Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.

The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.

Human Dermal Allograft Superior Capsule Reconstruction With Graft Length Determined at Glenohumeral Abduction Angles of 20° and 40° Decreases Joint Translation and Subacromial Pressure Without Compromising Range of Motion: A Cadaveric Biomechanical Study.

PURPOSE: To compare the biomechanical effects of superior capsule reconstruction (SCR) graft fixation length determined at 20° and 40° of glenohumeral (GH) abduction. METHODS: Humeral translation, rotational range of motion (ROM), and subacromial contact pressure were quantified at 0°, 30°, and 60° of GH abduction in the scapular plane in 6 cadaveric shoulders for the following states: intact, massive rotator cuff tear, SCR with dermal allograft fixed at 20° of GH abduction (SCR 20), and SCR with dermal allograft fixed at 40° of GH abduction (SCR 40). Statistical analysis was conducted using a repeated-measures analysis of variance and a paired t test (P < .05). RESULTS: A massive cuff tear significantly increased total ROM compared with the intact state at 0° and 60° of abduction. SCR 20 or SCR 40 did not affect ROM. Compared with the intact state, the massive cuff tear model significantly increased superior translation by an average of 4.6 ± 0.5 mm in 9 of 12 positions (P ≤ .002). Both SCR 20 and SCR 40 reduced superior translation compared with the massive cuff tear model (P < .05); however, SCR 40 significantly decreased superior translation compared with SCR 20 at 0° of abduction (P ≤ .046). Peak subacromial pressure for the massive cuff tear model increased by an average of 486.8 ± 233.9 kPa relative to the intact state in 5 of 12 positions (P ≤ .037). SCR 20 reduced peak subacromial pressure in 2 of 12 positions (P ≤ .012), whereas SCR 40 achieved this in 6 of 12 positions (P ≤ .024). CONCLUSIONS: SCR with dermal allograft fixed at 20° or 40° of GH abduction decreases GH translation and subacromial pressure without decreasing ROM. CLINICAL RELEVANCE: With an increasing abduction angle for graft fixation, the medial-to-lateral graft length is decreased and the graft tension is effectively increased. Surgeons may increase shoulder stability without restricting ROM by fixing the graft at higher abduction angles. However, surgeons should remain cognizant of potential graft failure due to increased tension.

Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study.

BACKGROUND: Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18-75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8-24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073. FINDINGS: Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2-10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). INTERPRETATION: These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. FUNDING: AB Science (Paris, France).

Masitinib for mild-to-moderate Alzheimer's disease: results from a randomized, placebo-controlled, phase 3, clinical trial.

BACKGROUND: Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer's disease (AD). METHODS: Study AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12-25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of 2.5%) were least-squares mean change from baseline to week 24 in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), or the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL). Safety for each masitinib dose level was compared against a pooled placebo population. RESULTS: Masitinib (4.5 mg/kg/day) (n=182) showed significant benefit over placebo (n=176) according to the primary endpoint of ADAS-cog, -1.46 (95% CI [-2.46, -0.45]) (representing an overall improvement in cognition) versus 0.69 (95% CI [-0.36, 1.75]) (representing increased cognitive deterioration), respectively, with a significant between-group difference of -2.15 (97.5% CI [-3.48, -0.81]); p<0.001. For the ADCS-ADL primary endpoint, the between-group difference was 1.82 (97.5% CI [-0.15, 3.79]); p=0.038 (i.e., 1.01 (95% CI [-0.48, 2.50]) (representing an overall functional improvement) versus -0.81 (95% CI [-2.36, 0.74]) (representing increased functional deterioration), respectively). Safety was consistent with masitinib's known profile (maculo-papular rash, neutropenia, hypoalbuminemia). Efficacy results from the independent parallel group of titrated masitinib 6.0 mg/kg/day versus placebo (n=186 and 91 patients, respectively) were inconclusive and no new safety signal was observed. CONCLUSIONS: Masitinib (4.5 mg/kg/day) may benefit people with mild-to-moderate AD. A confirmatory study has been initiated to substantiate these data. TRIAL REGISTRATION: EudraCT: 2010-021218-50. CLINICALTRIALS: gov : NCT01872598.

Mast cell leukemia: identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor.

