Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years.

BACKGROUND: Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study. OBJECTIVE: The aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years. METHODS: In the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group). RESULTS: Continuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66-0.92) p = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65-0.92) p = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term. CONCLUSION: The sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation. TRIAL REGISTRATION NUMBER: NCT01665144.

Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial.

BACKGROUND: Magnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS). OBJECTIVE: To examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM). METHODS: Patients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions. RESULTS: Compared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity. CONCLUSION: Siponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

Disability improvement as a clinically relevant outcome in clinical trials of relapsing forms of multiple sclerosis.

BACKGROUND: Disease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI). OBJECTIVE AND METHODS: Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5-1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNß-1a), or placebo. RESULTS: At 8 years' follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%-43.1%) of assessed participants in the IFNß-1a-fingolimod switch group and 41.9% (36.6%-47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNß-1a-fingolimod switch group than on continuous fingolimod (5.4% [3.0%-9.5%] vs 14.2% [10.8%-18.4%], p = 0.01). CONCLUSION: CDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments.

Siponimod: Disentangling disability and relapses in secondary progressive multiple sclerosis.

BACKGROUND: In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses. OBJECTIVE: To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial. METHODS: Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses. RESULTS: Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively. CONCLUSION: By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.

Multiple Sclerosis Progression Discussion Tool Usability and Usefulness in Clinical Practice: Cross-sectional, Web-Based Survey.

BACKGROUND: A digital tool, Multiple Sclerosis Progression Discussion Tool (MSProDiscuss), was developed to facilitate discussions between health care professionals (HCPs) and patients in evaluating early, subtle signs of multiple sclerosis (MS) disease progression. OBJECTIVE: The aim of this study is to report the findings on the usability and usefulness of MSProDiscuss in a real-world clinical setting. METHODS: In this cross-sectional, web-based survey, HCPs across 34 countries completed an initial individual questionnaire (comprising 7 questions on comprehensibility, usability, and usefulness after using MSProDiscuss during each patient consultation) and a final questionnaire (comprising 13 questions on comprehensibility, usability, usefulness, and integration and adoption into clinical practice to capture the HCPs' overall experience of using the tool). The responses were provided on a 5-point Likert scale. All analyses were descriptive, and no statistical comparisons were made. RESULTS: In total, 301 HCPs tested the tool in 6974 people with MS, of whom 77% (5370/6974) had relapsing-remitting MS, including those suspected to be transitioning to secondary progressive MS. The time taken to complete MSProDiscuss was reported to be in the range of 1 to 4 minutes in 97.3% (6786/6974; initial) to 98.2% (269/274; final) of the cases. In 93.54% (6524/6974; initial) to 97.1% (266/274; final) of the cases, the HCPs agreed (4 or 5 on the Likert scale) that patients were able to comprehend the questions in the tool. The HCPs were willing to use the tool again in the same patient, 90.47% (6310/6974; initial) of the cases. The HCPs reported MSProDiscuss to be useful in discussing MS symptoms and their impact on daily activities (6121/6974, 87.76% initial and 252/274, 92% final) and cognitive function (5482/6974, 78.61% initial and 271/274, 79.2% final), as well as in discussing progression in general (6102/6974, 87.49% initial and 246/274, 89.8% final). While completing the final questionnaire, 94.9% (260/274) of the HCPs agreed that the questions were similar to those asked in regular consultation, and the tool helped to better understand the impact of MS symptoms on daily activities (249/274, 90.9%) and cognitive function (220/274, 80.3%). Overall, 92% (252/274) of the HCPs reported that they would recommend MSProDiscuss to a colleague, and 85.8% (235/274) were willing to integrate it into their clinical practice. CONCLUSIONS: MSProDiscuss is a usable and useful tool to facilitate a physician-patient discussion on MS disease progression in daily clinical practice. Most of the HCPs agreed that the tool is easy to use and were willing to integrate MSProDiscuss into their daily clinical practice.

