Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer.

There is a continuing debate about the proportion of cancer patients that benefit from precision oncology, attributable in part to conflicting views as to which molecular alterations are clinically actionable. To quantify the expansion of clinical actionability since 2017, we annotated 47,271 solid tumors sequenced with the MSK-IMPACT clinical assay using two temporally distinct versions of the OncoKB knowledge base deployed 5 years apart. Between 2017 and 2022, we observed an increase from 8.9% to 31.6% in the fraction of tumors harboring a standard care (level 1 or 2) predictive biomarker of therapy response and an almost halving of tumors carrying nonactionable drivers (44.2% to 22.8%). In tumors with limited or no clinical actionability, TP53 (43.2%), KRAS (19.2%), and CDKN2A (12.2%) were the most frequently altered genes. SIGNIFICANCE: Although clear progress has been made in expanding the availability of precision oncology-based treatment paradigms, our results suggest a continued unmet need for innovative therapeutic strategies, particularly for cancers with currently undruggable oncogenic drivers. See related commentary by Horak and Fröhling, p. 18. This article is featured in Selected Articles from This Issue, p. 5.

QEEG markers of superior shooting performance in skilled marksmen: An investigation of cortical activity on psychomotor efficiency hypothesis.

For elite performers, psychomotor behavior's success or failure can be traced to differences in brain dynamics. The psychomotor efficiency hypothesis suggests refined cortical activity through 1) selective activation of task-relevant processes and 2) inhibition of non-essential processes. The use of electroencephalography (EEG) has been applied to investigate psychomotor performance's neural processes. The EEG markers that reflect an elevation of psychomotor efficiency include left temporal alpha (T3 alpha), frontal midline theta (Fm theta), sensorimotor rhythm (SMR), and the coherence between frontal and left temporal regions. However, the relationship between elite performers' task-relevant and non-essential neural processes is still not well understood. Therefore, this study aimed to explore how each task-relevant and inhibition of non-essential processes contribute to superior psychomotor behavior. Thirty-five highly skilled marksmen were recruited to perform 30 shots in the shooting task while the EEG was recorded. The marksmen were divided into two groups (superior & inferior) based on a median split of shooting performance. The superior group exhibited higher accuracy and precision, with a reduction in movement jerk. EEG measures revealed that the superior group exhibited higher SMR before the trigger pull than the inferior group. In addition, the superior group demonstrated reduced Fz-T3 coherence in their bull's eye shots than the missed shots. These results suggest that the superior group exhibited less effortful engagement of task-relevant processes and lower interference from non-essential cortical regions than the inferior group. The study's overall findings support the psychomotor efficiency hypothesis. When comparing highly skilled performers, the slight differences in brain dynamics ultimately contribute to the success or failure of psychomotor performance.

Collaborative neural processes predict successful cognitive-motor performance.

Psychomotor efficiency is achieved by expert performers who exhibit refined attentional strategies and efficient motor program execution. Further understanding of the psychomotor efficiency hypothesis requires examination of the co-activation of key electroencephalographic (EEG) indices, including frontal theta (Fθ) power, left temporal alpha (T3α) power, the sensory-motor rhythm (SMR), and frontocentral alpha power (FCα). This study examined the relationship between these selected neural processes and the odds of successful cognitive-motor performance. EEG indices of successful and failed putts observed in twenty-seven skilled golfers were subjected to mixed-effects logistic regression analysis. The results revealed that concurrent elevations of Fθ and T3α were associated with increased odds of successful performance. The co-activation from motoric processes indicated by SMR and FCα also elevated the odds. Overall, the findings emphasize that refined attention allocation and effective motor program processing are essential cognitive features of superior cognitive-motor performance for skilled golfers.

Effect of Self-Controlled Practice on Neuro-Cortical Dynamics During the Processing of Visual Performance Feedback.

Evidence has accumulated that learners participating in self-controlled practice can both acquire skills and process task-relevant information more effectively than those participating in externally controlled practice. However, the impact of self-controlled practice on neuro-cognitive information processing during visual performance-related feedback has received limited investigation. We expected that individuals participating in self-controlled practice would exhibit elevated neuro-cognitive information processing, as assessed via electroencephalography (EEG), compared with those engaged with externally controlled practice. Participants practiced a golf-putting task under self-controlled or externally controlled (yoked) conditions while EEG data were recorded. Results indicated that EEG theta power was maintained at an elevated level during the feedback period in the self-controlled group relative to the yoked group. The yoked group did not display increases in theta power until the time at which the ball stopped. Both groups displayed similar improvement over the course of the experiment. Correlational analyses revealed that performance improvement within each group was related differently to EEG theta power. Specifically, the self-controlled group displayed positive relationships between theta power and performance improvement, while the yoked group displayed negative relationships. These results have implications regarding the relative effectiveness of self-controlled and externally controlled practice and the instances in which they may provide the most benefit.

Changes in Mental Workload and Motor Performance Throughout Multiple Practice Sessions Under Various Levels of Task Difficulty.

The allocation of mental workload is critical to maintain cognitive-motor performance under various demands. While mental workload has been investigated during performance, limited efforts have examined it during cognitive-motor learning, while none have concurrently manipulated task difficulty. It is reasonable to surmise that the difficulty level at which a skill is practiced would impact the rate of skill acquisition and also the rate at which mental workload is reduced during learning (relatively slowed for challenging compared to easier tasks). This study aimed to monitor mental workload by assessing cortical dynamics during a task practiced under two difficulty levels over four days while perceived task demand, performance, and electroencephalography (EEG) were collected. As expected, self-reported mental workload was reduced, greater working memory engagement via EEG theta synchrony was observed, and reduced cortical activation, as indexed by progressive EEG alpha synchrony was detected during practice. Task difficulty was positively related to the magnitude of alpha desynchrony and accompanied by elevations in the theta-alpha ratio. Counter to expectation, the absence of an interaction between task difficulty and practice days for both theta and alpha power indicates that the refinement of mental processes throughout learning occurred at a comparable rate for both levels of difficulty. Thus, the assessment of brain dynamics was sensitive to the rate of change of cognitive workload with practice, but not to the degree of difficulty. Future work should consider a broader range of task demands and additional measures of brain processes to further assess this phenomenon.

A Phase II Clinical Trial of an Aromatase Inhibitor for Postmenopausal Women with Lymphangioleiomyomatosis.

RATIONALE: Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. OBJECTIVES: To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. METHODS: Seventeen postmenopausal women with LAM were enrolled in this phase II trial and randomized to receive letrozole 2.5 mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF-D) were measured at baseline and at 3-month intervals. RESULTS: Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was -3 ± 3 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was -0.024 ± 0.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (-0.029 ± 0.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, compared with only half of the patients who were not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated-placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole-treated patients. CONCLUSIONS: Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the same month as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline. Clinical trial registered with www.clinicaltrials.gov (NCT01353209).