RESUMEN
PURPOSE: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma. PATIENTS AND METHODS: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4-6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies. RESULTS: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001-treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine-DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted. CONCLUSIONS: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Receptor IGF Tipo 1/antagonistas & inhibidores , Adulto , Anciano , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Femenino , Glioblastoma/inmunología , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Oligodesoxirribonucleótidos Antisentido/efectos adversos , Receptor IGF Tipo 1/genéticaRESUMEN
OBJECTIVE: To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods. METHODS: A prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors. RESULTS: We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex (p = 0.02), higher Unified Parkinson's Disease Rating Scale motor score (p ≤ 0.001), and worse global cognitive score (p < 0.001). CONCLUSIONS: Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD.
Asunto(s)
Cognición/fisiología , Disfunción Cognitiva/complicaciones , Enfermedad de Parkinson/complicaciones , Anciano , Disfunción Cognitiva/diagnóstico , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estudios ProspectivosRESUMEN
Spatial motor-intentional "Aiming" bias is a dysfunction in initiation/execution of motor-intentional behavior, resulting in hypokinetic and hypometric leftward movements. Aiming bias may contribute to posture, balance, and movement problems and uniquely account for disability in post-stroke spatial neglect. Body movement may modify and even worsen Aiming errors, but therapy techniques, such as visual scanning training, do not take this into account. Here, we evaluated (1) whether instructing neglect patients to move midline body parts improves their ability to explore left space and (2) whether this has a different impact on different patients. A 68-year-old woman with spatial neglect after a right basal ganglia infarct had difficulty orienting to and identifying left-sided objects. She was prompted with four instructions: "look to the left," "point with your nose to the left," "point with your [right] hand to the left," and "stick out your tongue and point it to the left." She oriented leftward dramatically better when pointing with the tongue/nose, than she did when pointing with the hand. We then tested nine more consecutive patients with spatial neglect using the same instructions. Only four of them made any orienting errors. Only one patient made >50% errors when pointing with the hand, and she did not benefit from pointing with the tongue/nose. We observed that pointing with the tongue could facilitate left-sided orientation in a stroke survivor with spatial neglect. If midline structures are represented more bilaterally, they may be less affected by Aiming bias. Alternatively, moving the body midline may be more permissive for leftward orienting than moving right body parts. We were not able to replicate this effect in another patient; we suspect that the magnitude of this effect may depend upon the degree to which patients have directional akinesia, spatial Where deficits, or cerebellar/frontal cortical lesions. Future research could examine these hypotheses.