Aurora kinase A inhibitor, LY3295668 erbumine: a phase 1 monotherapy safety study in patients with locally advanced or metastatic solid tumors.

Background Aurora A kinase (AurA) overexpression likely contributes to tumorigenesis and therefore represents an attractive target for cancer therapeutics. This phase 1 study aimed to determine the safety, pharmacokinetics, and antitumor activity of LY3295668 erbumine, an AurA inhibitor, in patients with locally advanced or metastatic solid tumors. Methods Patients with locally advanced or metastatic solid tumors, Eastern Cooperative Oncology Group performance status 0-1, and disease progression after one to four prior treatment regimens were enrolled. Primary objective was to determine maximum tolerated dose (MTD); secondary objectives included evaluation of the tolerability and safety profile and pharmacokinetics of LY3295668. All patients received twice-daily (BID) oral LY3295668 in 21-day cycles in an ascending-dose schedule. Results Twelve patients were enrolled in phase 1 (25 mg, n = 8; 50 mg, n = 2; 75 mg, n = 2) and one patient was enrolled after. Overall, four patients experienced dose-limiting toxicities (DLTs) within the first cycle (75 mg: Grade 3 diarrhea [one patient], Grade 4 mucositis and Grade 3 corneal deposits [one patient]; 50 mg: mucositis and diarrhea [both Grade 3, one patient]; 25 mg: Grade 3 mucositis [one patient]). Patients exhibiting DLTs had the highest model-predicted exposures at steady state. Mucositis was the most common adverse event (67%), followed by diarrhea, fatigue, alopecia, anorexia, constipation, and nausea. Nine patients had best response of stable disease; the disease control rate was 69%. Conclusions MTD of LY3295668 was 25 mg BID. LY3295668 had a manageable toxicity profile and demonstrated activity in some patients with locally advanced or metastatic solid tumors.Trial registration ClinicalTrials.gov, NCT03092934. Registered March 22, 2017. https://clinicaltrials.gov/ct2/show/NCT03092934 .

Gait recovery in a girl with ischemic spinal cord stroke.

BACKGROUND AND PURPOSE: This case report describes an aggressive, task-specific program for the recovery of gait in a girl with a spinal cord stroke. CASE DESCRIPTION: The 11-year-old girl sustained a spinal cord stroke resulting in a T4 motor-incomplete lesion. Therapy was initiated 6 months after onset when she was not ambulating. INTERVENTION: The focus of all interventions was on the restoration of gait. Locomotor treadmill training and over ground walking were the primary practice interventions. Walking was facilitated by orthoses, neuromuscular electrical stimulation, laser treatments, and strengthening. Treatment continued for 18 months. OUTCOMES: At the conclusion of therapy, the client was able to walk independently in the community with a single ankle foot orthosis and reverse rolling walker. DISCUSSION: The outcome was not anticipated for this client, given the type and level of her injury and the delay in starting gait training.

Wolf Motor Function Test for characterizing moderate to severe hemiparesis in stroke patients.

OBJECTIVE: To extend the applicability of the Wolf Motor Function Test (WMFT) to describe the residual functional abilities of moderate to severely affected stroke patients. DESIGN: Data were collected as part of 2 double-blind, sham-controlled, randomized interventional studies: the Transcranial Direct Current Stimulation (tDCS) in Chronic Stroke Recovery and the tDCS Enhanced Stroke Recovery and Cortical Reorganization. Stroke patients were evaluated with the upper extremity Fugl-Meyer (UFM) and the WMFT in the same setting before treatment. SETTING: University inpatient rehabilitation and outpatient clinic. PARTICIPANTS: Stroke patients (N=32) with moderate to severe hemiparesis enrolled in the tDCS in Chronic Stroke Recovery and the tDCS Enhanced Stroke Recovery and Cortical Reorganization studies. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: WMFT scores were calculated using (1) median performance times and (2) a new calculation using the mean rate of performance. We compared the distribution of values from the 2 methods and examined the WMFT-UFM correlation for the traditional and the new calculation. RESULTS: WMFT rate values were more evenly distributed across their range than median WMFT time scores. The association between the WMFT rate and UFM was as good as the association between the median WMFT time scores and UFM (Spearman ρ, .84 vs -.79). CONCLUSIONS: The new WMFT mean rate of performance is valid and a more sensitive measure in describing the functional activities of the moderate to severely affected upper extremity of stroke subjects and avoids the pitfalls of the median WMFT time calculations.

Efficacy and Safety of LY3127804, an Anti-Angiopoietin-2 Antibody, in a Randomized, Double-Blind, Placebo-Controlled Clinical Trial in Patients Hospitalized with Pneumonia and Presumed or Confirmed COVID-19.

