Comparing Essential Tremor with and without Soft Dystonic Signs and Tremor Combined with Dystonia: The TITAN Study.

BACKGROUND: Tremor disorders remain as clinical diagnoses and the rate of misdiagnosis between the commonest non-parkinsonian tremors is relatively high. OBJECTIVES: To compare the clinical features of Essential Tremor without other features (pure ET), ET plus soft dystonic signs (ET + DS), and tremor combined with dystonia (TwD). METHODS: We compared the clinical features of patients with pure ET, ET + DS, and TwD enrolled in The ITAlian tremor Network (TITAN). Linear regression models were performed to determine factors associated with health status and quality of life. RESULTS: Three-hundred-eighty-three patients were included. Sex distribution was significantly different between the groups with males being more represented in pure ET and females in TwD. The initial site of tremor was different between the groups with about 40% of TwD having head tremor and ET + DS unilateral upper limb tremor at onset. This pattern mirrored the distribution of overt dystonia and soft dystonic signs at examination. Sensory trick, task-specificity, and position-dependence were more common, but not exclusive, to TwD. Pure ET patients showed the lowest degree of alcohol responsiveness and ET + DS the highest. Midline tremor was more commonly encountered and more severe in TwD than in the other groups. Regression analyses demonstrated that tremor severity, sex, age, and to a lesser degree the variable "group", independently predicted health status and quality of life, suggesting the existence of other determinants beyond tremor. CONCLUSIONS: Pure ET and TwD manifest with a phenotypic overlap, which calls for the identification of diagnostic biomarkers. ET + DS shared features with both syndromes, suggesting intra-group heterogeneity.

Does sex influence the natural history of idiopathic adult-onset dystonia?

BACKGROUND: Several earlier studies showed a female predominance in idiopathic adult-onset dystonia (IAOD) affecting the craniocervical area and a male preponderance in limb dystonia. However, sex-related differences may result from bias inherent to study design. Moreover, information is lacking on whether sex-related differences exist in expressing other dystonia-associated features and dystonia spread. OBJECTIVE: To provide accurate information on the relationship between sex differences, motor phenomenology, dystonia-associated features and the natural history of IAOD. METHODS: Data of 1701 patients with IAOD from the Italian Dystonia Registry were analysed. RESULTS: Women predominated over men in blepharospasm, oromandibular, laryngeal and cervical dystonia; the sex ratio was reversed in task-specific upper limb dystonia; and no clear sex difference emerged in non-task-specific upper limb dystonia and lower limb dystonia. This pattern was present at disease onset and the last examination. Women and men did not significantly differ for several dystonia-associated features and tendency to spread. In women and men, the absolute number of individuals who developed dystonia tended to increase from 20 to 60 years and then declined. However, when we stratified by site of dystonia onset, different patterns of female-to-male ratio over time could be observed in the various forms of dystonia. CONCLUSIONS: Our findings provide novel evidence on sex as a key mediator of IAOD phenotype at disease onset. Age-related sexual dimorphism may result from the varying exposures to specific age-related and sex-related environmental risk factors interacting in a complex manner with biological factors such as hormonal sex factors.

Oromandibular dystonia: from onset to spread a multicenter italian study.

BACKGROUND: Detailed information about the epidemiological and phenomenological differences among the aetiological subtypes of oromandibular dystonia (OMD) is lacking. Moreover, the OMD tendency to spread to other body sites has never been investigated. AIM: To compare the main demographic and clinical features of OMD in different aetiological groups and assess the risk of spread. MATERIALS AND METHODS: We retrospectively analysed data from patients contained in the Italian Dystonia Registry. The risk of spread was assessed by Kaplan Meyer curves and Cox regression analysis. RESULTS: The study included 273 patients (175 women) aged 55.7 years (SD 12.7) at OMD onset. Female predominance was observed. Idiopathic dystonia was diagnosed in 241 patients, acquired dystonia in 22. In 50/273 patients, dystonia started in the oromandibular region (focal OMD onset); in 96/273 patients the onset involved the oromandibular region and a neighbouring body site (segmental/multifocal OMD onset); and in 127/273 patients OMD was a site of spread from another body region. Sensory trick (ST) and positive family history predominated in the idiopathic group. No dystonia spread was detected in the acquired group, whereas spread mostly occurred within the first five years of history in 34% of the focal OMD onset idiopathic patients. Cox regression analysis revealed ST as a significant predictor of spread (HR, 12.1; 95% CI, 2.5 - 18.8; P = 0.002). CONCLUSION: This large study provides novel information about the clinical phenomenology of idiopathic and acquired OMD. We pointed out a possible role of oestrogens in favouring dystonia development. Moreover, we described for the first time the association between ST and dystonia spread, revealing possible common pathophysiological mechanisms. Our findings may be suggested as a referral point for future pathophysiological and therapeutic studies on OMD.

