Evasion of apoptosis and treatment resistance in squamous cell carcinoma of the head and neck.

Combinations of surgery, radiotherapy and chemotherapy can eradicate tumors in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), but a significant proportion of tumors progress, recur, or do not respond to therapy due to treatment resistance. The prognosis for these patients is poor, thus new approaches are needed to improve outcomes. Key resistance mechanisms to chemoradiotherapy (CRT) in patients with LA SCCHN are alterations to the pathways that mediate apoptosis, a form of programmed cell death. Targeting dysregulation of apoptotic pathways represents a rational therapeutic strategy in many types of cancer, with a number of proteins, including the pro-survival B-cell lymphoma 2 family and inhibitors of apoptosis proteins (IAPs), having been identified as druggable targets. This review discusses the mechanisms by which apoptosis occurs under physiological conditions, and how this process is abnormally restrained in LA SCCHN tumor cells, with treatment strategies aimed at re-enabling apoptosis in LA SCCHN also considered. In particular, the development of, and future opportunities for, IAP inhibitors in LA SCCHN are discussed, in light of recent encouraging proof-of-concept clinical trial data.

Model-Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure-response analyses of data from 62 patients in the phase II study showed exposure-related increases in probabilities of locoregional control at 18 months (primary end point), overall response, complete response, and the radiosensitization mechanism-related composite safety end point "mucositis and/or dysphagia" (P < 0.05). Exposure-response relationships were not discernible for 12 of 13 evaluated safety end points, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model-derived target inhibition profiles, positive exposure-efficacy relationships, and lack of discernible exposure-safety relationships for most safety end points, supports selection of xevinapant 200 mg/day on days 1-14 of a 3-week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.

Growth patterns in children and adolescents with cerebral palsy from Argentina and Germany.

To analyze growth patterns of children with CP between countries; to examine differences in growth; and to assess the fit of growth charts. Cross-sectional study in children with CP from 2 to 19 years old, 399 from Argentina and 400 from Germany. Growth measures were converted into z-scores and compared to WHO reference and US CP growth charts. Generalized Linear Model was used to analyze the growth expressed as mean z-scores. 799 children. Mean age 9 years (± 4). Compared to the WHO reference, the decrease in Height z-scores (HAZ) with age in Argentina (- 0.144/year) was double that in Germany (- 0.073/year). For children in GMFCS IV-V, BMI z-scores (BMIZ) decreased with age (- 0.102/year). Using the US CP charts, both countries showed decreasing HAZ with age, in Argentina (- 0.066/year) and in Germany (- 0.032/year). BMIZ increased more among children with feeding tubes (0.062/year), similar in both countries. Argentinian children with oral feeding decrease their Weight z-score (WAZ) by - 0.553 compared to their peers. With WHO charts BMIZ presented an excellent fit for GMFCS I-III. HAZ presents a poor fit to growth references. BMIZ and WAZ presented a good fit to US CP Charts. Growth differences due to ethnicity also act in children with CP, and are related to motor impairment, age and feeding modality, possibly reflecting differences in environment or health care.

First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma.

BACKGROUND: In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab. METHODS: In the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1-4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated. RESULTS: At data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug-drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges. CONCLUSIONS: M9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2.

Inhibiting the inhibitors: Development of the IAP inhibitor xevinapant for the treatment of locally advanced squamous cell carcinoma of the head and neck.

Standard of care for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) is surgery followed by chemoradiotherapy (CRT) or definitive CRT. However, approximately 50 % of patients with LA SCCHN develop disease recurrence or metastasis within 2 years of completing treatment, and the outcome for these patients is poor. Despite this, the current treatment landscape for LA SCCHN has remained relatively unchanged for more than 2 decades, and novel treatment options are urgently required. One of the key causes of disease recurrence is treatment resistance, which commonly occurs due to cancer cells' ability to evade apoptosis. Evasion of apoptosis has been in part attributed to the overexpression of inhibitor of apoptosis proteins (IAPs). IAPs, including X-linked IAP (XIAP) and cellular IAP 1 and 2 (cIAP1/2), are a class of proteins that regulate apoptosis induced by intrinsic and extrinsic apoptotic pathways. IAPs have been shown to be overexpressed in SCCHN, are associated with poor clinical outcomes, and are, therefore, a rational therapeutic target. To date, several IAP inhibitors have been investigated; however, only xevinapant, a potent, oral, small-molecule IAP inhibitor, has shown clinical proof of concept when combined with CRT. Specifically, xevinapant demonstrated superior efficacy in combination with CRT vs placebo + CRT in a randomized, double-blind, phase 2 trial in patients with unresected LA SCCHN. Here, we describe the current treatment landscape in LA SCCHN and provide the rationale for targeting IAPs and the clinical data reported for xevinapant.

