Romain Truillet

Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial

Background In patients with systemic sclerosis (scleroderma, SSc), impaired hand function greatly contributes to disability and reduced quality of life, and is insufficiently relieved by currently available therapies. Adipose tissue-derived stromal vascular fraction (SVF) is increasingly recognised as an easily accessible source of regenerative cells with therapeutic potential in ischaemic or autoimmune diseases. We aimed to measure for the first time the safety, tolerability and potential efficacy of autologous SVF cells local injections in patients with SSc with hand disability. Methods We did an open-label, single arm, at one study site with 6-month follow-up among 12 female SSc patients with Cochin Hand Function Scale score >20/90. Autologous SVF was obtained from lipoaspirates, using an automated processing system, and subsequently injected into the subcutaneous tissue of each finger in contact with neurovascular pedicles. Primary outcome was the number and the severity of adverse events related to SVF-based therapy. Secondary endpoints were changes in hand disability and fibrosis, vascular manifestations, pain and quality of life from baseline to 2 and 6 months after cell therapy. Findings All enrolled patients had surgery, and there were no dropouts or patients lost to follow-up. No severe adverse events occurred during the procedure and follow-up. Four minor adverse events were reported and resolved spontaneously. A significant improvement in hand disability and pain, Raynauds phenomenon, finger oedema and quality of life was observed. Interpretation This study outlines the safety of the autologous SVF cells injection in the hands of patients with SSc. Preliminary assessments at 6 months suggest potential efficacy needing confirmation in a randomised placebo-controlled trial on a larger population. Funding GFRS (Groupe Francophone de Recherche sur la Sclérodermie). Clinical Trials number NCT01813279.

Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up

OBJECTIVE Impaired hand function greatly contributes to disability and reduced quality of life in SSc patients. Autologous adipose-derived stromal vascular fraction (ADSVF) is recognized as an easily accessible source of regenerative cells. We reported positive 6-month safety and efficacy results from an open-label clinical trial assessing s.c. injection of autologous ADSVF into the fingers in SSc patients. The objective of this report is to describe the effects at 12 months. METHODS Twelve females, mean age 54.5 years (s.d. 10.3), were assessed 1 year after ADSVF injection. Patients were eligible if they had a Cochin Hand Function Scale score >20/90. ADSVF was obtained from lipoaspirate using an automated processing system and subsequently injected into the s.c. tissue of each finger in contact with neurovascular pedicles in a one-time procedure. Endpoints were changes in hand disability and skin fibrosis, vascular manifestations, pain and quality of life at the 12 month follow-up. During the visit, patients estimated the benefit of the procedure with a specific self-completed questionnaire. RESULTS A significant decrease from baseline of 51.3% (P < 0.001) for Cochin Hand Function Scale score, 63.2% (P < 0.001) for RP severity and 46.8% (P = 0.001) for quality of life (Scleroderma Health Assessment Questionnaire) was observed. A significant improvement of finger oedema, skin sclerosis, motion and strength of the hands and of the vascular suppression score was also noted. The reduction in hand pain approached statistical significance (P = 0.052). The questionnaire revealed a benefit in daily activities, housework and social activities. CONCLUSION ADSVF injection is a promising therapy and appears to have benefits that extend for at least 1 year.

Long-term follow-up after autologous adipose-derived stromal vascular fraction injection into fingers in systemic sclerosis patients

INTRODUCTION Hand involvement confers a substantial handicap in work and daily activities in patients with Systemic sclerosis (SSc). Autologous adipose-derived stromal vascular fraction is as an easily accessible source of cells with regenerative effects. We previously performed a phase I open-label clinical trial (NTC01813279) assessing the safety of subcutaneous injection of autologous adipose-derived stromal vascular fraction. Six and 12-month data have been reported. As patients were followed in our medical centre, we report their longer-term outcome beyond the end of the trial. PATIENTS AND METHOD Twelve females, mean age 54.5±10.3 years, initially enrolled in the clinical trial were assessed during a scheduled medical care, which took place between 22 and 30months after treatment. RESULTS Multiple patient-reported outcomes showed sustained improvement, in comparison with the assessment performed just before surgery: 62.5% in the Cochin Hand Function Scale, 51.1% in the Scleroderma Health Assessment Questionnaire, 33.1% in hand pain, and 88.3% in the Raynaud Condition Score. A decrease in the number of digital ulcers number was noted. Mobility, strength and fibrosis of the hand also showed improvement. None of the 8 patients who had previously received iloprost infusion required new infusion. CONCLUSION Despite the limits of an open label study, the data are in favour of the long-term safety of the adipose-derived stromal vascular fraction injection. Two randomized double blind, placebo-controlled trials of this therapeutic agent are ongoing in the USA (NCT02396238) and in France (NCT02558543) and will help determine the place of this innovative therapy for SSc patients.