OBJECTIVE: Most patients with systemic mastocytosis bear mutations in the tyrosine kinase receptor gene c-Kit. Limited treatment options exist for mast cell leukemia, a rare form of systemic mastocytosis associated with a dire prognosis. Our aim was to investigate c-Kit mutations associated with mast cell leukemia and find new treatment for this severe form of mastocytosis. PATIENT AND METHODS: We describe here a patient with mast cell leukemia characterized by 42% of circulating mast cells associated with a previously unidentified c-Kit mutation in adult mastocytosis: dup(501-502). MAIN FINDINGS: This patient was treated with masitinib, a novel c-Kit tyrosine kinase inhibitor, with a dramatic response observed following 3 months of treatment, including clinical improvement, disappearance of circulating mast cells, and decrease in both serum histamine and tryptase levels. In vitro and ex vivo research was performed on the patient's cells and revealed constitutive c-Kit phosphorylation in mast cell leukemia. CONCLUSIONS: This case highlights the importance of sequencing all c-Kit exons when the classical D816V c-Kit mutation is not found, even in adults with SM. It also indicates that masitinib may be safe and effective for the treatment for some mast cell leukemia.

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial.

BACKGROUND AND OBJECTIVES: Masitinib is a selective tyrosine kinase inhibitor, targeting innate immune cells (mast cells and microglia) that are involved in the pathophysiology of progressive multiple sclerosis (MS). Study AB07002 assessed oral masitinib in patients with progressive MS who were progressing but not clinically active. METHODS: This randomized, double-blind, 2 parallel-group, placebo-controlled trial assessing 2 dose levels of masitinib vs equivalent placebo was conducted at 116 hospital clinics and specialized MS centers in 20 countries. Randomization (2:1) with minimization was performed centrally using an automated system. Patients, physicians, and outcome assessors remained masked to treatment group allocation. Patients with primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS) without relapse for ≥2 years, aged 18-75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0-6.0, and regardless of time from onset were treated for 96 weeks. The primary end point was overall EDSS change from baseline using repeated measures (generalized estimating equation, timeframe W12-W96, measured every 12 weeks), with positive values indicating increased clinical deterioration. Efficacy and safety were assessed in all randomly assigned and treated patients. RESULTS: A total of 611 patients were randomized; 301 in the masitinib 4.5 mg/kg/d parallel group and 310 in the uptitrated masitinib 6.0 mg/kg/d parallel group. Masitinib (4.5 mg/kg/d) (n = 199) showed significant benefit over placebo (n = 101) according to the primary end point, 0.001 vs 0.098, respectively, with a between-group difference of -0.097 (97% CI -0.192 to -0.002); p = 0.0256. Safety was consistent with masitinib's known profile (diarrhea, nausea, rash, and hematologic events), with no elevated risk of infection. Efficacy results from the independent uptitrated masitinib 6.0 mg/kg/d parallel group were inconclusive, and no new safety signal was observed. DISCUSSION: Masitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data. TRIAL REGISTRATION INFORMATION: The first participant was randomized to study AB07002 on August 25, 2011. The trial was registered with the European Clinical Trials Database (#EudraCT 2010-021219-17) on July 1, 2011 (clinicaltrialsregister.eu/ctr-search/trial/2010-021219-17/ES) and with ClinicalTrials.gov (#NCT01433497) on September 14, 2011 (clinicaltrials.gov/ct2/show/NCT01433497). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that masitinib 4.5 mg/kg/d decreased progression of disability, measured by the EDSS, in adults with PPMS or patients with nSPMS (with no exacerbations in the last 2 years).

Efficacy and Safety of Masitinib in Corticosteroid-Dependent Severe Asthma: A Randomized Placebo-Controlled Trial.

Background: Masitinib is an oral tyrosine kinase inhibitor that selectively targets mast cell activity and platelet-derived growth factor receptor (PDGFR) signaling, both of which are implicated in various mechanisms of asthma pathogenesis. Objective: Assessment of masitinib as an add-on to standard maintenance therapy as compared with placebo in the treatment of oral corticosteroid-dependent severe asthma. Methods: We conducted a randomized (2:1), placebo-controlled study of masitinib (6 mg/kg/d) in adults with severe asthma uncontrolled by high dose inhaled corticosteroids and long-acting beta-adrenoreceptor agonists plus oral corticosteroids (OCS) (≥7.5 mg/d). No minimum baseline blood eosinophil count was specified. Following a protocol amendment, the primary endpoint was reduction of annualized severe asthma exacerbation rate adjusted for the overall time on treatment (SAER). Subgroup analysis according to yearly cumulative OCS intake was also performed, a higher OCS dose indicating more severe asthma that is harder to control. Results: Following an average exposure of approximately 13 months, masitinib (n = 240) reduced the SAER by 35% relative to placebo (n = 115) (rate ratio (RR) 0.65 (95% CI [0.47-0.90]; P = 0.010)). For patients with eosinophil ≥150 cell/µL, masitinib (n = 181) reduced SAER by 38% relative to placebo (n = 87); RR 0.62 (95% CI [0.42-0.91]; P = 0.016). Benefit of masitinib was shown to increase in the most severely affected patients (OCS intake of >1000 mg/year), with a significant (P < 0.01) reduction in SAER of 50%-70%. Safety was consistent with the known masitinib profile. Conclusion: Orally administered masitinib reduces the risk of asthma exacerbations in severe asthma patients, with an acceptable safety profile. Masitinib may potentially provide a new treatment option for oral corticosteroid-dependent severe asthma.