Avelumab in Combination With Cetuximab and Chemotherapy as First-Line Treatment for Patients With Advanced Squamous NSCLC.

Introduction: We present the results of a phase 2a trial of first-line avelumab (anti-programmed death-ligand 1 antibody) plus cetuximab (anti-EGFR antibody) in patients with advanced squamous NSCLC. Methods: Patients with recurrent or metastatic squamous NSCLC received avelumab 800 mg (d 1 and 8), cetuximab 250 mg/m2 (d 1) and 500 mg/m2 (d 8), cisplatin 75 mg/m2 (d 1), and gemcitabine 1250 mg/m2 (d 1 and 8) for four 3-week cycles, followed by avelumab 800 mg and cetuximab 500 mg/m2 every 2 weeks. The primary end point was the best overall response; the secondary end points were progression-free survival, duration of response, overall survival, and safety. Efficacy analyses were reported from an updated data cutoff. Results: A total of 43 patients were enrolled. The median follow-up was 6.6 months for the primary analyses and 9.2 months for the efficacy analyses. In the efficacy analyses, 15 patients had a confirmed partial response (objective response rate, 34.9% [95% confidence interval: 21.0%-50.9%]), and the median duration of response was 7.1 months (95% confidence interval: 4.2-12.5 mo). The median progression-free survival and overall survival were 6.1 months and 10.0 months, respectively. In the safety analyses (primary analysis), 38 patients (88.4%) had a treatment-related adverse event, of whom 24 (55.8%) had a grade 3 or higher treatment-related adverse event. Conclusions: The combination of avelumab + cetuximab and chemotherapy showed antitumor activity and tolerable safety; however, the ORR was not improved compared with those reported for current standards of care (NCT03717155).

Neurodevelopmental disorder with dystonia due to SOX6 mutations.

BACKGROUND: Mutations in SOX6 have recently been recognized as a new molecular cause of neurodevelopmental disorders characterized by intellectual disability, behavioral changes, and nonspecific facial and digital skeletal abnormalities. To date, <25 cases have been reported in the literature. METHODS AND FINDINGS: Here we report a new case of SOX6-associated neurodegeneration and expand the phenotype to include ceratoconus. The clinical picture consisted of early onset mildly reduced intellectual function, facial asymmetry, and dystonic tremor of hands and neck, substantially improved by levodopa. Skeletal abnormalities included scoliosis and hypertrophy of the mandibular coronoid process. A heterozygous de novo loss-of-function variant in SOX6 (c.277 C>T. p.Arg93*) was molecularly confirmed which leads to truncation of the SOX6 protein in its N-terminus, upstream of any known functional domain. CONCLUSION: SOX6-associated neurodevelopmental delayis ultrarare with less than 25 cases described in the literature. We report a new case who presented with early-onset mildly reduced intellectual function, facial asymmetry, skeletal abnormalities and dystonic tremor of hands and neck, substantially improved by levodopa. Given the therapeutic implications, SOX6 mutations should be considered in patients with complex dystonia parkinsonism.

Growth in infants, children and adolescents with unilateral and bilateral cerebral palsy.