A Physician-Completed Digital Tool for Evaluating Disease Progression (Multiple Sclerosis Progression Discussion Tool): Validation Study.

BACKGROUND: Defining the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) can be challenging and delayed. A digital tool (MSProDiscuss) was developed to facilitate physician-patient discussion in evaluating early, subtle signs of multiple sclerosis (MS) disease progression representing this transition. OBJECTIVE: This study aimed to determine cut-off values and corresponding sensitivity and specificity for predefined scoring algorithms, with or without including Expanded Disability Status Scale (EDSS) scores, to differentiate between RRMS and SPMS patients and to evaluate psychometric properties. METHODS: Experienced neurologists completed the tool for patients with confirmed RRMS or SPMS and those suspected to be transitioning to SPMS. In addition to age and EDSS score, each patient's current disease status (disease activity, symptoms, and its impacts on daily life) was collected while completing the draft tool. Receiver operating characteristic (ROC) curves determined optimal cut-off values (sensitivity and specificity) for the classification of RRMS and SPMS. RESULTS: Twenty neurologists completed the draft tool for 198 patients. Mean scores for patients with RRMS (n=89), transitioning to SPMS (n=47), and SPMS (n=62) were 38.1 (SD 12.5), 55.2 (SD 11.1), and 69.6 (SD 12.0), respectively (P<.001, each between-groups comparison). Area under the ROC curve (AUC) including and excluding EDSS were for RRMS (including) AUC 0.91, 95% CI 0.87-0.95, RRMS (excluding) AUC 0.88, 95% CI 0.84-0.93, SPMS (including) AUC 0.91, 95% CI 0.86-0.95, and SPMS (excluding) AUC 0.86, 95% CI 0.81-0.91. In the algorithm with EDSS, the optimal cut-off values were ≤51.6 for RRMS patients (sensitivity=0.83; specificity=0.82) and ≥58.9 for SPMS patients (sensitivity=0.82; specificity=0.84). The optimal cut-offs without EDSS were ≤46.3 and ≥57.8 and resulted in similar high sensitivity and specificity (0.76-0.86). The draft tool showed excellent interrater reliability (intraclass correlation coefficient=.95). CONCLUSIONS: The MSProDiscuss tool differentiated RRMS patients from SPMS patients with high sensitivity and specificity. In clinical practice, it may be a useful tool to evaluate early, subtle signs of MS disease progression indicating the evolution of RRMS to SPMS. MSProDiscuss will help assess the current level of progression in an individual patient and facilitate a more informed physician-patient discussion.

Learning ability correlates with brain atrophy and disability progression in RRMS.

OBJECTIVE: To assess the prognostic value of practice effect on Paced Auditory Serial Addition Test (PASAT) in multiple sclerosis. METHODS: We compared screening (day -14) and baseline (day 0) PASAT scores of 1009 patients from the FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial. We grouped patients into high and low learners if their PASAT score change was above or below the median change in their screening PASAT quartile group. We used Wilcoxon test to compare baseline disease characteristics between high and low learners, and multiple regression models to assess the respective impact of learning ability, baseline normalised brain volume and treatment on brain volume loss and 6-month confirmed disability progression over 2 years. RESULTS: The mean PASAT score at screening was 45.38, increasing on average by 3.18 from day -14 to day 0. High learners were younger (p=0.003), had lower Expanded Disability Status Scale score (p=0.031), higher brain volume (p<0.001) and lower T2 lesion volume (p=0.009) at baseline. Learning status was not significantly associated with disability progression (HR=0.953, p=0.779), when adjusting for baseline normalised brain volume, screening PASAT score and treatment arm. However, the effect of fingolimod on disability progression was more pronounced in high learners (HR=0.396, p<0.001) than in low learners (HR=0.798, p=0.351; p for interaction=0.05). Brain volume loss at month 24 tended to be higher in low learners (0.17%, p=0.058), after adjusting for the same covariates. CONCLUSIONS: Short-term practice effects on PASAT are related to brain volume, disease severity and age and have clinically meaningful prognostic implications. High learners benefited more from fingolimod treatment.

