Effects of fingolimod on focal and diffuse damage in patients with relapsing-remitting multiple sclerosis - The "EVOLUTION" study.

BACKGROUND AND OBJECTIVES: In multiple sclerosis (MS), MRI markers can measure the potential neuroprotective effects of fingolimod beyond its anti-inflammatory activity. In this study we aimed to comprehensively explore, in the real-word setting, whether fingolimod not only reduces clinical/MRI inflammatory activity, but also influences the progression of irreversible focal and whole brain damage in relapsing-remitting [RR] MS patients. METHODS: The "EVOLUTION" study, a 24-month observational, prospective, single-arm, multicenter study, enrolled 261 RRMS patients who started fingolimod at 32 Italian MS centers and underwent biannual neurological assessments and annual MRI evaluations. Study outcomes included the proportions of evaluable RRMS patients achieving at 24 months: (1) no new/enlarging T2-hyperintense white matter (WM) lesions and/or clinical relapses; (2) a modified classification of "No Evidence of Disease Activity 4" ("modified NEDA-4") defined as no new/enlarging T2-hyperintense WM lesions, clinical relapses, and 6-month confirmed disability progression, and a yearly percentage lateral ventricular volume change on T2-FLAIR images < 2%; (3) less than 40% of active lesions at baseline and month 12 evolving to permanent black holes (PBHs). RESULTS: At month 24, 76/160 (47.5%; 95% confidence interval [CI] = 39.8%;55.2%) RRMS patients had no clinical/MRI activity. Thirty-nine of 170 RRMS patients (22.9%; 95% CI = 16.6%;29.3%) achieved "modified NEDA-4" status. Forty-four of 72 RRMS patients (61.1%; 95% CI = 49.8%;72.4%) had less than 40% of active WM lesions evolving to PBHs. The study confirmed the established safety and tolerability profile of fingolimod. DISCUSSION: By comparing our results with those from the literature, the EVOLUTION study seems to indicate a neuroprotective effect of fingolimod, limiting inflammatory activity, brain atrophy and PBH development.

The effect of erenumab on brain network function in episodic migraine patients: a randomized, placebo-controlled clinical trial (RESET BRAIN).

BACKGROUND: We aimed to explore whether erenumab, a monoclonal antibody targeting the calcitonin gene-related peptide receptor, could exert a central effect on brain network function in migraine, and investigate the persistence of such an effect following treatment discontinuation. METHODS: This was a randomized, double-blind, placebo-controlled, multicenter trial with a crossover design performed in adult episodic migraine patients with previous treatment failure. Patients were randomized (1:1) to 12 weeks of erenumab 140 mg or placebo, followed by a 12-week crossover. Resting state (RS) functional connectivity (FC) changes of brain networks involved in migraine were investigated using a seed-based correlation approach. RESULTS: Sixty-one patients were randomized to treatment. In each treatment sequence, 27 patients completed the visit at week 12. Forty-four enrolled patients, 22 in each treatment sequence, completed the study procedures with no major protocol violations. We observed a carry-over effect of erenumab during the placebo treatment and therefore data analysis was performed as a parallel comparison of erenumab vs placebo of the first 12 weeks of treatment. From baseline to week 12, compared to placebo, patients receiving erenumab showed RS FC changes within the cerebellar, thalamic and periaqueductal gray matter networks, significantly associated with clinical improvement. Compared to non-responders, patients achieving a 50% reduction in migraine days had distinct patterns of thalamic and visual network RS FC. Brain RS FC changes reversed when erenumab was stopped. A lower baseline RS FC of the pontine network identified patients responding to erenumab. CONCLUSION: Erenumab modulates RS FC of networks involved in migraine pathophysiology. In line with clinical response, erenumab-induced brain RS FC changes tend to reverse when treatment is stopped.

Rationale for Use of Sphingosine-1-Phosphate Receptor Modulators in COVID-19 Patients: Overview of Scientific Evidence.

