevance of SCILs are not well established.

Methods: Cerebral MRI was performed within 7 days before TAVR to assess baseline status and age-related white matter change score. MRI was repeated post-operatively to assess the occurrence, location, number, and dimensions of SCILs. Patients developing SCILs underwent a third MRI examination at 3- to 5-month follow-up. A neurocognitive evaluation was performed before TAVR, at discharge, and at 3-month follow-up.

Results: Of the 117 patients enrolled, 96 underwent post-procedural MRI; SCILs were observed in 76% of patients, distributed in all vascular territories, with a median number of 2 lesions, a median diameter of 4.5 mm, and a median total volume of 140 mm. Independent predictors of SCIL occurrence were higher baseline age-related white matter change score and the use of self-expanding or mechanically expanded bioprostheses. Among 47 patients who underwent follow-up MRI, only 26.7% of post-procedural SCILs evolved into gliotic scar. SCIL occurrence was associated with a more pronounced transient neurocognitive decline early after TAVR and with lower recovery at follow-up.

Conclusions: SCILs occur in the vast majority of patients undergoing TAVR and are predicted by more diffuse white matter damage at baseline and by the use of non-balloon-expandable prostheses. Although most SCILs disappear within months, their occurrence has a limited but significant impact on neurocognitive function.
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http://dx.doi.org/10.1016/j.jcin.2020.03.004DOI Listing
June 2020

Determination of Total Silicon and SiO Particles Using an ICP-MS Based Analytical Platform for Toxicokinetic Studies of Synthetic Amorphous Silica.

Nanomaterials (Basel) 2020 May 6;10(5). Epub 2020 May 6.

Istituto Superiore di Sanità-National Institute of Health, 00161 Rome, Italy.

Synthetic amorphous silica (SAS), manufactured in pyrogenic or precipitated form, is a nanomaterial with a widespread use as food additive (E 551). Oral exposure to SAS results from its use in food and dietary supplements, pharmaceuticals and toothpaste. Recent evidence suggests that oral exposure to SAS may pose health risks and highlights the need to address the toxic potential of SAS as affected by the physicochemical characteristics of the different forms of SAS. For this aim, investigating SAS toxicokinetics is of crucial importance and an analytical strategy for such an undertaking is presented. The minimization of silicon background in tissues, control of contamination (including silicon release from equipment), high-throughput sample treatment, elimination of spectral interferences affecting inductively coupled plasma mass spectrometry (ICP-MS) silicon detection, and development of analytical quality control tools are the cornerstones of this strategy. A validated method combining sample digestion with silicon determination by reaction cell ICP-MS is presented. Silica particles are converted to soluble silicon by microwave dissolution with mixtures of HNO, HO and hydrofluoric acid (HF), whereas interference-free ICP-MS detection of total silicon is achieved by ion-molecule chemistry with limits of detection (LoDs) in the range 0.2-0.5 µg Si g for most tissues. Deposition of particulate SiO in tissues is assessed by single particle ICP-MS.
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http://dx.doi.org/10.3390/nano10050888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279390PMC
May 2020

The role of left fronto-parietal tracts in hand selection: Evidence from neurosurgery.

Cortex 2020 07 10;128:297-311. Epub 2020 Apr 10.

Neurosurgical Oncology Unit, Humanitas Clinical and Research Centre, IRCCS, Rozzano, Milan, Italy. Electronic address:

Strong right-hand preference on the population level is a uniquely human feature, although its neural basis is still not clearly defined. Recent behavioural and neuroimaging literature suggests that hand preference may be related to the orchestrated function and size of fronto-parietal white matter tracts bilaterally. Lesions to these tracts induced during tumour resection may provide an opportunity to test this hypothesis. In the present study, a cohort of seventeen neurosurgical patients with left hemisphere brain tumours were recruited to investigate whether resection of certain white matter tracts affects the choice of hand selected for the execution of a goal-directed task (assembly of jigsaw puzzles). Patients performed the puzzles, but also tests for basic motor ability, selective attention and visuo-constructional ability, preoperatively and one month after surgery. An atlas-based disconnectome analysis was conducted to evaluate whether resection of tracts was significantly associated with changes in hand selection. Diffusion tractography was also used to dissect fronto-parietal tracts (the superior longitudinal fasciculus) and the corticospinal tract. Results showed a shift in hand selection despite the absence of any motor or cognitive deficits, which was significantly associated with frontal and parietal resections rather than other lobes. In particular, the shift in hand selection was significantly associated with the resection of dorsal rather than ventral fronto-parietal white matter connections. Dorsal white matter pathways contribute bilaterally to control of goal-directed hand movements. We show that unilateral lesions, that may unbalance the cooperation of the two hemispheres, can alter the choice of hand selected to accomplish movements.
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http://dx.doi.org/10.1016/j.cortex.2020.03.018DOI Listing
July 2020

Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma.