To compare growth patterns during infancy, childhood and adolescence in children with unilateral and bilateral cerebral palsy (CP) phenotype and to assess the association with gross motor impairment, dysphagia and gestational age. We retrospectively studied 389 children with CP from a single center population in Munich, Germany. 1536 measurements of height and weight were tabulated and z-scored from 6 to 180 months of age. Generalized linear mixed model were used to examine the association between growth, GMFCS, dysphagia and gestational age by CP phenotype. Children with unilateral CP tend to grow similarly to their typically developed peers. In the main effect model, bilateral CP phenotype was significantly associated with decreased mean z-scores for height (ß [95% CI] - 0.953 [- 1.145, - 0.761], p < 0.001), weight (- 0.999 [- 1.176, - 0.807], p < 0.001) and BMI (ß [95% CI] - 0.437 [- 0.799, - 0.075]), compared with unilateral CP phenotype. This association remained significant in the interaction models. The height-for-age z-scores, weight-for-age decreased z-scores and BMI-for-age z-scores of children with bilateral CP and GMFCS III-V or dysphagia decreased more significantly than those of children with unilateral CP. Preterm birth was not significantly associated with decreased growth in height, weight and BMI. Reduced growth in children with bilateral CP was strongly associated with moderate to severe impairment in gross motor function (GMFCS III-V) and dysphagia.

Self-Rated Executive Function and Health-Related Quality of Life in Young Adults With Persistent Post-Concussion Symptoms: A Cross-Sectional Study.

OBJECTIVE: To assess self-reported executive dysfunction in young adult patients with persistent post-concussion symptoms (PCS) 2-6 months post-injury, and the association with self-reported Health-Related Quality of Life (HRQoL). METHOD: This cross-sectional study carried out in a hospital setting was a secondary analysis of data from a separate randomized trial testing the effect of a novel intervention, "Get going After concussIoN " (GAIN), for persistent PCS. Patients (18-30 years) were recruited from a clinical cohort of patients with a hospital diagnosis of concussion or referred by primary care physicians. Main measures were The Behaviour Rating Inventory of Executive Function-Adult Version providing two index scores, that is, the Metacognitive Index (MI) and the Behavioural Regulation Index (BRI), and the Quality of Life after Brain Injury-Overall Scale. RESULTS: Compared with normative data, patients had elevated scores (i.e., worse functioning) on both the MI and the BRI. In linear regression analysis, the MI score, but not the BRI score, was negatively associated with self-reported HRQoL (MI: slope = -.27, 95% confidence interval, CI [-.53, -.02], p = .03; BRI: slope = -.19, 95% CI [-.49, .13], p = .24), suggesting a positive association of subjective executive dysfunction and lower HRQoL. However, the association was attenuated after adjustment for self-reported psychological distress (MI: slope = -.09, 95% CI [-.34, .17], p = .51). CONCLUSION: Self-reported executive dysfunction is common in young adult patients with persistent PCS, but not strongly associated with decreased HRQoL after adjusting for concurrent psychological distress.

Quantitative Motion Measurements Based on Markerless 3D Full-Body Tracking in Children with SMA Highly Correlate with Standardized Motor Assessments.

BACKGROUND: Spinal Muscular Atrophy (SMA) is the most common neurodegenerative disease in childhood. New therapeutic interventions have been developed to interrupt rapid motor deterioration. The current standard of clinical evaluation for severely weak infants is the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), originally developed for SMA type 1. This test however, remains subjective and requires extensive training to be performed reliably. OBJECTIVE: Proof of principle of the motion tracking method for capturing complex movement patterns in ten children with SMA. METHODS: We have developed a system for tracking full-body motion in infants (KineMAT) using a commercially available, low-cost RGB-depth sensor. Ten patients with SMA (2-46 months of age; CHOP INTEND score 10-50) were recorded for 2 minutes during unperturbed spontaneous whole-body activity. Five predefined motion parameters representing 56 degrees of freedom of upper, lower extremities and trunk joints were correlated with CHOP INTEND scores using Pearson product momentum correlation (r). Test-retest analysis in two patients used descriptive statistics. RESULTS: 4/5 preselected motion parameters highly correlated with CHOP INTEND: 1. Standard deviation of joint angles (r = 0.959, test-retest range 1.3-1.9%), 2. Standard deviation of joint position (r = 0.933, test-retest range 2.9%), 3. Absolute distance of hand/foot travelled (r = 0.937, test-retest range 6-10.5%), 4. Absolute distance of hand/foot travelled against gravity (r = 0.923; test-retest range 4.8-8.5%). CONCLUSIONS: Markerless whole-body motion capture using the KineMAT proved to objectively capture motor performance in infants and children with SMA across different severity and ages.

Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer.

Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects. Here, we outline ongoing trials and review the rationale and evidence for the combination of avelumab, an anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), with cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 mAb. Avelumab is approved as a monotherapy for the treatment of Merkel cell carcinoma and urothelial carcinoma, and in combination with axitinib for renal cell carcinoma; cetuximab is approved in combination with chemotherapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN) and RAS wild-type metastatic colorectal cancer, and in combination with radiation therapy for SCCHN. Avelumab binds to PD-L1 expressed on tumor cells and immune regulatory cells, thus blocking its interaction with programmed death 1 and reventing T-cell suppression; cetuximab inhibits the EGFR signaling pathway, inhibiting proliferation and inducing apoptosis. Both therapies have complementary mechanisms of action and may also activate the immune system to induce innate effector function through the binding of their Fc regions to natural killer (NK) cells. Furthermore, cetuximab combined with chemotherapy has been shown to induce immunogenic cell death and leads to an increase in tumor-infiltrating CD8+ T and NK cells, which should synergize with the immunostimulatory effects of avelumab. Prospective studies will investigate this combination and inform future treatment strategies.

Surface conditioning of additively manufactured titanium implants and its influence on materials properties and in vitro biocompatibility.

Customized osteosynthesis materials of titanium alloy can be generated by additive manufacturing replacing the complex adaptation to the patient individual anatomy, especially to the lower jaw bone which shows a highly individual surface area. After printing further conditioning is necessary to adjust surface roughness. The aim of the present study was to analyse the effect of different grinding and polishing procedures on sample surface and composition and in vitro biocompatibility. Ti-6Al-4V ELI samples printed by laser powder bed fusion (LPBF) were post-treated by multi-level procedures to adjust surface roughness using the surface conditioning technologies sandblasting, vibratory finishing, electro polishing or plasma polishing. Topography and chemical composition of the surfaces was analysed. Furthermore, the release of metal ions in contact to cell culture medium was quantified. Human osteoblasts as well as primary human gingiva cells (fibroblasts and epithelial cells) were cultivated in extracts or directly on the surfaces to analyse cytotoxicity, cell adhesion and cell proliferation. Surface roughness of the different materials after final polishing was in between 0.2 and 0.5 µm, which is in the same range as usually found for conventional titanium materials used in maxillofacial surgery. Furthermore, the wettability was comparable for all post-processing techniques. The chemical compositions of the finished surfaces showed a remarkable impact by the applied finishing technique. Extracts of the samples showed low cytotoxicity with exception of the plasma polished samples, which were shown to release significantly higher amounts of vanadium ions. Accordingly, cells showed good adhesion and proliferation on all samples except plasma polished specimens. Customized devices for midline osseodistraction were exemplarily printed with LPBF starting with patient's 3D data. Those devices can be considered for clinical use, since the printed and finished material meets the requirements of ISO 10993-5 for medical devices.

Estado nutricional de niños y niñas con parálisis cerebral que asisten a centros de rehabilitación.

OBJETIVO: Describir el estado nutricional de niños con parálisis cerebral (PC) en centros de rehabilitación y terapéuticos de Argentina, y analizar el riesgo de desnutrición en relación su nivel según el sistema de la clasificación de la función motora gruesa (GMFCS). MÉTODO: Este fue un estudio transversal con datos recolectados de 321 niños (196 varones, 125 mujeres) con PC de 2 a 19 años (edad media 9 años 3 meses, DE 4 años) de 17 centros de rehabilitación y terapéuticos en cinco provincias argentinas. El estado nutricional se definió con puntajes z según peso, talla e índice de masa corporal para la edad utilizando patrones de crecimiento de la Organización Mundial de la Salud. Se utilizó Odds ratio para evaluar la asociación entre el nivel GMFCS y el estado nutricional. RESULTADOS: De los niños con PC estudiados, 52.4% tenían nivel IV y V de GMFCS. En cuanto al estado nutricional, 41,7% eran normales, 19,0% tenían desnutrición moderada, 33,9% desnutrición severa, 2,5 % sobrepeso, y 2,8% obesidad. En comparación con los niños con niveles I-III de GMFCS, los niños con niveles IV y V de GMFCS presentaron 4 veces más probabilidades de presentar desnutrición moderada y 14 veces más probabilidades de tener desnutrición severa. INTERPRETACIÓN: Existe una alta prevalencia de desnutrición asociada a la PC (niveles IV y V de GMFCS) entre niños de centros de rehabilitación y terapéuticos en Argentina. El riesgo de desnutrición severa aumenta cuando aumenta el compromiso motor.