Maladjusted immune responses to the coronavirus disease 2019 (COVID-19), for example, cytokine release syndrome, may result in immunopathology and acute respiratory distress syndrome. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, and its S1P receptor (S1PR) are crucial in maintaining endothelial cell chemotaxis and barrier integrity. Apart from the S1P1 receptor-mediated mechanisms of sequestration of cytotoxic lymphocytes, including Th-17 and S1P1/2/3-mediated endothelial barrier functions, S1PR modulators may also attenuate cytokine release via activation of serine/threonine protein phosphatase 2A and enhance the pulmonary endothelial barrier via the c-Abl tyrosine kinase pathway. Chronic treatment with fingolimod (S1PR1,3,4,5 modulator) and siponimod (S1PR1,5 modulator) has demonstrated efficacy in reducing inflammatory disease activity and slowing down disease progression in multiple sclerosis. The decision to selectively suppress the immunity of a critically ill patient with COVID-19 remains a difficult choice. It has been suggested that treatment with fingolimod or siponimod may be appropriate to attenuate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced hyperinflammation in patients with COVID-19 since these patients are already monitored in an intensive care setting. Here, we review the use of S1PR modulators, fingolimod and siponimod, in regulating the inflammatory response to SARS-CoV-2 with the aim of understanding their potential rationale use in patients with COVID-19.

Unmet needs and gaps in the identification of secondary progression in multiple sclerosis: a Southern Italy healthcare professionals' perspective.

OBJECTIVE: Multiple sclerosis (MS) is a chronic disease with different clinical courses and a tendency to worsening. The relapsing-remitting MS presents acute onset and relapses of neurological symptoms, followed by their remission. This form can convert to secondary progressive MS (SPMS) with irreversible neurological worsening and disability. The identification of signs, symptoms, markers of progression, and strategies to manage MS patients is mandatory to allow early identification of those at higher risk of conversion to SPMS, for prompt intervention to cope with the progression of the disease. METHODS: A panel of Italian experts from Southern Italy have reviewed the current knowledge on MS and its management and identified the crucial tools for SPMS recognition. RESULTS: More effective communication between patients and clinicians should be established, with the support of digital tools. Moreover, the improvement in the clinical use of biomarkers for progression (cellular structures and tissue organization, such as neurofilaments and chitinase 3-like 1, axonal and neurons density) and of instrumental analyses for recognition of whole-brain atrophy, chronic active lesions, spinal cord lesions and atrophy, and the improvement the combination of the Expanded Disability Status Scale and the evaluation of cognitive dysfunction are discussed. CONCLUSION: Given the availability of a pharmacological option, adequate education both for patients, regarding the evolution of the disease and the specific treatment, and for professionals, to allow more effective and sensitive communication and the best use of diagnostic and management tools, could represent a strategy to improve patient management and their quality of life.

Description and preliminary experience with Virtual Visit Assessment (ViVA) during the COVID-19 pandemic, a structured virtual management protocol for patients with multiple sclerosis.

In people with multiple sclerosis (PwMS), strict follow-up is essential. Telemedicine has the potential to overcome many of the difficulties in routine management. Herein, we present a structured protocol that can be used to remotely manage patients with MS, describing in detail the steps to be taken and exams needed at each stage. A working group was established which developed a tailored protocol that can be adapted to a variety of settings. The overall protocol consisted of 5 phases: enrolment, document sharing phase, pre-evaluation, virtual visit, and post-visit phase, which was divided into 14 individual steps. As of October 2020, 25 virtual visits have been carried out, all via Skype. The patient's caregiver was present during visits and had an active role. The average duration of the virtual visit was 24 min, and that of the pre-visit and post-visit were around 15 min each. Overall satisfaction as rated by physicians was considered high (8.0 ± 0.5). Using the system usability scale (SUS), patients also favorably rated the virtual visit (96.6 ± 6.1). In 20% of cases, the virtual visit was not sufficient to provide adequate information and an in-person clinical visit was recommended. The described protocol has the potential to provide benefits for the healthcare system as well as patients and their caregivers both during and beyond COVID-19 pandemic.

Narrative Medicine to integrate patients', caregivers' and clinicians' migraine experiences: the DRONE multicentre project.