The role of ethnicity and native-country income in multiple sclerosis: the Italian multicentre study (MS-MigIT).

OBJECTIVE: Multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. This multicentre, case-control study involving 18 Italian MS Centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy. METHODS: We identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were White Europeans and White Northern Americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) Country and 241 (17.9%) in a low-middle-income (LMI) Country. Medical records and patients interviews were used to collect demographic and disease data. RESULTS: We included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. At onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had > 3 STIR spine lesions. At recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). At disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032). DISCUSSION: Our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective.

Does thyroid diseases contribute to the natural history of idiopathic adult-onset dystonia? Data from the Italian Dystonia Registry.

A few earlier observations and recent controlled studies pointed to the possible contribution of thyroid diseases in idiopathic adult-onset dystonia (IAOD). The aim of this study was to investigate the association between thyroid status and clinical characteristics of IAOD, focusing on dystonia localization, spread, and associated features such as tremors and sensory tricks. Patients were identified from those included in the Italian Dystonia Registry, a multicentre dataset of patients with adult-onset dystonia. The study population included 1518 IAOD patients. Patients with hypothyroidism and hyperthyroidism were compared with those without any thyroid disease. In the 1518 IAOD patients, 167 patients (11%; 95% CI 9.5-12.6%) were diagnosed with hypothyroidism and 42 (2.8%; 95% CI 1.99-3.74) with hyperthyroidism. The three groups were comparable in age at dystonia onset, but there were more women than men in the groups with thyroid disease. Analysing the anatomical distribution of dystonia, more patients with blepharospasm were present in the hyperthyroidism group, but the difference did not reach statistical significance after the Bonferroni correction. The remaining dystonia-affected body sites were similarly distributed in the three groups, as did dystonia-associated features and spread. Our findings provided novel information indicating that the high rate of thyroid diseases is not specific for any specific dystonia subpopulation and does not appear to influence the natural history of the disease.

Circular RNAs: A New Approach to Multiple Sclerosis.

Multiple sclerosis, a condition characterised by demyelination and axonal damage in the central nervous system, is due to autoreactive immune cells that recognise myelin antigens. Alteration of the immune balance can promote the onset of immune deficiencies, loss of immunosurveillance, and/or development of autoimmune disorders such as MS. Numerous enzymes, transcription factors, signal transducers, and membrane proteins contribute to the control of immune system activity. The "transcriptional machine" of eukaryotic cells is a complex system composed not only of mRNA but also of non-coding elements grouped together in the set of non-coding RNAs. Recent studies demonstrate that ncRNAs play a crucial role in numerous cellular functions, gene expression, and the pathogenesis of many immune disorders. The main purpose of this review is to investigate the role of circular RNAs, a previously unknown class of non-coding RNAs, in MS's pathogenesis. CircRNAs influence post-transcriptional control, expression, and functionality of a microRNA and epigenetic factors, promoting the development of typical MS abnormalities such as neuroinflammation, damage to neuronal cells, and microglial dysfunction. The increase in our knowledge of the role of circRNAs in multiple sclerosis could, in the future, modify the common diagnostic-therapeutic criteria, paving the way to a new vision of this neuroimmune pathology.

Diagnostic utility of Sudoscan for detecting bortezomib-induced painful neuropathy: a study on 18 patients with multiple myeloma.