BACKGROUND: Severe cases of coronavirus disease 2019 (COVID-19) are characterized by progressive respiratory failure and the development of acute respiratory distress syndrome (ARDS), with high mortality rates for patients requiring mechanical ventilation. Levels of the vascular growth factor Angiopoietin 2 (Ang2) in plasma have been strongly correlated with increased ARDS risk in patients with pneumonia or sepsis. The intent of this study was to determine whether LY3127804, an anti-Ang2 monoclonal antibody, could reduce the need for mechanical ventilation among patients admitted to the hospital with pneumonia and presumed or confirmed COVID-19. METHODS: Patients admitted to hospital with confirmed pneumonia, presumed or confirmed COVID-19, and infiltrates on chest imaging and/or oxygen saturation of ≤ 95% on room air were stratified by age group (< 65 years and ≥ 65 years), sex, and site and randomly assigned 1:1 within each stratum to receive either LY3127804 (20 mg/kg) or placebo on Day 1 and possibly on Day 15. The primary end point for this study was number of days in which a patient did not require a ventilator over the 28-day study period. RESULTS: Interim analysis assessed study futility after 95 randomized patients had 28-day data available and showed no benefit of LY3127804 in reducing the number of ventilator days over placebo. The study was subsequently terminated. CONCLUSION: LY3127804 treatment did not decrease the need for ventilator usage in patients hospitalized with pneumonia and presumed or confirmed COVID-19. ClinicalTrialsgov identifier: NCT04342897.

Erratum: Erratum.

[This corrects the article DOI: 10.1177/11795484221119316.].

Excellent outcomes for adults who experienced early standardized treadmill training during acute phase of recovery from stroke: a case series.

OBJECTIVE: To describe gait outcomes, including assistive device use and incidence of falls, in a group of adults post stroke who received early standardized treadmill training (ESTT) in the acute phase of rehabilitation. DESIGN: A case series of 18 individuals post stroke with varied lesion size, location, and comorbidities. SETTING: Inpatient rehabilitation unit. INTERVENTION: Daily 30-minute sessions of ESTT initiated before overground training in the acute rehabilitation period. OUTCOME MEASURES: Three-dimensional gait analysis, 6-minute walk test (6MWT), assistive device inventory, and fall history. RESULTS: Gait analysis revealed better temporal and spatial symmetry than have been previously documented. Twelve participants walked at speeds of greater than 0.80 m/s and 10 walked without the use of an assistive device or orthoses. Mean 6MWT distance was 322.42 m (±114.33). Thirteen participants (72%) reported no falls over a 6-month period. CONCLUSION: These outcomes far surpass the current data reported in the literature for this patient population and were achieved by the application of an intervention that was feasible in the acute rehabilitation setting.

The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in AKT1, RAS, and AURKA-have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.This article is highlighted in the In This Issue feature, p. 1079.

Effects of repetitive electrical stimulation to treat sensory loss in persons poststroke.

UNLABELLED: Smith PS, Dinse HR, Kalisch T, Johnson M, Walker-Batson D. Effects of repetitive electrical stimulation to treat sensory loss in persons poststroke. OBJECTIVE: To explore the effectiveness of repetitive electrical stimulation referred to here as tactile coactivation and to improve sensory discrimination and function in the most involved hand of a person recovering from stroke. DESIGN: Pre-experimental 1-group (n=4) design with multiple measures. SETTING: Outpatient stroke treatment center. PARTICIPANTS: Subjects with 6 months or longer poststroke with self-reported sensory loss and a mild motor impairment in the most involved hand. INTERVENTION: Electrical stimulation (coactivation) of the fingers of the involved hand for 90 minutes 4 days a week for 6 weeks. MAIN OUTCOME MEASURES: Primary-dependent measures included touch threshold, tactile acuity, haptic object recognition, motor tapping task, pegboard activities, and functional tasks from the Wolf Motor Function Test. RESULTS: Posttreatment assessments revealed improvements in sensory discrimination and motor task performance in all subjects in varying degrees; these results held 4 weeks posttreatment. CONCLUSIONS: The type of repetitive electrical stimulation or tactile coactivation used in this study has not been explored previously in subjects with sensory loss caused by stroke. The results of this pilot study suggest that coactivation may have the potential to be a useful therapeutic modality for this population.

Locomotor treadmill training with partial body-weight support before overground gait in adults with acute stroke: a pilot study.