BACKGROUND: Although migraine is widespread and disabling, stigmatisation and poor awareness of the condition still represent barriers to effective care; furthermore, research on migraine individual and social impact must be enhanced to unveil neglected issues, such as caregiving burden. The project investigated the migraine illness experience through Narrative Medicine (NM) to understand daily life, needs and personal resources of migraneurs, their caregivers and clinicians, and to provide insights for clinical practice. METHODS: The project involved 13 Italian headache centres and targeted migraneurs, their caregivers and migraine specialists at these centres. Written narratives, composed by a sociodemographic survey and illness plot or parallel chart, were collected through the project's webpage. Illness plots and parallel charts employed open words to encourage participants' expression. Narratives were analysed through Nvivo software, interpretive coding and NM classifications. RESULTS: One hundred and seven narratives were collected from patients and 26 from caregivers, as well as 45 parallel charts from clinicians. The analysis revealed migraine perception in social, domestic and work life within the care pathway evolution and a bond between chaos narratives and day loss due to migraine; furthermore, narratives suggested the extent of the caregiving burden and a risk of underestimation of migraine burden in patients' and caregivers' life. CONCLUSION: The project represents the first investigation on migraine illness experience through NM simultaneously considering migraneurs', caregivers' and clinicians' perspectives. Comparing narratives and parallel charts allowed to obtain suggestions for clinical practice, while NM emerged as able to foster the pursuing of migraine knowledge and awareness.

Cardiovascular autonomic individual profile of relapsing-remitting multiple sclerosis patients and risk of extending cardiac monitoring after first dose fingolimod.

Fingolimod exerts its therapeutic effect in multiple sclerosis by modulating sphingosine-1P receptors which are expressed in the heart mediating fingolimod first dose effects. Understanding potential interactions of baseline characteristics and autonomic profile with fingolimod first dose effects may add novel safety information and help explain cases requiring extension of the 6-hour ECG monitoring period. We aimed at characterizing the patient population treated with the first dose of fingolimod in clinical practice in an observational, multicenter, prospective 6-hours (up to 24) study. ECG was recorded for 15 min before first fingolimod administration and for 6 h after. Heart rate (HR) and HR variability in the frequency domain were derived from ECG traces. Out of the 625 enrolled patients, 580 (92.8%) were discharged at the sixth hour after fingolimod first dose; 45 (7.2%) required monitoring extension. Data confirm the well characterized cardiovascular fingolimod profile upon treatment initiation. Ten (1.6%) patients showed an atrioventricular block, all asymptomatic and self-resolving. Normalized spectral power in the High Frequency band (marking vagal modulation) and previous annualized relapse rate were independently correlated with the probability of undergoing extended monitoring. Our results could provide useful information for the stratification and individualized monitoring of MS patients prescribed with fingolimod.

Efficacy of fingolimod and interferon beta-1b on cognitive, MRI, and clinical outcomes in relapsing-remitting multiple sclerosis: an 18-month, open-label, rater-blinded, randomised, multicentre study (the GOLDEN study).

Cognitive impairment (CI) affects 40-65% of multiple sclerosis (MS) patients. This study attempted evaluating the effects of fingolimod and interferon beta-1b (IFN ß-1b) on CI progression, magnetic resonance imaging (MRI) and clinical outcomes in relapsing-remitting MS (RRMS) patients over 18 months. The GOLDEN study was a pilot study including RRMS patients with CI randomised (2:1) to fingolimod (0.5 mg daily)/IFN ß-1b (250 µg every other day). CI was assessed via Rao's Brief Repeatable Battery and Delis-Kaplan Executive Function System test. MRI parameters, Expanded Disability Status Scale scores and relapses were measured. Overall, 157 patients were randomised, of whom 30 discontinued the study (fingolimod, 8.49%; IFN ß-1b, 41.18%; p ≤ 0.0001). Patients randomised to fingolimod had more severe clinical and MRI disease characteristics at baseline compared with IFN ß-1b. At Month (M) 18, both treatment groups showed improvements in all cognitive parameters. At M18, relapse rate, total number and volume of T2/T1 gadolinium-enhancing lesions were higher with IFN ß-1b, as well as the percentage brain volume change during the study. Safety and tolerability of both treatments were similar to previous studies. Both treatments showed improvements in cognitive parameters. Fingolimod demonstrated significantly better effects on MRI parameters and relapse rate. Imbalance in baseline characteristics and the drop-out pattern may have favoured IFN ß-1b. A longer duration trial may be needed to observe the complete expression of differential effects on CI scales reflecting the between-groups differences on MRI. Although limited in size, the GOLDEN study confirms the favourable benefit-risk profile of fingolimod reported in previous studies.

Safety and tolerability of fingolimod in patients with relapsing-remitting multiple sclerosis: results of an open-label clinical trial in Italy.