Introduction: In the past few years, treatment of multiple myeloma has undergone a deep change for the employment of novel treatment comprising proteasome inhibitors. Bortezomib is a first-line drug in therapy of multiple myeloma. The onset of peripheral neuropathy is a dose-limiting collateral effect of the drug. This neuropathy is a distal symmetric neuropathy that affects both large and small fibers. Nerve conduction study (NCS) can be used for the diagnosis of bortezomib neuropathy, but this technique demonstrates alterations of the large nerve fibers. Sudoscan is a novel technique utilized to offer an evaluation of sudomotor function. The main objective of this study was to compare the sensitivity and diagnostic specificity of Sudoscan with respect to the nerve conduction study after bortezomib treatment. Material and methods: A total of 18 multiple myeloma patients were studied, 10 (55.5%) men and 8 (44.5%) women. Patients were analyzed at baseline and after 6 months of treatment with bortezomib. Subjects were submitted to nerve conduction study and electrochemical skin conductance evaluation with the Sudoscan device. Patients were also submitted to a clinical measure of pain and neuropathy. Results: At baseline NCS showed that only the mean sural SAP amplitude was below the 2SD lower limit of normal in 3 (16.7%) patients, while at same time we found an alteration of Sudoscan profiles in 2 (11.1%) patients. After 6 months of treatment, the NCS profiles were altered in 13 (72.2%) patients, and the Sudoscan profiles were modified in 11 (61.1%) subjects. Conclusions: Our results suggest that Sudoscan can be considered for the diagnosis of bortezomib-induced neuropathy. It is objective, reproducible, and surely easier than the traditional nerve conduction study. Sudoscan may be a useful help to manage the therapeutic interventions in multiple myeloma.

Sulci and gyri are topological cerebral landmarks in individual subjects: a study of brain navigation during tumour resection.

Surgical resection of brain tumours aims at the maximal safe resection of the pathological tissue with minimal functional impairment. To achieve this objective, reliable anatomical landmarks are indispensable to navigate into the brain. The neuronavigation system can provide information to target the location of the patient's lesion, but after the craniotomy, a brain shift and relaxation mismatch with it often occur. By contrast, sulci/gyri are topological cerebral landmarks in individual patients and do shift with the brain parenchyma during lesion removal, but remain independent from brain shift in relation to the sulci/gyri. Here, we present a case report of a novel strategy based on anatomical landmarks to guide intraoperative brain tumour resection, without using a standard neuronavigation system. A preoperative brain mapping of the peri-tumoural sulci by the MRI and surface reconstruction was followed by confirmation of the anatomical landmarks for the motor cortex using navigated transcranial magnetic stimulation. The resulting location was used as a seed for diffusion tensor imaging tractography to reconstruct the corticospinal tracts. These selected cortical landmarks (sulci/gyri) delimited the margins of the two lesions and the specific location under which the corticospinal tract courses, thus facilitating monitoring of the peri-tumoural region during brain resection. In this case, 96% of the brain tumour from the pericentral somatomotor region was successfully removed without chronic post-operative motor impairments. This approach is based on cortical anatomy that is fixed during surgery and does not suffer from the brain shift that could misplace the lesion according to the neuronavigation system.

Adverse Drug Reactions with Drugs Used in Multiple Sclerosis: An Analysis from the Italian Pharmacovigilance Database.

Given the importance of inflammation at the onset of multiple sclerosis (MS), therapy is mainly based on the use of anti-inflammatory drugs including disease modifying therapies (DMTs). Considering the recent approval of some DMTs, pharmacovigilance becomes a fundamental tool for the acquisition of new safety data. The aim of the study was to analyze adverse drug reactions (ADRs) related to the use of drugs approved for MS. All national publicly-available aggregated ADR reports recorded from 2002 to 2020 into the Reports of Adverse Reactions of Medicines (RAM) system and all complete Sicilian data reported into the Italian spontaneous reporting system (SRS) database having as suspected drugs interferon ß-1a (IFN ß-1a), interferon ß-1b (IFN ß-1b), peginterferon ß-1a (PEG-IFN ß-1a), glatiramer acetate (GA), natalizumab (NTZ), fingolimod (FNG), teriflunomide (TRF), dimethyl fumarate (DMF), alemtuzumab (Alem), ocrelizumab (OCZ), or cladribine (Cladr), were collected. Descriptive analyses of national, publicly-available aggregated data and full-access regional data were performed to assess demographic characteristics and drug-related variables followed by a more in-depth analysis of all Sicilian ADRs with a case-by-case assessment and a disproportionality analysis of unexpected ADRs. A total of 13,880 national reports have been collected from 2002 to 2020: they were mainly not serious ADRs (67.9% vs. 26.1%) and related to females (71.7% vs. 26.3%) in the age group 18-65 years (76.5%). The most reported ADRs were general and administration site conditions (n = 6,565; 47.3%), followed by nervous (n = 3,090; 22.3%), skin (n = 2,763; 19.9%) and blood disorders (n = 2,180; 15.7%). Some unexpected Sicilian ADRs were shown, including dyslipidemia for FNG (n = 10; ROR 28.5, CI 14.3-59.6), NTZ (n = 5; 10.3, 4.1-25.8), and IFN ß-1a (n = 4; 8.7, 3.1-24.1), abortion and alopecia for NTZ (n = 9; 208.1, 73.4-590.1; n = 3; 4.9, 1.5-15.7), and vitamin D deficiency for GA (n = 3; 121.2, 30.9-475.3). Moreover, breast cancer with DMF (n = 4, 62.8, 20.5-191.9) and hypothyroidism with Cladr (n = 3; 89.2, 25.9-307.5) were also unexpected. The reporting of drugs-related ADRs in MS were mostly reported in the literature, but some unknown ADRs were also found. However, further studies are necessary to increase the awareness about the safety profiles of new drugs on the market.