Predicting risk of secondary progression in multiple sclerosis: A nomogram.

OBJECTIVES: We aimed at designing a nomogram, a prediction tool, to predict the individual's risk of conversion to secondary progressive multiple sclerosis (SPMS) at the time of multiple sclerosis (MS) onset. METHODS: One derivation and three validation cohorts were established. The derivation cohort included 8825 relapsing-onset MS patients in Sweden. A nomogram was built based on a survival model with the best statistical fit and prediction accuracy. The nomogram was validated using data from 3967 patients in the British Columbia cohort, 176 patients in the ACROSS and 2355 patients in FREEDOMS/FREEDOMS II extension studies. RESULTS: Sex, calendar year of birth, first-recorded Expanded Disability Status Scale (EDSS) score, age at the first EDSS and age at disease onset showed significant predictive ability to estimate the risk of SPMS conversion at 10, 15 and 20 years. The nomogram reached 84% (95% confidence intervals (CIs): 83-85) internal and 77% (95% CI: 76-78), 77% (95% CI: 70-85) and 87% (95% CI: 84-89) external accuracy. CONCLUSIONS: The SPMS nomogram represents a much-needed complementary tool designed to assist in decision-making and patient counselling in the early phase of MS. The SPMS nomogram may improve outcomes by prompting timely and more efficacious treatment for those with a worse prognosis.

Cutaneous Tumors in Swiss Dogs: Retrospective Data From the Swiss Canine Cancer Registry, 2008-2013.

Data collected in animal cancer registries comprise extensive and valuable information, even more so when evaluated in context with precise population data. The authors evaluated 11 740 canine skin tumors collected in the Swiss Canine Cancer Registry from 2008-2013, considering data on breed, sex, age, and anatomic locations. Their incidence rate (IR) per 100 000 dogs/year in the Swiss dog population was calculated based on data from the official and mandatory Swiss dog registration database ANIS. The most common tumor types were mast cell tumors (16.35%; IR, 60.3), lipomas (12.47%; IR, 46.0), hair follicle tumors (12.34%; IR, 45.5), histiocytomas (12.10%; IR, 44.6), soft tissue sarcomas (10.86%; IR, 40.1), and melanocytic tumors (8.63%; IR, 31.8) with >1000 tumors per type. The average IR of all tumor types across the 227 registered breeds was 372.2. The highest tumor incidence was found in the Giant Schnauzer (IR, 1616.3), the Standard Schnauzer (IR, 1545.4), the Magyar Vizsla (IR, 1534.6), the Rhodesian Ridgeback (IR, 1445.0), the Nova Scotia Duck Tolling Retriever (IR, 1351.7), and the Boxer (IR, 1350.0). Mixed-breed dogs (IR, 979.4) had an increased IR compared to the average of all breeds. Previously reported breed predispositions for most tumor types were confirmed. Nevertheless, the data also showed an increased IR for mast cell tumors and melanocytic tumors in the Nova Scotia Duck Tolling Retriever and for histiocytomas in the Flat Coated Retriever. The results from this study can be taken into consideration when selecting purebred dogs for breeding to improve a breed's health.

Foscan and foslip based photodynamic therapy in osteosarcoma in vitro and in intratibial mouse models.