The safety profile of fingolimod is well established in clinical trials and post-marketing studies. This study aimed to evaluate the safety and tolerability of fingolimod in a cohort of Italian patients with relapsing-remitting multiple sclerosis (RRMS). This is a non-comparative, open-label, multicentre, interventional study conducted in patients with RRMS with no suitable alternative treatment option. Safety and tolerability of fingolimod 0.5 mg were assessed by recording adverse events (AEs) and serious AEs (SAEs). Of the 906 patients enrolled in the study, 91 % of the patients completed the study. AEs and SAEs were reported in 35.4 and 2.9 % of the patients, respectively. Most common AEs reported were headache (4.1 %), influenza (2.1 %), lymphopenia (1.8 %), asthenia (1.8 %) and pyrexia (1.8 %). Increased alanine aminotransferase levels and hypertension were reported as AE in 1.0 and 1.4 % of the patients, respectively. Macular oedema was reported in three patients. These results emphasize the safety of fingolimod in patients representing the real-world clinical practice in the Italian population. Fingolimod was safe and well tolerated in this population, which, compared to those enrolled in pivotal trials in terms of concomitant diseases and used medications, is broader. TRIAL REGISTRATION: EudraCT 2011-000770-60.

Safety of the first dose of fingolimod for multiple sclerosis: results of an open-label clinical trial.

BACKGROUND: In patients with relapsing-remitting MS (RRMS) fingolimod prevents disease relapses and delays disability progression. First dose administration of fingolimod is associated with a transient, dose-dependent decrease in heart rate (HR) in the 6 hours after drug intake.The aim of the study is to to assess safety and tolerability of the first dose of fingolimod in a cohort of Italian patients with RRMS without alternative therapeutic options. METHODS: Open-label, single arm, multicentre study. After the first dose of fingolimod, patients were observed for 6 hours and had their vital signs monitored hourly. Extended on-site monitoring was provided when required. RESULTS: Of the 906 patients enrolled in the study, most (95.2%) did not experience any adverse event (AE) following fingolimod administration. Cardiovascular AEs occurred in 18 patients and included bradycardia (1.3%), first-and second-degree atrioventricular block (0.1% and 0.2%), palpitations (0.1%), sinus arrhythmia (0.1%) and ventricular premature beats (0.1%). All events were self-limiting and did not require any intervention. Extended monitoring was required in 34 patients. CONCLUSIONS: These results, in a population who better resembled real-world clinical practice in terms of concomitant diseases and medications, are consistent with previous clinical trials and confirmed that the first dose administration of fingolimod is generally safe and well tolerated. TRIAL REGISTRATION: EudraCT 2011-000770-60.

Fingolimod protects cultured cortical neurons against excitotoxic death.

Fingolimod (FTY720), a novel drug approved for the treatment of relapsing-remitting multiple sclerosis, activates different sphingosine-1-phosphate receptor (S1PR) subtypes. Its primary mechanism of action is to reduce the egress of T lymphocytes from secondary lymphoid organs, thus restraining neuroinflammation and autoimmunity. However, recent evidence suggests that the action of FTY720 involves S1PRs expressed by cells resident in the CNS, including neurons. Here, we examined the effect of FTY720, its active metabolite, FTY720-P, and sphingosine-1-phosphate (S1P) on neuronal viability using a classical in vitro model of excitotoxic neuronal death. Mixed cultures of mouse cortical cells were challenged with toxic concentrations of N-methyl-d-aspartate (NMDA) for 10 min, and neuronal death was assessed 20 h later. FTY720, FTY720-P, and S1P were all neuroprotective when applied 18-20 h prior to the NMDA pulse. Neuroprotection was attenuated by pertussis toxin, and inhibited by the selective type-1 S1PR (S1P1R) antagonist, W146, and by inhibitors of the mitogen associated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PtdIns-3-K) pathways. Both FTY720 and FTY720-P retained their protective activity in pure cultures of mouse or rat cortical neurons. These data offer the first direct demonstration that FTY720 and its active metabolite protect neurons against excitotoxic death.

Efficacy of radiofrequency ablation of hepatocellular carcinoma associated with chronic liver disease without cirrhosis.

