Autologous cord blood in children with cerebral palsy: a review.

The aim of this narrative review is to report on the current knowledge regarding the clinical use of umbilical cord blood (CB) based on articles from PubMed and clinical trials registered on ClinicalTrials.gov. An increasing amount of evidence suggests that CB may be used for both early diagnostics and treatment of cerebral palsy. The acidity of CB and its biochemical parameters, including dozens of cytokines, growth factors, and other metabolites (such as amino acids, acylcarnitines, phosphatidylcholines, succinate, glycerol, 3-hydroxybutyrate, and O-phosphocholine) are predictors of future neurodevelopment. In addition, several clinical studies confirmed the safety and efficacy of CB administration in both autologous and allogeneic models, including a meta-analysis of five clinical trials involving a total of 328 participants. Currently, nine clinical trials assessing the use of autologous umbilical CB in children diagnosed with hypoxic-ischemic encephalopathy or cerebral palsy are in progress. The total population assessed in these trials exceeds 2500 patients.

Classification-Predictive Model Based on Artificial Neural Network Validated by Histopathology and Direct Immunofluorescence for the Diagnosis of Oral Lichen Planus.

The diagnosis of oral lichen planus (OLP) poses many challenges due to its nonspecific clinical symptoms and histopathological features. Therefore, the diagnostic process should include a thorough clinical history, immunological tests, and histopathology. Our study aimed to enhance the diagnostic accuracy of OLP by integrating direct immunofluorescence (DIF) results with clinical data to develop a multivariate predictive model based on the Artificial Neural Network. Eighty patients were assessed using DIF for various markers (immunoglobulins of classes G, A, and M; complement 3; fibrinogen type 1 and 2) and clinical characteristics such as age, gender, and lesion location. Statistical analysis was performed using machine learning techniques in Statistica 13. The following variables were assessed: gender, age on the day of lesion onset, results of direct immunofluorescence, location of white patches, locations of erosions, treatment history, medications and dietary supplement intake, dental status, smoking status, flossing, and using mouthwash. Four statistically significant variables were selected for machine learning after the initial assessment. The final predictive model, based on neural networks, achieved 85% in the testing sample and 71% accuracy in the validation sample. Significant predictors included stress at onset, white patches under the tongue, and erosions on the mandibular gingiva. In conclusion, while the model shows promise, larger datasets and more comprehensive variables are needed to improve diagnostic accuracy for OLP, highlighting the need for further research and collaborative data collection efforts.

The Impact of Umbilical Cord Mesenchymal Stem Cells on Motor Function in Children with Cerebral Palsy: Results of a Real-world, Compassionate use Study.

The aim of this study was to analyze the impact of human umbilical cord-derived MSCs (hUC-MSCs) on motor function in children with cerebral palsy (CP). The study enrolled 152 children with CP who received up to two courses of five hUC-MSCs injections. Children's motor functions were assessed with the Gross Motor Function Measure (GMFM), 6-Minute Walk Test (6-MWT), Timed Up and Go test (Up&Go test), and Lovett's test, and mental abilities were assessed with the Clinical Global Impression (CGI) scale. Data collected at visit 1 (baseline) and visit 5 (after four injections) were analyzed retrospectively. After four hUC-MSCs administrations, all evaluated parameters improved. The change in GMFM score, by a median of 1.9 points (IQR: 0.0-8.0), correlated with age. This change was observed in all GFMCS groups and was noticed in all assessed GMFM areas. A median increase of 75 m (IQR: 20.0-115.0) was noted on the 6-MWT, and this correlated with GMFM score change. Time on the Up&Go test was reduced by a median of 2 s (IQR: -3 to - 1) and the change correlated with age, GMFM score at baseline, and the difference observed on the 6-MWT. Results of Lovett's test indicated slight changes in muscle strength. According to the CGI, 75.5% (96/151) of children were seriously (level VI) or significantly ill (level V) at the 1st visit, with any improvement observed in 63.6% (96/151) of patients at the 5th visit, 23.8% (36/151) with improvement (level II) or great improvement (level I). In conclusion, the application of hUC-MSCs generally enhanced functional performance, but individual responses varied. The therapy also benefited children with high level of disability but not to the same extent as the initially less disabled children. Although younger patients responded better to the treatment, older children can also benefit. Trial Registration 152/2018/KB/VII and 119/2021/KB/VIII. Retrospective registration in ClinicalTrials: ongoing.