Long-term survival analysis of masitinib in amyotrophic lateral sclerosis.

BACKGROUND: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001. METHODS: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity. RESULTS: A significant survival benefit of 25 months (p = 0.037) and 47% reduced risk of death (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo (n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31-0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001. CONCLUSIONS: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality.This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015).

Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study.

Treatment options for patients suffering from indolent forms of mastocytosis remain inadequate with the hyperactivation of mast cells responsible for many of the disease's systemic manifestations. Masitinib is a potent and highly selective oral tyrosine kinase inhibitor. A combined inhibition of c-Kit and Lyn make it particularly efficient in controlling the activity of mast cells and therefore, of potential therapeutic benefit in mastocytosis. Masitinib was administered to 25 patients diagnosed as having systemic or cutaneous mastocytosis with related handicap (i.e., disabilities associated with flushes, depression, pruritus and quality-of-life) at the initial dose levels of 3 or 6 mg/kg/day over 12 weeks. In accordance with the AFIRMM study, response was based upon change of clinical symptoms associated with patient handicap at week 12 relative to baseline, regardless of disease subtype. Improvement was observed in all primary endpoints at week 12 including a reduction of flushes, Hamilton rating, and pruritus as compared with baseline by 64% (P = 0.0005), 43% (P = 0.0049), and 36% (P = 0.0077), respectively. An overall clinical response was observed in 14/25 patients (56%; [95%CI = 37%-75%]), with sustainable improvement observed throughout an extension phase (>60 weeks). Common adverse events were edema (44%), nausea (44%), muscle spasms (28%), and rash (28%), the majority of which were of mild or moderate severity with a significant decline in frequency observed after 12 weeks of treatment. One patient experienced a serious adverse event of reversible agranulocytosis. Masitinib is a promising treatment for indolent forms of mastocytosis with handicap and indicates acceptable tolerability for long-term treatment regimens.

Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial.

Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib (n = 99) showed significant benefit over placebo (n = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65-6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53-6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.

Toward point-of-care diagnostic metabolic fingerprinting: quantification of plasma creatinine by infrared spectroscopy of microfluidic-preprocessed samples.

Infrared (IR) spectroscopy has previously been established as a means to accurately quantify several serum and urine metabolites, based upon spectroscopy of dry films. The same technique has also provided the basis to develop certain diagnostic tests, developed in the 'metabolomics' spirit. Here, we report on the further development of an integrated microfluidic-IR technology and technique, customized with the aim of dramatically extending the capabilities of IR spectroscopy in both analytical and diagnostic (metabolomic) applications. By exploiting the laminar fluid diffusion interface (LFDI), serum specimens are processed to yield product streams that are better suited for metabolic fingerprinting; metabolites are captured within the aqueous product stream, while proteins (which otherwise dominate the spectra of films dried from serum) are present in much reduced concentration. Spectroscopy of films dried from the aqueous stream then provides enhanced diagnostic and analytical sensitivity. The manuscript introduces an LFDI card design that is customized for integration with IR spectroscopy, and details the development of a quantitative assay for serum creatinine--based upon LFDI-processed serum samples--that is substantially more accurate (standard error of calibration, SEC = 43 micromol/L) than the corresponding assay based upon unprocessed serum specimens (SEC = 138 micromol/L). Preliminary results of diffusion modeling are reported, and the prospects for further optimization of the technique, guided by accurate modeling, are discussed.

Grafting of antibodies inside integrated microfluidic-microoptic devices by means of automated microcontact printing.

A novel approach to integrating biochip and microfluidic devices is reported in which microcontact printing is a key fabrication technique. The process is performed using an automated microcontact printer that has been developed as an application-specific tool. As proof-of-concept the instrument is used to consecutively and selectively graft patterns of antibodies at the bottom of a glass channel for use in microfluidic immunoassays. Importantly, feature collapse due to over compression of the PDMS stamp is avoided by fine control of the stamp's compression during contact. The precise alignment of biomolecules at the intersection of microfluidic channel and integrated optical waveguides has been achieved, with antigen detection performed via fluorescence excitation. Thus, it has been demonstrated that this technology permits sequential microcontact printing of isolated features consisting of functional biomolecules at any position along a microfluidic channel and also that it is possible to precisely align these features with existing components.

