Phase 1 Clinical Trial of Trametinib and Ponatinib in Patients With NSCLC Harboring KRAS Mutations.

INTRODUCTION: Somatic KRAS mutations occur in 25% of patients with NSCLC. Treatment with MEK inhibitor monotherapy has not been successful in clinical trials to date. Compensatory activation of FGFR1 was identified as a mechanism of trametinib resistance in KRAS-mutant NSCLC, and combination therapy with trametinib and ponatinib was synergistic in in vitro and in vivo models. This study sought to evaluate this drug combination in patients with KRAS-mutant NSCLC. METHODS: A phase 1 dose escalation study of trametinib and ponatinib was conducted in patients with advanced NSCLC with KRAS mutations. A standard 3-plus-3 dose escalation was done. Patients were treated with the study therapy until intolerable toxicity or disease progression. RESULTS: A total of 12 patients with KRAS-mutant NSCLC were treated (seven at trametinib 2 mg and ponatinib 15 mg, five at trametinib 2 mg and ponatinib 30 mg). Common toxicities observed were rash, diarrhea, and fever. Serious adverse events potentially related to therapy were reported in five patients, including one death in the study and four cardiovascular events. Serious events were observed at both dose levels. Of note, 75% (9 of 12) were assessable for radiographic response and no confirmed partial responses were observed. The median time on study was 43 days. CONCLUSIONS: In this phase 1 study, in patients with KRAS-mutant advanced NSCLC, combined treatment with trametinib and ponatinib was associated with cardiovascular and bleeding toxicities. Exploring the combination of MEK and FGFR1 inhibition in future studies is potentially warranted but alternative agents should be considered to improve safety and tolerability.

Pain Neuroscience Education: State of the Art and Application in Pediatrics.

Chronic pain is a widespread problem in the field of pediatrics. Many interventions to ameliorate pain-related dysfunction have a biobehavioral focus. As treatments for chronic pain (e.g., increased movement) often stand in stark contrast to treatments for an acute injury (e.g., rest), providing a solid rationale for treatment is necessary to gain patient and parent buy-in. Most pain treatment interventions incorporate psychoeducation, or pain neuroscience education (PNE), as an essential component, and in some cases, as a stand-alone approach. The current topical review focuses on the state of pain neuroscience education and its application to pediatric chronic pain. As very little research has examined pain neuroscience education in pediatrics, we aim to describe this emerging area and catalyze further work on this important topic. As the present literature has generally focused on adults with chronic pain, pain neuroscience education merits further attention in the realm of pediatric pain in order to be tailored and implemented in this population.

Predicting episodic memory formation for movie events.

Episodic memories are long lasting and full of detail, yet imperfect and malleable. We quantitatively evaluated recollection of short audiovisual segments from movies as a proxy to real-life memory formation in 161 subjects at 15 minutes up to a year after encoding. Memories were reproducible within and across individuals, showed the typical decay with time elapsed between encoding and testing, were fallible yet accurate, and were insensitive to low-level stimulus manipulations but sensitive to high-level stimulus properties. Remarkably, memorability was also high for single movie frames, even one year post-encoding. To evaluate what determines the efficacy of long-term memory formation, we developed an extensive set of content annotations that included actions, emotional valence, visual cues and auditory cues. These annotations enabled us to document the content properties that showed a stronger correlation with recognition memory and to build a machine-learning computational model that accounted for episodic memory formation in single events for group averages and individual subjects with an accuracy of up to 80%. These results provide initial steps towards the development of a quantitative computational theory capable of explaining the subjective filtering steps that lead to how humans learn and consolidate memories.