Giant sacral schwannoma excised under intraoperative neuromonitoring in an elderly patient: case report.

Schwannomas are mainly benign tumors arising from the Schwann cells of the peripheral nerve sheath. These tumors can often be associated with non-specific symptoms, such as abdominal heaviness. In this article, we present a detailed description of the surgical management of a giant sacral schwannoma in an elderly patient, for which intraoperative neuromonitoring made it possible to distinguish easily the nerves of the sacral plexus from which the tumor originated and to remove it without complications. Treatment of these rare and symptomatic giant tumors is still a challenge for surgeons; to treat adequately these tumors; a multidisciplinary approach is required to ensure an optimal therapeutic approach to reduce the risk of recurrence and, on the other hand, is not associated with unnecessary iatrogenic neurological damage.

Patient Perceptions and Knowledge of Ionizing Radiation From Medical Imaging.

Importance: Although imaging has become a standard tool of modern medicine, its widespread use has been paralleled by an increasing cumulative radiation dose to patients despite technological advancements and campaigns calling for better awareness and minimization of unnecessary exposures. Objective: To assess patients' knowledge about medical radiation and related risks. Design, Setting, and Participants: A survey study of hospitals in Italy was conducted; all patients in waiting rooms for medical imaging procedures before undergoing imaging examinations at 16 teaching and nonteaching hospitals were approached to take the survey. The survey was performed from June 1, 2019, to May 31, 2020. Main Outcomes and Measures: Survey respondents' basic knowledge of ionizing radiation levels and health risks, earlier imaging tests performed, and information and communication about radiation protection issues. Results: Among 3039 patients invited to participate, the response rate was 94.3% (n = 2866). Participants included 1531 women (53.4%); mean (SD) age was 44.9 (17.3) years. Of the 2866 participants, 1529 (53.3%) were aware of the existence of natural sources of ionizing radiation. Mammography (1101 [38.4%]) and magnetic resonance imaging (1231 [43.0%]) were categorized as radiation-based imaging modalities. More than half of the 2866 patients (1579 [55.1%]; P = .03) did not know that chest computed tomography delivers a larger dose of radiation than chest radiography, and only 1499 (52.3%) knew that radiation can be emitted after nuclear medicine examinations (P = .004). A total of 667 patients (23.3%) believed that radiation risks were unrelated to age, 1273 (44.4%) deemed their knowledge about radiation risks inadequate, and 2305 (80.4%) preferred to be informed about radiation risks by medical staff. A better knowledge of radiation issues was associated with receiving information from health care professionals (odds ratio [OR], 1.71; 95% CI, 1.43-2.03; P < .001) and having a higher educational level (intermediate vs low: OR, 1.48; 95% CI, 1.17-1.88; P < .001; high vs low: OR, 2.68; 95% CI, 2.09-3.43; P < .001). Conclusions and Relevance: The results of this survey suggest that patients undergoing medical imaging procedures have overall limited knowledge about medical radiation. Intervention to achieve better patient awareness of radiation risks related to medical exposures may be beneficial.

Cortical Excitability and Connectivity in Patients With Brain Tumors.