A new instrument for automated microcontact printing with stamp load adjustment.

An instrument for automated microcontact printing (microCP) on microscope slides is described. The movement of the stamp, which is actuated by a computer controlled pneumatic actuator, is precisely guided until it makes contact with the substrate. As a consequence, the absolute position of the microprinted patterns is reproducible over a series of substrates with 1 mum standard deviation. Exchange of substrates and stamps is a quick and simple procedure. This makes possible the microprinting of adjacent or superimposable patterns, with different products, in a reproducible manner. Furthermore, a novel approach is described for adjusting the load on the stamp during contact. Two adjustable screws are set up so that their length (with reference to the substrate holder) limits the stamp compression during contact. The load on the stamp is proportional to the stamp compression and from the experimental point of view, this is controlled by the operator adjusting the screws. This makes possible the microCP with stamps incorporating large surface features as well as stamps with isolated features raised on the surface. For proof of concept, automated microCP of a single parallelepiped polydimethylsiloxane feature, with a surface of 2 cm x 30 microm and a height of 25 mum, is demonstrated inside a microfluidic channel without roof collapse. A second example is provided with a single cross feature, possessing an overall surface of 140 x 140 microm(2) and a height of 14 microm. Potential applications of this versatile, inexpensive and compact instrument are discussed. The machine's potential for high throughput also makes it suitable for mass production applications.

ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?

Amyotrophic lateral sclerosis (ALS) is a devastating condition with an estimated mortality of 30,000 patients a year worldwide. The median reported survival time since onset ranges from 24 to 48 months. Riluzole is the only currently approved mildly efficacious treatment. Riluzole received marketing authorization in 1995 in the USA and in 1996 in Europe. In the years that followed, over 60 molecules have been investigated as a possible treatment for ALS. Despite significant research efforts, the overwhelming majority of human clinical trials (CTs) have failed to demonstrate clinical efficacy. In the past year, oral masitinib and intravenous edaravone have emerged as promising new therapeutics with claimed efficacy in CTs in ALS patients. Given their advanced phase of clinical development one may consider these drugs as the most likely near-term additions to the therapeutic arsenal available for patients with ALS. In terms of patient inclusion, CT with masitinib recruited a wider, more representative, less restrictive patient population in comparison to the only successful edaravone CT (edaravone eligibility criteria represents only 18% of masitinib study patients). The present manuscript reviews >50 CTs conducted in the last 20 years since riluzole was first approved. A special emphasis is put on the analysis of existing evidence in support of the clinical efficacy of edaravone and masitinib and the possible implications of an eventual marketing authorisation in the treatment of ALS.

Optimizing Radiation Dose in Computed Tomography of Articular Fractures.

OBJECTIVES: To determine whether a substantially lowered radiation protocol would provide satisfactory information for the surgeon, using the distal tibia as a model. METHODS: Eleven adult cadaveric distal tibia specimens were used to create Orthopaedic Trauma Association (OTA/AO) 43C distal tibia fractures with varying displacements in 2 planes. Each specimen was scanned at 3 modified protocols, which were then subsequently read by both qualified attending orthopaedists and midlevel residents. Observer reliability was evaluated, as well as confidence levels of identifying fracture pattern and treatment protocols. RESULTS: On average, there was less than a millimeter of variability in the measured gap to true gap as a whole (mean = 0.74 mm, P < 0.0001). With regard to measurements in gap, pattern, and treatment plans, no significant difference was found between CT images acquired with standard (110 mAs) compared with medium (60 mAs; mean 0.0 mm, P = 1.0; k = 0.14, P = 0.56; k = 0.38, P = 0.13, respectively) and low protocols (45 mAs; mean 0.01 mm, P = 0.95; k = 0.24, P = 0.32; k = 0.31, P = 0.13, respectively). Furthermore, no significant difference was found in measuring step-off across standard, medium, and low radiation dose (0.21 mm, P = 0.46; 0.28 mm, P = 0.39; -0.16 mm, P = 0.48, respectively). CONCLUSION: The results of this study show no significant difference when evaluating current standard and low-dose CT scans using less than one-half the amount of exposure. This suggests that in complex extremity fractures, a new CT protocol may potentially be used. Our initial data show promise that we may retain satisfactory imaging to formulate a treatment plan while also reducing the collective radiation burden to the population.

Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology.