Efficacy of Autologous Microfat Graft on Facial Handicap in Systemic Sclerosis Patients

Background: Autologous adipose tissue injection is used in plastic surgery for correction of localized tissue atrophy and has also been successfully offered for treatment of localized scleroderma. We aimed to evaluate whether patients with systemic sclerosis (SSc) and facial handicap could also benefit from this therapy. Methods: We included 14 patients (mean age of 53.8 ± 9.6 years) suffering from SSc with facial handicap defined by Mouth Handicap in Systemic Sclerosis Scale (MHISS) score more than or equal to 20, a Rodnan skin score on the face more than or equal to 1, and maximal mouth opening of less than 55 mm. Autologous adipose tissue injection was performed under local anesthesia using the technique of subcutaneous microinjection. The main objective of this study was an improvement of the MHISS score 6 months after the surgical treatment. Results: The procedure was well tolerated. We observed a mean decrease in the MHISS score of 10.7 points (±5.1; P < 0.0001) at 6 months (35% improvement). Secondary efficacy parameters assessing perioral skin sclerosis, maximum mouth opening, sicca syndrome, and facial pain significantly improved at 3 and 6 months postsurgery. At a 6-month follow-up, 75% of patients were satisfied or very satisfied of the adipose tissue microinjection therapy. Conclusions: Our study suggests that subcutaneous perioral microfat injection in patients with SSc is beneficial in the treatment of facial handicap, skin sclerosis, mouth opening limitation, sicca syndrome, and facial pain. Thus, this minimally invasive approach offers a new hope for face therapy for patients with SSc.

Brain Networks are Independently Modulated by Donepezil, Sleep, and Sleep Deprivation

Resting-state connectivity has been widely studied in the healthy and pathological brain. Less well-characterized are the brain networks altered during pharmacological interventions and their possible interaction with vigilance. In the hopes of finding new biomarkers which can be used to identify cortical activity and cognitive processes linked to the effects of drugs to treat neurodegenerative diseases such as Alzheimer’s disease, the analysis of networks altered by medication would be particularly interesting. Eleven healthy subjects were recruited in the context of the European Innovative Medicines Initiative ‘PharmaCog’. Each underwent five sessions of simultaneous EEG-fMRI in order to investigate the effects of donepezil and memantine before and after sleep deprivation (SD). The SD approach has been previously proposed as a model for cognitive impairment in healthy subjects. By applying network based statistics (NBS), we observed altered brain networks significantly linked to donepezil intake and sleep deprivation. Taking into account the sleep stages extracted from the EEG data we revealed that a network linked to sleep is interacting with sleep deprivation but not with medication intake. We successfully extracted the functional resting-state networks modified by donepezil intake, sleep and SD. We observed donepezil induced whole brain connectivity alterations forming a network separated from the changes induced by sleep and SD, a result which shows the utility of this approach to check for the validity of pharmacological resting-state analysis of the tested medications without the need of taking into account the subject specific vigilance.

Effect of desipramine on patients with breathing disorders in RETT syndrome

Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced the number of apneas in Mecp2‐deficient mice, a model of RTT. We planned a phase 2 trial to test its efficacy and its safety on breathing patterns in 36 girls with RTT.

Early Halt of a Randomized Controlled Study with 3% Hypertonic Saline in Acute Bronchiolitis

Background: Albeit not recommended because of contradictory results, nebulized 3% hypertonic saline is widely used for treating acute viral bronchiolitis. Whether clinical differences may be attributed to the type of nebulizer used has never been studied. Objectives: By modifying the amount of salt deposited into the airways, the nebulizer characteristics might influence clinical response. Methods: A prospective, randomized, controlled trial included infants hospitalized in a French university hospital for a first episode of bronchiolitis. Each child received 6 nebulizations of 3% hypertonic saline during 48 h delivered with 1 of the 3 following nebulizers: 2 jet nebulizers delivering large or small particles, with a low aerosol output, and 1 mesh nebulizer delivering small particles, with a high aerosol output. The primary endpoint was the difference in the Wang score at 48 h. Results: Only 61 children of 168 were recruited before stopping this study because of severe adverse events (n = 4) or parental requests for discontinuation due to discomfort to their child during nebulization (n = 2). One minor adverse event was noted in 91.8% (n = 56/61) of children. A high aerosol output induced 75% of the severe adverse events; it was significantly associated with the nebulization-induced cough between 24 and 48 h (p = 0.036). Decreases in Wang scores were not significantly different between the groups at 48 h, 9 recoveries out of 10 being obtained with small particles. Conclusion: No beneficial effects and possibly severe adverse events are observed with 3% hypertonic saline in the treatment of bronchiolitis.