Background: Brain tumors can cause different changes in excitation and inhibition at the neuronal network level. These changes can be generated from mechanical and cellular alterations, often manifesting clinically as seizures. Objective/Hypothesis: The effects of brain tumors on cortical excitability (CE) have not yet been well-evaluated. The aim of the current study was to further investigate cortical-cortical and cortical-spinal excitability in patients with brain tumors using a more extensive transcranial magnetic stimulation protocol. Methods: We evaluated CE on 12 consecutive patients with lesions within or close to the precentral gyrus, as well as in the subcortical white matter motor pathways. We assessed resting and active motor threshold, short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), long-latency afferent inhibition, cortical silent period, and interhemispheric inhibition. Results: CE was reduced in patients with brain tumors than in healthy controls. In addition, SICI, ICF, and SAI were lower in the affected hemisphere compared to the unaffected and healthy controls. Conclusions: CE is abnormal in hemispheres affected by brain tumors. Further studies are needed to determine if CE is related with motor impairment.

Facioscapulohumeral Muscular Dystrophy and Poliomyelitis followed by Multiple Sclerosis: A "triple trouble" case report and review of the literature on the association of MS and muscle disorders.

We describe herein a "triple trouble" case of a patient affected by Facioscapulohumeral muscular dystrophy type 1 (FSHD1), with a previous history of poliomyelitis, who later developed multiple sclerosis (MS). Association of muscle disorders and MS is uncommon; in fact, there are only three case reports of this unusual co-occurrence. As regard as this combination, some hypotheses have been raised about the role of immunological factors. Genetic basis of FSHD1 is a deletion of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, resulting in transcriptional de-repression of a gene DUX4. This molecular change could induce an alteration of immune responses, likely conferring susceptibility to both diseases. In this case, poliomyelitis could have delayed the FSHD1 diagnosis and likely acted as a trigger for MS onset. Association of multiple neurological disorders has to be kept in mind to avoid misinterpretation of symptoms and diagnostic delays.

Mapping and Preserving the Visuospatial Network by repetitive nTMS and DTI Tractography in Patients With Right Parietal Lobe Tumors.

INTRODUCTION: The goal of brain tumor surgery is the maximal resection of neoplastic tissue, while preserving the adjacent functional brain tissues. The identification of functional networks involved in complex brain functions, including visuospatial abilities (VSAs), is usually difficult. We report our preliminary experience using a preoperative planning based on the combination of navigated transcranial magnetic stimulation (nTMS) and DTI tractography to provide the preoperative 3D reconstruction of the visuospatial (VS) cortico-subcortical network in patients with right parietal lobe tumors. MATERIAL AND METHODS: Patients affected by right parietal lobe tumors underwent mapping of both hemispheres using an nTMS-implemented version of the Hooper Visual Organization Test (HVOT) to identify cortical areas involved in the VS network. DTI tractography was used to compute the subcortical component of the network, consisting of the three branches of the superior longitudinal fasciculus (SLF). The 3D reconstruction of the VS network was used to plan and guide the safest surgical approach to resect the tumor and avoid damage to the network. We retrospectively analyzed the cortical distribution of nTMS-induced errors, and assessed the impact of the planning on surgery by analyzing the extent of tumor resection (EOR) and the occurrence of postoperative VSAs deficits in comparison with a matched historical control group of patients operated without using the nTMS-based preoperative reconstruction of the VS network. RESULTS: Twenty patients were enrolled in the study (Group A). The error rate (ER) induced by nTMS was higher in the right vs. the left hemisphere (p=0.02). In the right hemisphere, the ER was higher in the anterior supramarginal gyrus (aSMG) (1.7%), angular gyrus (1.4%) superior parietal lobule (SPL) (1.3%), and dorsal lateral occipital gyrus (dLoG) (1.2%). The reconstruction of the cortico-subcortical VS network was successfully used to plan and guide tumor resection. A gross total resection (GTR) was achieved in 85% of cases. After surgery no new VSAs deficits were observed and a slightly significant improvement of the HVOT score (p=0.02) was documented. The historical control group (Group B) included 20 patients matched for main clinical characteristics with patients in Group A, operated without the support of the nTMS-based planning. A GTR was achieved in 90% of cases, but the postoperative HVOT score resulted to be worsened as compared to the preoperative period (p=0.03). The comparison between groups showed a significantly improved postoperative HVOT score in Group A vs. Group B (p=0.03). CONCLUSIONS: The nTMS-implemented HVOT is a feasible approach to map cortical areas involved in VSAs. It can be combined with DTI tractography, thus providing a reconstruction of the VS network that could guide neurosurgeons to preserve the VS network during tumor resection, thus reducing the occurrence of postoperative VSAs deficits as compared to standard asleep surgery.