Rationale for the Use of Cord Blood in Hypoxic-Ischaemic Encephalopathy.

Hypoxic-ischaemic encephalopathy (HIE) is a severe complication of asphyxia at birth. Therapeutic hypothermia, the standard method for HIE prevention, is effective in only 50% of the cases. As the understanding of the immunological basis of these changes increases, experiments have begun with the use of cord blood (CB) because of its neuroprotective properties. Mechanisms for the neuroprotective effects of CB stem cells include antiapoptotic and anti-inflammatory actions, stimulation of angiogenesis, production of trophic factors, and mitochondrial donation. In several animal models of HIE, CB decreased oxidative stress, cell death markers, CD4+ T cell infiltration, and microglial activation; restored normal brain metabolic activity; promoted neurogenesis; improved myelination; and increased the proportion of mature oligodendrocytes, neuron numbers in the motor cortex and somatosensory cortex, and brain weight. These observations translate into motor strength, limb function, gait, and cognitive function and behaviour. In humans, the efficacy and safety of CB administration were reported in a few early clinical studies which confirmed the feasibility and safety of this intervention for up to 10 years. The results of these studies showed an improvement in the developmental outcomes over hypothermia. Two phase-2 clinical studies are ongoing under the United States regulations, namely one controlled study and one blinded study.

The use of umbilical cord-derived mesenchymal stem cells in patients with muscular dystrophies: Results from compassionate use in real-life settings.

Muscular dystrophies are genetically determined progressive diseases with no cause-related treatment and limited supportive treatment. Although stem cells cannot resolve the underlying genetic conditions, their wide-ranging therapeutic properties may ameliorate the consequences of the involved mutations (oxidative stress, inflammation, mitochondrial dysfunction, necrosis). In this study, we administered advanced therapy medicinal product containing umbilical cord-derived mesenchymal stem cells (UC-MSCs) to 22 patients with muscular dystrophies. Patients received one to five intravenous and/or intrathecal injections per treatment course in up to two courses every 2 months. Four standard doses of 10, 20, 30, or 40 × 106 UC-MSCs per injection were used; the approximate dose per kilogram was 1 × 106 UC-MSCs. Muscle strength was measured with a set of CQ Dynamometer computerized force meters (CQ Elektronik System, Czernica, Poland). Statistical analysis of muscle strength in the whole group showed significant improvement in the right upper limb (+4.0 N); left hip straightening (+4.5 N) and adduction (+0.5 N); right hip straightening (+1.0 N), bending (+7.5 N), and adduction (+2.5 N); right knee straightening (+8.5 N); left shoulder revocation (+13.0 N), straightening (+5.5 N), and bending (+6.5 N); right shoulder adduction (+3.0 N), revocation (+10.5 N), and bending (+5 N); and right elbow straightening (+9.5 N); all these differences were statistically significant. In six patients (27.3%) these changes led to improvement in gait analysis or movement scale result. Only one patient experienced transient headache and lower back pain after the last administration. In conclusion, UC-MSC therapy may be considered as a therapeutic option for these patients.

Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is still incurable. Although different therapies can affect the health and survival of patients. Our aim is to evaluate the effect of umbilical mesenchymal stem cells administrated intrathecally to patients with amyotrophic lateral sclerosis on disability development and survival. METHODS: This case-control study involved 67 patients treated with Wharton's jelly mesenchymal stem cells (WJ-MSC). The treated patients were paired with 67 reference patients from the PRO-ACT database which contains patient records from 23 ALS clinical studies (phase 2/3). Patients in the treatment and reference groups were fully matched in terms of race, sex, onset of symptoms (bulbar/spinal), FT9 disease stage at the beginning of therapy and concomitant amyotrophic lateral sclerosis medications. Progression rates prior to treatment varied within a range of ± 0.5 points. All patients received three intrathecal injections of Wharton's jelly-derived mesenchymal stem cells every two months at a dose of 30 × 106 cells. Patients were assessed using the ALSFRS-R scale. Survival times were followed-up until March 2020. RESULTS: Median survival time increased two-fold in all groups. In terms of progression, three response types measured in ALSFRS-R were observed: decreased progression rate (n = 21, 31.3%), no change in progression rate (n = 33, 49.3%) and increased progression rate (n = 13, 19.4%). Risk-benefit ratios were favorable in all groups. No serious adverse drug reactions were observed. INTERPRETATION: Wharton's jelly-derived mesenchymal stem cells therapy is safe and effective in some ALS patients, regardless of the clinical features and demographic factors excluding sex. The female sex and a good therapeutic response to the first administration are significant predictors of efficacy following further administrations. Graphical Abstract Medical therapeutic experiment with retrospective case-control analyses.

Wharton's Jelly Mesenchymal Stem Cell Administration Improves Quality of Life and Self-Sufficiency in Children with Cerebral Palsy: Results from a Retrospective Study.

The aim of this paper was to describe the outcome of the therapeutic administration of allogenic mesenchymal stem cells obtained from Wharton's jelly (WJ-MSCs) in children with cerebral palsy (CP) during a medical therapeutic experiment. We retrospectively analyzed the records of 109 patients recruited in daily clinical practice. Each patient received 1-10 injections and was examined by the same neurologist (study investigator (SI)) on the day of each infusion. The SI used a 6-point Likert scale to assess the quality of life (QoL) and self-sufficiency of the patients on the basis of the neurological examination. Children with >50% follow-ups after this administration were included into the quantitative analysis. In addition, the assessments of the parents and other health care professionals were obtained for 23 patients and compared with those of the SI. Forty-eight of 54 analyzed patients (88.9%) achieved some improvement in health status. Forty-eight (88.9%) patients experienced an increase in their QoL, and 21 patients (38.9%) achieved an increase in their self-sufficiency level. Improvement was achieved in 17 areas. Adverse events were mild and temporary except one case of epilepsy deterioration leading to treatment discontinuation. Age, body mass, and cell dose were not significant predictors of QoL response, contrary to epilepsy; developmental breakthrough was dose-dependent.

A Retrospective Analysis of Safety and Efficacy of Wharton's Jelly Stem Cell Administration in Children with Spina Bifida.

The aim of this paper was to describe the outcome of therapeutic administration of mesenchymal stem cells (MSC) obtained from Wharton's jelly (WJ-MSCs) in paediatric patients with spina bifida (SB) during a medical therapeutic experiment. We retrospectively analysed the records of twenty-eight patients aged 1-18 years (median age 4 years) recruited in daily clinical practice. Each patient received 0.9-5.0 × 106 WJ-MSCs/kg (median 2.6 × 106 WJ-MSCs/kg) administered in 1-5 injections as an experimental treatment for SB (allogenic administration). All the patients were examined by the same neurologist (study investigator, SI) on the day of each infusion. Based on the neurological examination, the SI used a six-point Likert scale to assess the quality of life and self-service of each patient. Twenty-six follow-up observations after MSC administration were analysed retrospectively. In addition, the assessments of the parents and other healthcare professionals were obtained for 5 patients and compared with the SI's assessment. Twenty-one of 26 patients (81%) experienced some improvement in their health status. Twenty-one (81%) patients experienced increased quality of life (median 2.0) and 10 patients (38%) achieved a slight increase in their self-service level (median 1). Improvement was achieved in 12 out of 17 areas. Five were significant in low-power sign test: muscle tension, muscle strength, gross motor development, micturition/defecation control, and cognitive functions. Adverse events were mild and temporary. Age, body mass, single dose or poor response after the first administration were not significant predictors of later response to treatment in contrast to the total cell dose per one kg in the whole treatment course. WJ-MSC administration is a safe and effective procedure that improves motor functions, micturition/defecation control, and cognitive functions, and improves the quality of life in children with SB.