Masitinib, a highly selective protein kinase inhibitor, can sensitise gemcitabine-refractory cancer cell lines when used in combination with gemcitabine. Here we report a reverse proteomic approach that identifies the target responsible for this sensitisation: the deoxycytidine kinase (dCK). Masitinib, as well as other protein kinase inhibitors, such as imatinib, interact with dCK and provoke an unforeseen conformational-dependent activation of this nucleoside kinase, modulating phosphorylation of nucleoside analogue drugs. This phenomenon leads to an increase of prodrug phosphorylation of most of the chemotherapeutic drugs activated by this nucleoside kinase. The unforeseen dual activity of protein kinase inhibition/nucleoside kinase activation could be of great therapeutic benefit, through either reducing toxicity of therapeutic agents by maintaining effectiveness at lower doses or by counteracting drug resistance initiated via down modulation of dCK target.

Laminar fluid diffusion interface preconditioning of serum and urine for reagent-free infrared clinical analysis and diagnostics.

A number of reagent-free infrared spectroscopic diagnostic and analytical methods have been established previously making use of dry biofluid films. For example, this approach has successfully measured high concentration analytes of serum and urine. However, a number of low concentration diagnostically relevant analytes presently elude detection by infrared spectroscopy. This is due in part to their relatively low concentration and in part to spectral interference by other strongly absorbing constituents. The applicability of the technique would be broadened substantially if it were possible to concentrate and separate lower concentration analytes, e. g., serum creatinine and urine proteins, from the obscuring presence of relatively high concentration compounds. One possible means to achieve this is through microfluidic sample preconditioning based on laminar fluid diffusion interfaces. The objective of this study was therefore to qualitatively assess the performance of this technology in preferentially separating certain serum and urine analytes of clinical interest that presently lie just below the threshold of detection by infrared spectroscopy. Observations from simulated and genuine urine and serum samples strongly suggest that this process should improve existing accuracy and extend the range of detectable analytes.

Neuroprotective effect of masitinib in rats with postischemic stroke.

This study evaluated the therapeutic potential of masitinib, an oral tyrosine kinase inhibitor with activity against c-Kit and platelet-derived growth factor receptors (PDGFR), to reduce ischemic brain area and neurological deficit. Using a well-established filament model of ischemic stroke in rats, the responses to oral treatment with masitinib alone or in combination with recombinant tissue plasminogen activator (rt-PA) were compared to those after rt-PA (10 mg/kg intravenously (i.v.)) monotherapy. In both cases, two doses of masitinib were used--25 or 100 mg/kg, twice per day. Ischemic brain area and the neurological deficit were assessed using the triphenyltetrazolium chloride (TTC) method and behavioral neurological tests, respectively. Masitinib, as a single agent, reduced significantly the infarct size, as compared with the stroke control group. Brain ischemic area decreased from 9.14 to 4.36 % (25 mg/kg) or 2.60 % (100 mg/kg). Moreover, a combined treatment of masitinib with rt-PA produced a stronger effect than the one observed after each of the compound alone. The size of the brain ischemic area (rt-PA 1.67 %) was further reduced to 0.83 or 0.7 % at masitinib doses of 25 and 100 mg/kg, respectively. Masitinib reduced significantly brain ischemia induced by experimental stroke and potentiated the therapeutic effect of rt-PA.

Rapid and clinically significant response to masitinib in the treatment of mucosal primary esophageal melanoma with somatic KIT exon 11 mutation involving brain metastases: A case report.

BACKGROUND: Malignant melanoma in the gastrointestinal tract may be primary or metastatic. Mucosal melanoma is a quite rare and aggressive disease, growing hidden and diagnosed with a certain delay which makes treatment difficult. CASE REPORT: The authors present the first patient with c-kit exon 11 mutated primary esophageal melanoma treated with oral tyrosine kinase inhibitor masitinib. A 55-year-old-man presented with esophageal melanoma metastising into visceral organs and to the brain. The patient showed objective and clinical significant therapeutic response to masitinib. After initiation of masitinib, dysphagia and odynophagia disappeared within 1 week. Following 1 month of treatment, computed tomography showed a regression in the number and size of brain metastatic lesions and regression in visceral lesions. This therapeutic response, despite the aggressive disease on treatment initiation, effectively enabled the patient to have 6 months of quality life. CONCLUSION: This report corroborates the plausibility of treating advanced melanoma carrying a mutation of KIT with masitinib. It also raises the question of masitinib treatment beyond progression. Additionally, the observed masitinib treatment effect on the brain suggests accumulation of therapeutically relevant concentration of masitinib in the central nervous system. This observation has possible ramifications for treatment of intracranial neoplasms.