Genetic Heterogeneity in Chronic Myeloid Leukemia: How Clonal Hematopoiesis and Clonal Evolution May Influence Prognosis, Treatment Outcome, and Risk of Cardiovascular Events.

Chronic myeloid leukemia (CML) has long been considered as a model of cancer caused by a single-driver genetic lesion (BCR/ABL1 rearrangement) that codes for a unique, gain-of-function, deregulated protein. However, in the last decade, high-throughput sequencing technologies have shed light on a more complex genetic landscape, in which additional mutations may be found in different disease phases, including diagnosis. These genetic lesions may even precede the occurrence of the Philadelphia (Ph) chromosome, pointing to an antecedent premalignant state of clonal hematopoiesis (CH) at least in some patients. Preliminary data support the hypothesis that the most frequent CH-associated mutations (DNMT3A, TET2, and ASXL1) may be associated with a risk of vascular event, but a definitive answer for this topic is still lacking. Moreover, several recent studies have linked a much more complex genetic background in chronic-phase CML, including signs of clonal evolution over time, with depth of treatment responses or with patient survival. In the present review, we address the current state of the art on age-related CH, its association with cardiovascular risk, and its pathophysiology; review the current knowledge on CH that precedes the acquisition of the Ph chromosome in CML patients; and discuss available evidence on the prognostic and predictive value of additional mutations in chronic-phase CML, either as a sign of clonal dynamics under treatment or as markers of an antecedent CH.

Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma.

Multiple myeloma (MM) remains an incurable tumor due to the high rate of relapse that still occurs. Acquired drug resistance represents the most challenging obstacle to the extension of survival and several studies have been conducted to understand the mechanisms of this phenomenon. Mitochondrial pathways have been extensively investigated, demonstrating that cancer cells become resistant to drugs by reprogramming their metabolic assessment. MM cells acquire resistance to proteasome inhibitors (PIs), activating protection programs, such as a reduction in oxidative stress, down-regulating pro-apoptotic, and up-regulating anti-apoptotic signals. Knowledge of the mechanisms through which tumor cells escape control of the immune system and acquire resistance to drugs has led to the creation of new compounds that can restore the response by leading to cell death. In this scenario, based on all literature data available, our review represents the first collection of anti-mitochondrial compounds able to overcome drug resistance in MM. Caspase-independent mechanisms, mainly based on increased oxidative stress, result from 2-methoxyestradiol, Artesunate, ascorbic acid, Dihydroartemisinin, Evodiamine, b-AP15, VLX1570, Erw-ASNase, and TAK-242. Other agents restore PIs' efficacy through caspase-dependent tools, such as CDDO-Im, NOXA-inhibitors, FTY720, GCS-100, LBH589, a derivative of ellipticine, AT-101, KD5170, SMAC-mimetics, glutaminase-1 (GLS1)-inhibitors, and thenoyltrifluoroacetone. Each of these substances improved the efficacy rates when employed in combination with the most frequently used antimyeloma drugs.

Technique of neuromonitoring during pelvic peritonectomy.

OBJECTIVES: Pelvic peritonectomy can induce anorectal and urogenital dysfunctions. To reduce this type of complications during the procedure, we propose to use intraoperative neuromonitoring (IONM). CONTENT: Stimulation with a bipolar probe allows the identification of the obturator and ilioinguinal and pudendal nerves. At the end of the cytoreductive surgery, the motor and somatosensory evoked potentials must be evaluated to confirm the preservation of pelvic innervation. SUMMARY: The use of IONM during pelvic peritonectomy is technically feasible, and it can help to preserve pelvic nerves. OUTLOOK: Obviously, its definitive value remains to be elucidated.

Identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign.

The LIBRA compound library is a collection of 522 non-commercial molecules contributed by various Italian academic laboratories. These compounds have been designed and synthesized during different medicinal chemistry programs and are hosted by the Italian Institute of Technology. We report the screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1. Nine compounds were active against parasitic PTR1 and were selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified was 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, six new LIB_66 derivatives were synthesized to explore its Structure-Activity-Relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The results indicate that PTR1 has a preference to bind inhibitors, which resemble its biopterin/folic acid substrates, such as the 2,4-diaminopyrimidine derivatives.