Childhood Arterial Ischaemic Stroke: Clinical Presentation, Risk Factors and Management.

Childhood arterial ischaemic stroke (AIS) is a rare, but potentially life-threatening event which requires early diagnosis and adequate treatment. The reported significant time delay to childhood AIS diagnosis may be associated with low awareness, the more nonspecific clinical presentation as well as difficult clinical differentiation to more common "stroke mimics" and a less established "acute care structure" with delayed access to proper neuroimaging. Compared with adult stroke care, experiences with acute reperfusion therapies like thrombolysis and mechanical thrombectomy are promising but limited and not based on clinical trials. The etiological work-up is absolutely essential, as the child's individual risk profile determines acute management, secondary prevention, risk of recurrence and outcome. Follow-up care should be organized in a multidisciplinary setting covering all bio-psycho-social aspects to achieve the best integration of the child into its educational, later professional and social environments.

Exposure and cognitive-behavioural therapy for chronic back pain: An RCT on treatment processes.

BACKGROUND: To improve treatment outcomes, it is essential to understand the processes involved in therapeutic change. The aim of this study was to investigate the processes involved in treatment of individuals with chronic lower back pain (CLBP) and high fear-avoidance. Graded in vivo exposure (Exposure), a specific treatment, and cognitive-behavioural therapy (CBT), a general treatment, were compared. METHODS: Our study used data from a three-arm randomized controlled trial. The sample comprised 61 CLBP patients (pain duration >3 months; sufficient level of fear-avoidance). Assessments of session-by-session processes were done weekly for a maximum 14 weeks. The primary outcome, functional disability, was assessed at pre-treatment, post-treatment and 6-months follow-up. First, two-level models were used to test for treatment-related similarities and differences in the changes in session-by-session measures (i.e., common and unique treatment processes respectively). Second, we analysed treatment processes as predictors of treatment outcome. RESULTS: Contrary to our expectations, we found no evidence of unique treatment processes. Our results indicate that Exposure and CBT share some treatment processes. Specifically, patients reported a reduction in fear of movement and improvements in their ability to relax, to distract themselves, to manage their pain, to confront feared movements, to be active and to enjoy things despite their pain. Changes in fear of movement, relaxation, distraction, confrontation, activity and pain-related self-efficacy were also related to disability reduction. CONCLUSIONS: Despite conceptual differences, Exposure and CBT may share common treatment processes. Future research needs to address, however, whether these processes need to be targeted directly or can be supported indirectly. SIGNIFICANCE: We identified several treatment processes (e.g., reduction of fear of movement, enhancement of self-efficacy), which were associated with disability reduction during the management of chronic pain and fear-avoidance. These processes appeared to be equally important for Exposure and CBT. Practitioners should optimize these processes to improve their patients' functioning.

Symptom patterns in childhood arterial ischemic stroke: Analysis of a population-based study in Germany.