Blood 2020 07;136(2):199-209

Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain.

Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14-CD15+CD33+HLADR- cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC-related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.
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http://dx.doi.org/10.1182/blood.2019004537DOI Listing
July 2020

Quantifying eloquent locations for glioblastoma surgery using resection probability maps.

J Neurosurg 2020 Apr 3:1-11. Epub 2020 Apr 3.

1Brain Tumor Center & Department of Neurosurgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, The Netherlands.

Objective: Decisions in glioblastoma surgery are often guided by presumed eloquence of the tumor location. The authors introduce the "expected residual tumor volume" (eRV) and the "expected resectability index" (eRI) based on previous decisions aggregated in resection probability maps. The diagnostic accuracy of eRV and eRI to predict biopsy decisions, resectability, functional outcome, and survival was determined.

Methods: Consecutive patients with first-time glioblastoma surgery in 2012-2013 were included from 12 hospitals. The eRV was calculated from the preoperative MR images of each patient using a resection probability map, and the eRI was derived from the tumor volume. As reference, Sawaya's tumor location eloquence grades (EGs) were classified. Resectability was measured as observed extent of resection (EOR) and residual volume, and functional outcome as change in Karnofsky Performance Scale score. Receiver operating characteristic curves and multivariable logistic regression were applied.

Results: Of 915 patients, 674 (74%) underwent a resection with a median EOR of 97%, functional improvement in 71 (8%), functional decline in 78 (9%), and median survival of 12.8 months. The eRI and eRV identified biopsies and EORs of at least 80%, 90%, or 98% better than EG. The eRV and eRI predicted observed residual volumes under 10, 5, and 1 ml better than EG. The eRV, eRI, and EG had low diagnostic accuracy for functional outcome changes. Higher eRV and lower eRI were strongly associated with shorter survival, independent of known prognostic factors.

Conclusions: The eRV and eRI predict biopsy decisions, resectability, and survival better than eloquence grading and may be useful preoperative indices to support surgical decisions.
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http://dx.doi.org/10.3171/2020.1.JNS193049DOI Listing
April 2020

Exploiting MYC-induced PARPness to target genomic instability in multiple myeloma.

Haematologica 2021 01 1;106(1):185-195. Epub 2021 Jan 1.

Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro.

Multiple Myeloma (MM) is a hematologic malignancy strongly characterized by genomic instability, which promotes disease progression and drug resistance. Since we previously demonstrated that LIG3-dependent repair is involved in the genomic instability, drug resistance and survival of MM cells, we here investigated the biological relevance of PARP1, a driver component of Alternative-Non Homologous End Joining (Alt-NHEJ) pathway, in MM. We found a significant correlation between higher PARP1 mRNA expression and poor prognosis of MM patients. PARP1 knockdown or its pharmacological inhibition by Olaparib impaired MM cells viability in vitro and was effective against in vivo xenografts of human MM. Anti-proliferative effects induced by PARP1-inhibition were correlated to increase of DNA double-strand breaks, activation of DNA Damage Response (DDR) and finally apoptosis. Importantly, by comparing a gene expression signature of PARP inhibitors (PARPi) sensitivity to our plasma cell dyscrasia (PC) gene expression profiling (GEP), we identified a subset of MM patients which could benefit from PARP inhibitors. In particular, Gene Set Enrichment Analysis (GSEA) suggested that high MYC expression correlates to PARPi sensitivity in MM. Indeed, we identified MYC as promoter of PARP1-mediated repair in MM and, consistently, we demonstrate that cytotoxic effects induced by PARP inhibition are mostly detectable on MYC-proficient MM cells. Taken together, our findings indicate that MYC-driven MM cells are addicted to PARP1 Alt-NHEJ repair, which represents therefore a druggable target in this still incurable disease.
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http://dx.doi.org/10.3324/haematol.2019.240713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776341PMC
January 2021