Current osteosarcoma therapies cause severe treatment-related side effects and chemoresistance, and have low success rates. Consequently, alternative treatment options are urgently needed. Photodynamic therapy (PDT) is a minimally invasive, local therapy with proven clinical efficacy for a variety of tumor types. PDT is cytotoxic, provokes anti-vascular effects and stimulates tumor cell targeting mechanisms of the immune system and, consequently, has potential as a novel therapy for osteosarcoma patients. This study investigated the uptake and the dark- and phototoxicity and cytotoxic mechanisms of the photosensitizer (PS) 5,10,15,20-tetrakis(meta-hydroxyphenyl) chlorine (mTHPC, Foscan) and a liposomal mTHPC formulation (Foslip) in the human 143B and a mouse K7M2-derived osteosaroma cell line (K7M2L2) in vitro. Second, the tumor- and metastasis-suppressive efficacies of mTHPC formulations based PDT and associated mechanisms in intratibial, metastasizing osteosarcoma mouse models (143B/SCID and syngeneic K7M2L2/BALB/c) were studied. The uptake of Foscan and Foslip in vitro was time- and dose-dependent and resulted in mTHPC and light dose-dependent phototoxicity associated with apoptosis. In vivo, the uptake of both i.v. administered mTHPC formulations was higher in tumor than in healthy control tissue. PDT caused significant (Foscan p < 0.05, Foslip p < 0.001) tumor growth inhibition in both models. A significant (Foscan p < 0.001, Foslip p < 0.001) immune system-dependent suppression of lung metastasis was only observed in the K7M2L2/BALB/c model and was associated with a marked infiltration of T-lymphocytes at the primary tumor site. In conclusion, mTHPC-based PDT is effective in clinically relevant experimental osteosarcoma and suppresses lung metastasis in immunocompetent mice with beneficial effects of the liposomal mTHPC formulation Foslip.

Defining brain volume cutoffs to identify clinically relevant atrophy in RRMS.

OBJECTIVE: To define values of normalized brain volume (NBV) that can be categorized as low, medium, or high, according to baseline characteristics of relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: Expected NBV (eNBV) was calculated for each patient based on age, disease duration, sex, baseline Expanded Disability Status Scale (EDSS), and T2-lesion volume, entering these variables into a multiple regression model run on 2342 RRMS patients (pooled FREEDOMS/FREEDOMS-II population). According to the difference between their observed NBV and their eNBV, patients were classified as having low NBV, medium NBV, or high NBV. We evaluated whether these NBV categories were clinically meaningful by assessing correlation with disability worsening. RESULTS: The distribution of differences between observed NBV and eNBV was used to categorize patients as having low NBV, medium NBV or high NBV. Taking the high-NBV group as reference, the hazard ratios (HRs) for 2-year disability worsening, adjusted for treatment effect, were 1.23 (95% confidence interval (CI): 0.92-1.63, p = 0.16) for the medium NBV and 1.75 (95% CI: 1.26-2.44, p = 0.001) for the low NBV. The predictive value of NBV groups was preserved over 4 years. Treatment effect appeared more evident in low-NBV patients (HR = 0.58) than in medium-NBV (HR = 0.72) and in high-NBV (HR = 0.80) patients; however, the difference was not significant ( p = 0.57). CONCLUSION: RRMS patients can be categorized into disability risk groups based on individual eNBV values according to baseline demographics and clinical characteristics.

Inclusion of brain volume loss in a revised measure of 'no evidence of disease activity' (NEDA-4) in relapsing-remitting multiple sclerosis.

BACKGROUND: 'No evidence of disease activity' (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression ('NEDA-3'), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity. Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression. OBJECTIVE: To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 ('NEDA-4') METHODS: We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%-1.2%). RESULTS: At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001). Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001). NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01-4.41; p < 0.0001). CONCLUSION: NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies.

Incidence rates of the most common canine tumors based on data from the Swiss Canine Cancer Registry (2008 to 2020).