HINTERGRUND: Die zeitliche Verzögerung zwischen Symptombeginn und Diagnose ist eine Herausforderung in der Behandlung von Kindern mit arteriell ischämischem Schlaganfall. Frühere Studien zur klinischen Präsentation beschäftigten sich v. a. mit kumulativen Symptomen. ZIELSETZUNG: Ziel dieser Studie ist es, mögliche Symptommuster aufzuzeigen. METHODEN: In einer aktiven Beobachtungsstudie zwischen 01/2015 und 12/2016 (ESPED-Studie) wurden Kinder mit Erstdiagnose eines arteriell ischämischen Schlaganfalls eingeschlossen. Isoliert auftretende Erstsymptome wurden verschiedenen Symptomkombinationen gegenübergestellt. Zudem wurde untersucht, inwieweit ein als "akut" oder "progredient" klassifiziertes Auftreten der Symptome Rückschlüsse auf die zugrundeliegende Ätiologie erlaubt. ERGEBNISSE: Es wurden 99 Kinder in die Studie eingeschlossen. Unabhängig vom Alter traten überwiegend fokale Symptome auf (86%). Krampfanfälle als Initialsymptom wurden insbesondere bei Säuglingen beschrieben (67%), wohin-gegen diffuse, unspezifische Symptome vor allem bei Vorschulkindern (38%) und älteren Kindern (59%) auftraten. Isoliert traten fokale Symptome bei 37 Kindern auf, 48 Kinder zeigten zusätzlich unspezifische Symptome, darunter auch 9 Kinder mit Krampfanfällen. Isolierte unspezifische Symptome zeigten sich lediglich bei 7 Kindern, 2 Kinder wurden nur mit Krampfanfällen symptomatisch. Die Akuität des Symptombeginns wurde bei 53/78 als "akut" und bei "25/78 Fällen als "progredient" klassifiziert, lieferte jedoch keinen Hinweis auf die zugrundeliegende Ätiologie. SCHLUSSFOLGERUNG: Jedes neue fokal neurologische Defizit sollte unabhängig vom Auftreten (isoliert oder kombiniert, akut oder progredient) an einen kindlichen Schlaganfall denken lassen. BACKGROUND: Time delay between onset of clinical symptoms and diagnosis is a challenge in childhood arterial ischemic stroke. Most previous studies reported cumulative symptoms. OBJECTIVE: We attempted to identify typical symptom patterns and assessed their emergence in childhood stroke. METHODS: Prospective active surveillance in ESPED, a hospital based Pediatric Surveillance Unit for rare diseases in Germany, between January 2015 and December 2016. Case definition: first diagnosis of a radiologically confirmed arterial ischemic stroke. Symptom patterns were identified as occurring in isolation or in combination. We distinguished acute vs. progressive onset. We ascertained risk factors to identify the possible etiology. RESULTS: 99 children with childhood arterial ischemic stroke were reported. Focal symptoms were the predominant presenting feature (86%), independent of age. Seizures were more often seen in infants < 1 year (67%), whereas diffuse symptoms were more present in pre-school children (38%) and older children (59%). 37 children had focal features alone and 48 additional non-specific features, including 9 with seizures. Isolated non-specific features accounted for 7 cases, and 2 children had (focal) seizures as the only symptom. In 77% of all cases at least one risk factor was identified. The emergence of symptoms was acute in 53/78 cases and progressive in 25/78 cases. The pattern of emergence was unrelated to the underlying etiology. CONCLUSIONS: Any new focal neurological deficit in isolation, or associated with seizures or further non-specific symptoms should alert to childhood stroke.

Successful mechanical thrombectomy in a three-year-old boy with cardioembolic occlusion of both the basilar artery and the left middle cerebral artery.

BACKGROUND: Paediatric stroke is a potentially life-threatening emergency and requires immediate treatment to improve clinical outcome. In contrast to adult treatment recommendations, little is known about safety and efficacy of thrombolysis and mechanical thrombectomy in children. CASE DESCRIPTION AND CONCLUSION: We report on a three-year-old boy with a cardioembolic intracranial two-vessel occlusion and successful therapy with thrombolysis and mechanical thrombectomy. Furthermore, this case emphasizes the need of standardized protocols for acute management of paediatric stroke.

Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.