BACKGROUND: Hepatocellular carcinoma is one of the leading causes of death for compensated chronic liver disease. AIM: The evaluation of technical success as primary ablation rate, local tumor progression, safety, and long--term patients outcome of radiofrequency ablation in single (less than 3.5 cm in diameter) or multiple nodules (up to 3, sized less than 3 cm) of hepatocellular carcinoma associated to chronic liver disease without cirrhosis. MATERIALS AND METHODS: 25 consecutive patients, mainly chronic hepatitis C, with surgical unresectable hepatocellular carcinoma due to comorbidity or tumor location recruited from a local sonographic screening, were treated. RESULTS: Primary ablation was obtained in 96% of patients (24 out of 25) and in 93 % of nodules (27 out of 29). 1, 3, and 5-year local tumor progression rates after treatment were 4, 14, and 14%. Survival rates at 1,3, and 5-year were 92, 72, and 64%. No treatment-related deaths and severe complications were recorded.Conclusions. Radiofrequency ablation is effective with 96% of primary ablation with few tumoral recurrence and limited morbidity in patients with hepatocellular carcinoma associated with chronic liver disease without cirrhosis, it could represent a valid alternative treatment whenever surgical therapy is not safe.

Long-term effectiveness of radiofrequency ablation for hepatocellular carcinoma of 3.5 cm or less.

BACKGROUND/AIMS: Hepatocellular carcinoma is one of the leading causes of death for cirrhosis, and patients are often not eligible for surgery. To evaluate the effectiveness of radiofrequency ablation in single (less than 3.5cm in diameter) or multiple nodules (up to 3, sized less than 3cm) in respect of acceptability, applicability, primary ablation rate, local recurrence, complications, and long-term patients outcome. METHODOLOGY: 184 hepatic nodules detected in 156 consecutive patients recruited from a local sonographic screening were treated. In 10.2% of patients under study, a laparoscopic or laparotomy guided technique was preferred to the percutaneous approach. Overall and tumor-free survivals were estimated by Kaplan-Meier method. For the multivariate analysis, the hazard ratios and their 95 percent confidence intervals were computed by Cox model regression analysis. RESULTS: No treatment-related deaths and a severe complication rate of 3.2% were recorded. Primary complete ablation was obtained in 83.7% of nodules (87.1% of patients), and in a significantly higher rate for nodules up to 2cm (91.3%; p<0.013). Acceptability was 100%, and eligibility was very high (156 out of 160 cases). Local recurrence rate at 1 and 3 years was 10% and 25% respectively. The overall 3- and 5-year survival rates after treatment were 69.3% and 34.6%. Higher survival rates were obtained in the Child A cirrhosis subgroup (p<0.03) after complete response (p<0.001) and in the absence of new lesions (p<0.023). CONCLUSIONS: Radiofrequency ablation has great acceptability and applicability, and is a safe and effective treatment to be used after sonographic screening for small hepatocellular carcinomas.

[Gallbladder adenoma with focal adenocarcinoma: a case report]. / Adenoma con focale adenocarcinoma della colecisti: descrizione di un caso.

Gallbladder polyps represent a frequent and asymptomatic finding on abdominal sonography. We describe the ultrasound features of an asymptomatic 13-mm gallbladder polyp in a 29-year-old male. Video-laparoscopic cholecystectomy was performed, and histological examination of the lesion revealed a severely dysplastic tubular adenoma and chronic cholecystitis. To our knowledge, this is the first report of a gallbladder polyp already presenting severe dysplasia in a young Caucasian male without risk factors.

Multicentre observational study evaluating immediate and progressive switching from carbamazepine to oxcarbazepine in patients with epilepsy.

This observational study was performed to identify the clinical reasons leading physicians to opt for immediate or progressive procedures when switching patients from carbamazepine to oxcarbazepine, and to evaluate the clinical feasibility of the two procedures in a general unselected patient population. Five hundred and twenty-seven patients (aged 14 years or older, treated with carbamazepine as monotherapy or in combination therapy) were recruited at 50 Italian centres and freely assigned to immediate (n=361) or progressive (n=166) switch procedures. Vital and clinical data (including seizure frequency) were comparable in the two groups at baseline. The proportion of patients with simple partial seizures only was significantly higher in the immediate group (immediate: 33.0% vs progressive: 23.5%, p=0.0275), whereas the proportion of patients on combination therapy was slightly higher in the progressive group (immediate: 47.1 vs progressive: 55.4%, p=0.0756). At the end of the switch period, overall treatment satisfaction was greater in the immediate switch group, both in patients (p<0.002) and physicians (p<0.0005). Physicians preferred the immediate over the progressive switch procedure. The only clinical features of patients found to relate to the physician?s choice of switch procedure were simple partial seizures only (favouring the immediate switch) and, possibly, combination therapy with other anti-epileptic drugs (favouring the progressive switch). "Overnight" switching from carbamazepine to oxcarbazepine also appears feasible in most patients on polytherapy.