Monitoring neoplasms in standardized registries facilitates epidemiologic studies of risk factors for tumor development and predisposition. In an observational study, we determined incidence rates (IR) and malignant tumor incidence rate ratios (IRR) by age, sex, and breed in Swiss dogs using demographic data from the official Swiss dog registration database Amicus. The dataset analyzed included 54'986 tumors diagnosed by histology and cytology in four Swiss veterinary pathology laboratories between 2008 and 2020. Diagnoses were coded according to the Vet-ICD-O-canine-1 system. Most tumors occurred in the skin (n = 19'045; 34.64%), soft tissues (n = 11'092; 20.17%), and mammary glands (n = 7'974; 14.50%). The IRs for all and for malignant tumors were 775/100'000 dog-years at risk (95%CI 764-777) and 338/100'000 dog-years at risk (95%CI 333-342), respectively. Females (850; 95%CI 834-853) had a higher overall tumor IR than males (679; 95%CI 666-684). The highest tumor IR was found at 11 years of age (1'857; 95%CI 1'780-1'867). Potential novel breed-specific predispositions were uncovered, with high IRs for several benign and malignant tumors in Polski Owczarek Nizinnys (overall IR: 3'303; 95%CI 2'502-3'864) and high IRs for malignant tumors in Russian Black Terriers (melanomas: 345; 95%CI 138-708), Field Spaniels (adenocarcinomas: 376; CI95% 138-817), Dogo Argentinos (mast cell tumors: 844; CI95% 591-1'169), King Charles Spaniels and Manchester Terriers (lymphomas: 319; CI95% 137-627 and 302; CI95% 98-704, respectively), Landseers (osteosarcomas: 74; CI95% 15-216), Bouvier des Flandres (hemangiosarcomas: 127; CI95% 26-371), and Bearded Collies and Cane Corso Italianos (gliomas: 91; CI95% 45-162 and 34; CI95% 7-99, respectively). Nordic hunting dogs had the highest (8.08; CI95% 3.55-16.7) and Chihuahueno the lowest cancer IRRs (0.42; 95%CI 0.31-0.57) compared to mixed breeds. In conclusion, the calculated IRs and IRRs revealed previously unknown predisposing factors, including novel breed-specific susceptibilities. The results may have implications for cancer screening, diagnostic work-up, breeding management and oncologic and translational research.

Disturbed eating at high altitude: influence of food preferences, acute mountain sickness and satiation hormones.

PURPOSE: Hypoxia has been shown to reduce energy intake and lead to weight loss, but the underlying mechanisms are unclear. The aim was therefore to assess changes in eating after rapid ascent to 4,559 m and to investigate to what extent hypoxia, acute mountain sickness (AMS), food preferences and satiation hormones influence eating behavior. METHODS: Participants (n = 23) were studied at near sea level (Zurich (ZH), 446 m) and on two days after rapid ascent to Capanna Margherita (MG) at 4,559 m (MG2 and MG4). Changes in appetite, food preferences and energy intake in an ad libitum meal were assessed. Plasma concentrations of cholecystokinin, peptide tyrosine-tyrosine, gastrin, glucagon and amylin were measured. Peripheral oxygen saturation (SpO(2)) was monitored, and AMS assessed using the Lake Louis score. RESULTS: Energy intake from the ad libitum meal was reduced on MG2 compared to ZH (643 ± 308 vs. 952 ± 458 kcal, p = 0.001), but was similar to ZH on MG4 (890 ± 298 kcal). Energy intake on all test days was correlated with hunger/satiety scores prior to the meal and AMS scores on MG2 but not with SpO(2) on any of the 3 days. Liking for high-fat foods before a meal predicted subsequent energy intake on all days. None of the satiation hormones showed significant differences between the 3 days. CONCLUSION: Reduced energy intake after rapid ascent to high altitude is associated with AMS severity. This effect was not directly associated with hypoxia or changes in gastrointestinal hormones. Other peripheral and central factors appear to reduce food intake at high altitude.

Epithelial membrane antigen-reactive feline chordoid meningioma in a European wildcat (Felis silvestris).