Adaptability and reproducibility of a memory disruption rTMS protocol in the PharmaCog IMI European project

Transcranial magnetic stimulation (TMS) can interfere with cognitive processes, such as transiently impairing memory. As part of a multi-center European project, we investigated the adaptability and reproducibility of a previously published TMS memory interfering protocol in two centers using EEG or fMRI scenarios. Participants were invited to attend three experimental sessions on different days, with sham repetitive TMS (rTMS) applied on day 1 and real rTMS on days 2 and 3. Sixty-eight healthy young men were included. On each experimental day, volunteers were instructed to remember visual pictures while receiving neuronavigated rTMS trains (20 Hz, 900 ms) during picture encoding at the left dorsolateral prefrontal cortex (L-DLPFC) and the vertex. Mixed ANOVA model analyses were performed. rTMS to the L-DLPFC significantly disrupted recognition memory on experimental day 2. No differences were found between centers or between fMRI and EEG recordings. Subjects with lower baseline memory performances were more susceptible to TMS disruption. No stability of TMS-induced memory interference could be demonstrated on day 3. Our data suggests that adapted cognitive rTMS protocols can be implemented in multi-center studies incorporating standardized experimental procedures. However, our center and modality effects analyses lacked sufficient statistical power, hence highlighting the need to conduct further studies with larger samples. In addition, inter and intra-subject variability in response to TMS might limit its application in crossover or longitudinal studies.

Cannabis smoking impairs driving performance on the simulator and real driving: a randomized, double-blind, placebo-controlled, crossover trial

Driving experiments in real conditions are considered as a ‘gold standard’ to evaluate the effects of drugs on driving performance. Several constraints are difficult to manage in these conditions, so driving simulation appears as the best alternative. A preliminary comparison is crucial before being able to use driving simulation as a valid evaluation method. The aim of this study was to design a driving simulation method for assessing drug effects on driving. We used cannabis (THC) as a positive control and assessed whether THC affects driving performance in simulation conditions and whether these effects are consistent with performance in real driving conditions. A double‐blind, placebo‐controlled, two successive two‐way crossover design was performed using cigarettes containing 20 mg of THC. Healthy occasional users of THC, aged 25–35 years, who had a consistent driving experience were included. The first two sessions were realized in simulation conditions, and the last two sessions were in real driving conditions. Driving performance was estimated through inappropriate line crossings (ILC) and the standard deviation of the vehicles lateral position. Participants felt significantly drowsier and more tired after THC, whatever the driving condition. Driving stability was significantly impaired after THC, both in simulated and real driving conditions. We also found that ILC were significantly more numerous in driving simulation conditions, as compared to real driving. In conclusion, the driving simulator was proven to be more sensitive for demonstrating THC‐induced effects on driving performances. Driving simulation appears to be a good qualitative predictor of driving safety after drug intake.

Metronomic Four-Drug Regimen Has Anti-tumor Activity in Pediatric Low-Grade Glioma; The Results of a Phase II Clinical Trial

Background: Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. MC has shown its efficacy in adult tumor types such as breast and ovarian cancer and has to some extent been studied in pediatrics. Objective: To assess the anti-tumor activity and toxicity of a four-drug metronomic regimen in relapsing/refractory pediatric brain tumors (BT) with progression-free survival (PFS) after two cycles as primary endpoint. Methods: Patients ≥4 to 25 years of age were included with progressing BT. Treatment consisted of an 8-week cycle of celecoxib, vinblastine, and cyclophosphamide alternating with methotrexate. Kepner and Chang two-steps model was used with 10 patients in the first stage. If stabilization was observed in ≥2 patients, 8 additional patients were recruited. Assessment was according WHO criteria with central radiology review. Results: Twenty-nine patients (27 evaluable) were included in two groups: ependymoma (group 1, N = 8), and miscellaneous BT (group 2): 3 medulloblastoma (MB), 5 high grade glioma (HGG), 11 low grade glioma (LGG), 2 other BT. After first stage, recruitment for ependymoma was closed [one patient had stable disease (SD) for 4 months]. Cohort 2 was opened for second stage since 1 HGG and 3 LGG patients had SD after two cycles. Recruitment was limited to LGG for the second stage and 2 partial responses (PR), 6 SD and 2 progressive disease (PD) were observed after two cycles. Of these patients with LGG, median age was 10 years, nine patients received vinblastine previously. Median number of cycles was 6.8 (range: 1–12). Treatment was interrupted in five patients for grade 3/4 toxicity. Conclusion: This regimen is active in patients with LGG, even if patients had previously received vinblastine. Toxicity is acceptable. Trial Registration: This study was registered under clinicaltrials.gov – NCT01285817; EUDRACT nr: 2010-021792-81.