Altered brain metabolism is associated with progression of Alzheimer's Disease (AD). Mitochondria respond to bioenergetic changes by continuous fission and fusion. To account for three dimensional architecture of the brain tissue and organelles, we applied 3-dimensional electron microscopy (3D EM) reconstruction to visualize mitochondrial structure in the brain tissue from patients and mouse models of AD. We identified a previously unknown mitochondrial fission arrest phenotype that results in elongated interconnected organelles, "mitochondria-on-a-string" (MOAS). Our data suggest that MOAS formation may occur at the final stages of fission process and was not associated with altered translocation of activated dynamin related protein 1 (Drp1) to mitochondria but with reduced GTPase activity. Since MOAS formation was also observed in the brain tissue of wild-type mice in response to hypoxia or during chronological aging, fission arrest may represent fundamental compensatory adaptation to bioenergetic stress providing protection against mitophagy that may preserve residual mitochondrial function. The discovery of novel mitochondrial phenotype that occurs in the brain tissue in response to energetic stress accurately detected only using 3D EM reconstruction argues for a major role of mitochondrial dynamics in regulating neuronal survival.

Index of contrast sensitivity (ICS) in pseudophakic eyes with different intraocular lens designs.

PURPOSE: To evaluate the index of contrast sensitivity (ICS) in eyes after cataract surgery with various intraocular lens designs and to compare with the area under log contrast sensitivity curve (AULCSF). METHODS: The study comprised 395 eyes of 198 patients in the age of 73.1 ± 7.86 years receiving 11 different aspheric IOL designs (aberration-free and correcting) and a spherical (IOL) as control group. Follow-up examination after bilateral cataract surgery was completed within 71 ± 21.4 days after second IOL implantation. Patients underwent complete examination and biometry before surgery. The follow-up examination included visual acuity, pupil diameter, residual spherical aberration and mesopic as well as photopic contrast sensitivity (CS) measured with the Optec 6500 Functional Vision Analyzer. From the contrast sensitivity, we calculated the ICS according to Haughom and Strand. RESULTS: The median mesopic ICS was -144, -131 and -85, and the median photopic ICS was -289, -285 and -212 for the spherical, aberration-free and aberration-correcting IOL group, respectively. While we could not detect a significant difference between the aberration groups in some spatial frequencies, the ICS showed a significant difference between the aberration-correcting and the aberration-free or the spherical group, respectively. No significant difference was found between the aberration-free and the spherical group. CONCLUSIONS: The ICS is a useful index for evaluation of overall CS and comparison of different patient groups. With aberration-correcting IOLs, ICS was statistically better than with aberration-free or spherical IOLs, whereas the latter two showed no significant difference.

Patient-specific determinants of responsiveness to robot-enhanced treadmill therapy in children and adolescents with cerebral palsy.

AIM: The aim of the study was to evaluate patient-specific determinants of responsiveness to robot-enhanced repetitive treadmill therapy (ROBERT) in patients with early-developed movement disorders. METHOD: Patients were treated over 12 sessions during a 3-week period. Gross Motor Function Measure-66 (GMFM-66) scores 1 day before ROBERT were compared with scores recorded 1 day after ROBERT. The association of GMFM-66 baseline score, age, sex, aetiology, and add-on botulinum toxin therapy to response to treatment was assessed. RESULTS: Eighty-three patients aged between 4 and 18 years (48 males, 35 females; mean age 10y 8mo, SD 6y 1mo; Gross Motor Function Classification System level I [n=12], II [n=21], III [n=35], IV [n=10], and V [n=1]) were each treated for a total of 7.2 (SD 1.9) treadmill walking hours. Aetiology was bilateral spastic cerebral palsy (BS-CP; n=69), unilateral CP (n=3), ataxic CP (n=3), hereditary spastic paraparesis (n=6), and genetic syndrome including spasticity (n=2). Meaningful improvements were observed in GMFM-66 (+2.5; 95% CI 2.0-3.0), GMFM-D (+5.2; 95% CI 3.6-6.8), and GMFM-E (+4.0; 95% CI 2.8-5.3). There was a high inter-individual variability in treatment response. After multivariable adjustment, the improvements in GMFM-66 and GMFM-E scores were positively associated with the GMFM-66 baseline score. The effect on GMFM-D improvement was inversely associated with age. INTERPRETATION: Gross motor abilities at baseline and age were identified as relevant determinants for the high degree of interpersonal variability in response to ROBERT.