Meningioma is the most frequent intracranial neoplasm in cats. Here we describe the first case of chordoid meningioma (CM), a rare grade II meningioma subtype, in a 5.5-year-old European wildcat (Felis silvestris) from a Swiss zoo. The wildcat was found dead after a clinical history of neurological signs and clinical suspicion of a carcinoma in the right external ear canal with concurrent chronic otitis. Post-mortem examination revealed a large intracranial, extra-axial and intradural neoplasm that invaded into the right ear canal and had histological features compatible with CM, which has been only reported in humans and dogs. Neoplastic cells expressed vimentin but were negative for glial fibrillary acidic protein, S100 and pancytokeratin. Immunohistochemistry revealed epithelial membrane antigen (EMA) expression in neoplastic cells. To the best of our knowledge, we provide the first evidence of EMA expression in feline meningioma.

Proteomic profiling of canine fibrosarcoma and adjacent peritumoral tissue.

Fibrosarcoma (FSA) are rare soft tissue tumors that display aggressive local behavior and invasive growth leading to high rates of tumor recurrence. While the low incidence in humans hampers detailed understanding of the disease, FSA are frequent in dogs and present potential models for the human condition. However, a lack of in-depth molecular characterization of FSA and unaffected peritumoral tissue (PTT) in both species impedes the translational potential of dogs. To address this shortcoming, we characterized canine FSA and matched skeletal muscle, adipose and connective tissue using laser-capture microdissection (LCM) and LC-MS/MS in 30 formalin-fixed paraffin embedded (FFPE) specimens. Principal component analysis of 3'530 different proteins detected across all samples clearly separates the four tissues, with several targets strongly differentiating tumor from all three PTTs. 25 proteins were exclusively found in tumor tissue in ≥80% of cases. Among these, CD68 (a macrophage marker), Optineurin (OPTN), Nuclear receptor coactivator 5 (NCOA5), RAP1GDS1 (Rap1 GTPase-GDP dissociation stimulator 1) and Stromal cell derived factor 2 like 1 (SDF2L1) were present in ≥90% of FSA. Protein expression across all FSA was highly homogeneous and characterized by MYC and TP53 signaling, hyperactive EIF2 and immune-related changes as well as strongly decreased oxidative phosphorylation and oxidative lipid metabolism. Finally, we demonstrate significant molecular homology between canine FSA and human soft-tissue sarcomas, emphasizing the relevance of studying canine FSA as a model for human FSA. In conclusion, we provide the first detailed overview of proteomic changes in FSA and surrounding PTT with relevance for the human disease.

The effect of disease modifying therapies on fatigue in multiple sclerosis.

INTRODUCTION: Fatigue is one of the most common and debilitating symptoms in people with multiple sclerosis (PwMS). Disease-modifying therapies (DMTs) are currently the gold standard in the treatment of MS and their effectiveness has been assessed through randomized clinical trials (RCTs). However, there is limited evidence on the impact of DMTs on fatigue in (PwMS). We conducted a systematic review to 1) understand whether fatigue is included as an outcome in MS trials of DMTs; 2) determine the effects on fatigue of treating MS with DMTs and 3) assess the quality of MS trials including fatigue as an outcome. METHODS: Two independent researchers systematically searched MEDLINE, EMBASE and ClinicalTrials.gov from 1993 to January 2023 for RCTs that measured fatigue as an outcome. Adherence to reporting standards was assessed with the Consolidated Standards of Reporting Trials (CONSORT)-Patient-Reported Outcomes (PRO), while the risk of bias (RoB) was assessed with the RoB 2 tool by the Cochrane Handbook for Systematic Reviews of Interventions. The systematic review protocol was registered in PROSPERO (CRD42022383321). RESULTS: The search strategy identified 130 RCTs of DMTs of which 7 (5%) assessed fatigue as an outcome. Of the 7 trials, only two presented statistically significant results. In addition, the reporting of fatigue among RCTs was suboptimal with a mean adherence to the CONSORT-PRO Statement of 36% across all trials. Of the 7 trials included, four were assessed as 'high' RoB.. CONCLUSIONS: Fatigue has a major impact on PwMS yet there is limited trial-based evidence on the impact of DMTs on fatigue. Assessment of fatigue as an outcome is underrepresented in trials of DMTs and the reporting of PRO trial data is suboptimal. Thus, it is imperative that MS researchers conduct RCTs that include fatigue as an outcome, to support clinicians and people with MS (PwMS) to consider the impact of the different DMTs on fatigue.