OBJECTIVE: To investigate the impact of locomotor treadmill training with partial body-weight support (BWS) before the initiation of overground gait for adults less than 6 weeks poststroke. DESIGN: Parallel group, posttest only. SETTING: Inpatient rehabilitation center. PARTICIPANTS: Adults after first stroke admitted to an inpatient rehabilitation unit: treadmill group (n=7) and comparison group (n=7). INTERVENTIONS: Locomotor treadmill training with partial BWS or traditional gait training methods. MAIN OUTCOME MEASURES: Gait kinematics, symmetry, velocity, and endurance at least 6 months postinsult. RESULTS: Data from 3-dimensional gait analysis and 6-minute walk test (6MWT) supported improved gait for adults postacute stroke who practiced gait on a treadmill before walking over ground. Gait analysis showed increased knee flexion during swing and absence of knee hyperextension in stance for the treadmill group. In addition, more normal ankle kinematics at initial contact and terminal stance were observed in the treadmill group. Improved gait symmetry in the treadmill group was confirmed by measures of single support time, hip flexion at initial contact, maximum knee flexion, and maximum knee extension during stance. The treadmill group also walked further and faster in the 6MWT than the comparison group. CONCLUSIONS: Application of locomotor treadmill training with partial BWS before overground gait training may be more effective in establishing symmetric and efficient gait in adults postacute stroke than traditional gait training methods in acute rehabilitation.

Locomotor treadmill training with body-weight support prior to over-ground gait: promoting symmetrical gait in a subject with acute stroke.

BACKGROUND AND PURPOSE: An asymmetrical gait pattern is frequently observed in persons recovering from stroke. Locomotor training with partial body-weight support (BWS) has been demonstrated to be effective for restoring ambulation abilities in persons poststroke. However, the optimal treatment parameters for this intervention have not been defined. The purpose of this case study was to report outcomes for a person in the acute period poststroke who experienced locomotor treadmill training with BWS prior to walking over ground. METHOD: The subject of this report was a 60-year-old male with a large right-sided infarct extending into the basal ganglia. Locomotor training with BWS began on day 10 following the infarct. The subject had five sessions, totaling 40 minutes of walking practice, prior to starting gait training over ground. RESULTS: The subject walked with a single-point cane (contact guard to standby assistance) for a total of 1,000 feet at a speed of 0.94 m/s (185 ft/min) when discharged on day 25 of rehabilitation. He demonstrated comparable stance time and step length bilaterally. DISCUSSION/CONCLUSION: The subject of this case report experienced a good outcome using a combination of early locomotor treadmill training and traditional therapeutic activities. Further investigation of early treadmill training may be warranted in subjects with acute stroke.

Treadmill training post stroke: are there any secondary benefits? A pilot study.

OBJECTIVE: To explore the secondary benefits of treadmill training for people in the chronic stage of recovery from stroke. DESIGN: Modified random assignment, matched-pair control group design with repeated measures. SETTING: Outpatient stroke centre. PARTICIPANTS: Twenty individuals post first stroke who acknowledged walking slower than pre stroke. Participants matched by side of hemiparesis and motor impairment. INTERVENTIONS: Twelve 20-minute sessions of walking on a treadmill or weekly phone call. MAIN OUTCOME MEASURES: Depression (Beck Depression Index), mobility and social participation (Stroke Impact Scale 3.0 subscales) were assessed initially, at the end of 12 treatments (four weeks) and six weeks later. RESULTS: No significant difference was found between groups for any dependent measure. The ANOVA to investigate main effects in each group found no significant findings in the control group; however in the treatment group significant improvements over time for depression (P = 0.005, P < 0.001), mobility (P = 0.008) and social participation (P = 0.004) were demonstrated. CONCLUSIONS: A task-specific intervention designed to improve gait speed may potentially provide secondary benefits by positively impacting depression, mobility and social participation for people post stroke.

Berg Balance Scale and Functional Reach: determining the best clinical tool for individuals post acute stroke.

OBJECTIVE: To begin the process of determining the best clinical tool for measuring balance in individuals post stroke. DESIGN: Prospective with descriptive and relational analyses. SETTING: Rehabilitation centres and stroke support group meetings. SUBJECTS: Seventy-five subjects who had suffered a stroke were divided into four groups based on the Duncan classification for stroke severity. MAIN OUTCOME MEASURES: The motor section of the Fugl-Meyer Assessment of Physical Performance was completed for each person to classify the motor deficit. Subjects performed Functional Reach twice with the nonparetic arm and the average was recorded. Subjects performed the Berg Balance Scale and the total score on the first attempt was recorded. RESULTS: As motor impairment increased, balance ability declined and both the Functional Reach and Berg Balance Scale proved sensitive to this decline. Spearman rank correlation coefficient was excellent among the entire sample (r(s) =0.78). CONCLUSION: Subjects' performance on the Berg Balance Scale was closely associated with performance on the Functional Reach. Therefore, the clinician may elect to use the shorter Functional Reach as a measure of balance where efficient use of time is the primary goal.