RESUMEN
BACKGROUND: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. PATIENTS AND METHODS: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). RESULTS: With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61-0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation. CONCLUSIONS: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.
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Mesotelioma Maligno , Nivolumab , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Ipilimumab/efectos adversos , Nivolumab/uso terapéutico , Supervivencia sin ProgresiónRESUMEN
Animal models have facilitated basic neuroscience research investigating the pathophysiology of tinnitus. It has been hypothesized that partial deafferentation produces a loss of tonic inhibition in the auditory system that may lead to inappropriate neuroplastic changes eventually expressed as tinnitus. The pathological down-regulation of gamma-amino butyric acid (GABA) provides a potential mechanism for this loss of inhibition. Using an animal model previously demonstrated to be sensitive to treatments that either induce or attenuate tinnitus, the present study examined the effect of the specific GABA agonist vigabatrin on chronic tinnitus. It was hypothesized that vigabatrin would decrease the evidence of tinnitus by restoring central inhibitory function through increased GABA availability. Vigabatrin has been demonstrated to elevate central GABA levels (Mattson et al. 1995). Tinnitus was induced in rats using a single 1-h unilateral exposure to band-limited noise, which preserved normal hearing in one ear. Psychophysical evidence of tinnitus was obtained using a free-operant conditioned-suppression method: Rats lever-pressed for food pellets and were trained to discriminate between the presence and absence of sound by punishing lever pressing with a mild foot shock (0.5 mA; 1 s) at the conclusion of randomly introduced silent periods (60 s) inserted into background low-level noise. Additional random insertion of pure tone and noise periods of variable intensity enabled the derivation of psychophysical functions that reflected the presence of tinnitus with features similar to 20-kHz tones. Vigabatrin was chronically administered via drinking water at 30 and 81 mg kg-1 day-1, with each dose level tested over 2 weeks, followed by a 0-mg washout test. Vigabatrin completely and reversibly eliminated the psychophysical evidence of tinnitus at both doses. Although vigabatrin has serious negative side effects that have prevented its clinical use in the USA, it is nevertheless a potentially useful tool in unraveling tinnitus pathophysiology.
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GABAérgicos/farmacología , Acúfeno/tratamiento farmacológico , Acúfeno/fisiopatología , Vigabatrin/farmacología , 4-Aminobutirato Transaminasa/antagonistas & inhibidores , Adaptación Fisiológica , Animales , Umbral Auditivo , Conducta Animal , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico , Masculino , Inhibición Neural/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Ruido , Psicofísica , Ratas , Ratas Long-EvansRESUMEN
Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.
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Encéfalo/metabolismo , Memoria , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/fisiopatología , Ovillos Neurofibrilares/patología , Proteínas tau/metabolismo , Envejecimiento , Animales , Atrofia , Encéfalo/patología , Cognición , Progresión de la Enfermedad , Doxiciclina/farmacología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Aprendizaje por Laberinto , Ratones , Ratones Transgénicos , Enfermedades Neurodegenerativas/metabolismo , Ovillos Neurofibrilares/metabolismo , Plasticidad Neuronal , Neuronas/metabolismo , Neuronas/patología , Tamaño de los Órganos , Fosforilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Solubilidad , Proteínas tau/química , Proteínas tau/genéticaRESUMEN
The Verebelyi-Ogston (V-O) procedure, consisting of subchrondral excision of the talus and cuboid, was used for the treatment of 13 resistant clubfeet secondary to myelomeningocele or arthrogryposis. Nine feet were initially satisfactory, but the condition recurred in both feet of one patient after bracing was discontinued 3 years postoperatively. Three feet were graded as satisfactory after a second V-O procedure, and one after a third. The procedure must be monitored by intraoperative fluoroscopy or radiography, and followed by orthotic support. Despite the theoretical long-term disadvantage of incongruent joint surfaces, we consider the V-O procedure to be a good method for the treatment of this subset of rigid neuropathic clubfeet.
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Artrogriposis/complicaciones , Pie Equinovaro/cirugía , Meningomielocele/complicaciones , Moldes Quirúrgicos , Niño , Preescolar , Pie Equinovaro/etiología , Femenino , Humanos , Cuidados Intraoperatorios , Masculino , Métodos , Aparatos Ortopédicos , Cuidados Posoperatorios , Astrágalo/cirugíaRESUMEN
Extremely large carbon tubes, some exceeding 5 microm in diameter, were produced with both laser and electric arc techniques using graphite, a transition metal catalyst, and a reactive third-body gas. We have named these structures carbon megatubes. They are the first carbonaceous tubes large enough to observe using optical microscopy. We also report the synthesis of what we believe to be the first self-assembled branched nanotubes. In addition to their extreme diameters and unique morphologies, X-ray photoelectron spectroscopy has shown that these tubes also contain a significant amount of nitrogen atom incorporation into the graphite lattice. Subsequently, these nitrogen functionalities were shown to interact with rhenium pentacarbonyl bromide and serve as anchor points to tether molecules to the surface of the tubules.