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.

Siponimod vs placebo in active secondary progressive multiple sclerosis: a post hoc analysis from the phase 3 EXPAND study.

BACKGROUND: Siponimod is a sphingosine 1-phosphate receptor modulator approved for active secondary progressive multiple sclerosis (aSPMS) in most countries; however, phase 3 EXPAND study data are from an SPMS population with/without disease activity. A need exists to characterize efficacy/safety of siponimod in aSPMS. METHODS: Post hoc analysis of participants with aSPMS (≥ 1 relapse in 2 years before study and/or ≥ 1 T1 gadolinium-enhancing [Gd +] magnetic resonance imaging [MRI] lesions at baseline) receiving oral siponimod (2 mg/day) or placebo for up to 3 years in EXPAND. ENDPOINTS: 3-month/6-month confirmed disability progression (3mCDP/6mCDP); 3-month confirmed ≥ 20% worsening in Timed 25-Foot Walk (T25FW); 6-month confirmed improvement/worsening in Symbol Digit Modalities Test (SDMT) scores (≥ 4-point change); T2 lesion volume (T2LV) change from baseline; number of T1 Gd + lesions baseline-month 24; number of new/enlarging (N/E) T2 lesions over all visits. RESULTS: Data from 779 participants with aSPMS were analysed. Siponimod reduced risk of 3mCDP/6mCDP vs placebo (by 31%/37%, respectively; p < 0.01); there was no significant effect on T25FW. Siponimod increased likelihood of 6-month confirmed SDMT improvement vs placebo (by 62%; p = 0.007) and reduced risk of 6-month confirmed SDMT worsening (by 27%; p = 0.060). Siponimod was associated with less increase in T2LV (1316.3 vs 13.3 mm3; p < 0.0001), and fewer T1 Gd + and N/E T2 lesions than placebo (85% and 80% reductions, respectively; p < 0.0001). CONCLUSIONS: In aSPMS, siponimod reduced risk of disability progression and was associated with benefits on cognition and MRI outcomes vs placebo. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01665144.

Inhibition of the activin receptor signaling pathway: A novel intervention against osteosarcoma.

Osteosarcoma is a cancer of pathological bone remodeling with high mortality and severe comorbidity. New therapies are urgently needed. Activin A, a member of the transforming growth factor ß (TGFß) superfamily, has been suggested to stimulate proliferation and invasion of osteosarcoma cells in vitro, thus representing a potential therapeutic target. In this study, inhibition of the activin receptor signaling pathway was explored as a therapy for osteosarcoma. In a murine intratibial osteosarcoma xenograft model, two types of inhibitors were tested: (a) a soluble activin type IIA decoy receptor (ActRIIA-mFc), or (b) a modified variant of follistatin (FSTΔHBS -hFc), either alone or in combination with a bisphosphonate. Both inhibitors reduced primary tumor development by nearly 50% compared to vehicle treatment. When ActRIIA-mFc was combined with bisphosphonate, the effect on tumor size became even more pronounced (78% reduction vs. vehicle). Moreover, FSTΔHBS -hFc increased body weight in the face of tumor progression (14% increase vs. vehicle), and ActRIIA-mFc reduced the number of lung metastases when combined with bisphosphonate. The present study demonstrates a novel approach to treating osteosarcoma and encourages further investigation of inhibition of the activin receptor signaling pathway as an intervention against the disease.