Epidermal Growth Factor Receptor Inhibitor Treatment Timing does not Impact Survival in Stage 4 Colon Cancer Treatment: A Retrospective Study.

Introduction: Colon cancer impacts the lives of Kansans and those across the United States. Epidermal growth factor receptor (EGFR) inhibitors, such as panitumumab and cetuximab, have gained popularity as first-line treatment for stage 4 colon cancer despite their toxicities and have been used by clinicians in later lines of therapy. EGFR inhibitors have been proven to be an efficacious first-line treatment for stage 4 colon cancer, but no study has investigated outcomes comparing EGFR inhibitors as first-line treatment to its use as second- or third-line treatment. This study investigated EGFR inhibitor therapy estimated overall survival when used as first-, second-, and third-line treatment for stage 4 colon cancer. Methods: A retrospective review was done for patients with stage 4 colon cancer who underwent EGFR inhibitor treatment at a large academic center from November 2007 to August 2021. The patients were stratified into five groups by the line in which they received the EGFR inhibitor treatment. A log-rank test was used to analyze the groups, and the median survival for each group was determined. Results: A total of 68 patients were reviewed; 18 received first-line, 23 received second-line, 18 received third-line, 6 received fourth-line, and 3 received sixth-line treatment with an EGFR inhibitor. Fourth- and sixth-line therapies were excluded due to small patient size. There was no significant difference in estimated survival time between any of the lines. Median survival of the therapies was found. Conclusions: There was no statistical difference in survival between the first-, second-, or third-line groups, which may provide justification for its use as a second- or third-line therapy.

Adult visual experience promotes recovery of primary visual cortex from long-term monocular deprivation.

Prolonged visual deprivation from early childhood to maturity is believed to cause permanent visual impairment. However, there have been case reports of substantial improvement of binocular vision in human adults following lifelong visual impairment or deprivation. These observations, together with recent findings of adult ocular dominance plasticity in rodents, led us to re-examine whether adult primary visual cortex (V1) is capable of any recovery following long-term monocular deprivation starting in development. Using mice as a model, we find that monocular deprivation from early development to mature ages (well past the critical period) severely impaired binocular vision by reducing the amplitude of responses elicited by stimulation of the deprived eye. Surprisingly, we find little effect on nondeprived eye responses. Restoration of binocular vision in mature adults yields modest but significant improvement of visual responses in V1. Remarkably, we find that when binocular vision is followed by occlusion of the nondeprived eye, visual responses in V1 recover almost fully, as measured by visual evoked potential amplitude, spatial frequency threshold, and single-unit activity. We conclude that adult V1 can recover from long-term deprivation when provided with an optimal regimen of visual experience.

Monocular deprivation in adult mice alters visual acuity and single-unit activity.

It has been discovered recently that monocular deprivation in young adult mice induces ocular dominance plasticity (ODP). This contradicts the traditional belief that ODP is restricted to a juvenile critical period. However, questions remain. ODP of young adults has been observed only using methods that are indirectly related to vision, and the plasticity of young adults appears diminished in comparison with juveniles. Therefore, we asked whether the newly discovered adult ODP broadly reflects plasticity of visual cortical function and whether it persists into full maturity. Single-unit activity is the standard physiological marker of visual cortical function. Using a more optimized protocol for recording single-units, we find evidence of adult ODP of single-units and show that it is most pronounced in deep cortical layers. Furthermore, using visual evoked potentials (VEP), we find that ODP is equally robust in young adults and mature adults and is observable after just one day of monocular deprivation. Finally, we find that monocular deprivation in adults changes spatial frequency thresholds of the VEP, decreasing the acuity of the deprived pathway and improving the acuity of the non-deprived pathway. Thus, in mice, the primary visual cortex is capable of remarkable adaptation throughout life.

Opposing functions of CREB and MKK1 synergistically regulate the geometry of dendritic spines in visual cortex.

Most excitatory inputs onto pyramidal neurons are made on dendritic spines. The geometry of dendritic spines modulates synaptic function; yet we know little regarding the molecular signals that regulate spine geometry. Here we report that neurons coordinately regulate the geometry of spines to compensate for variability in spine number, by a process requiring the transcription factor CREB and the kinase MKK1. We find that CREB function is induced, whereas MKK1 is inhibited, by activity blockade. To obtain evidence that CREB and MKK1 regulate dendritic spine geometry in vivo, we coexpressed green fluorescent protein and dominant negative CREB or MKK1 in pyramidal neurons of the intact rat visual cortex. Spines on apical dendrites of layer 3 neurons were then characterized by confocal microscopy. We find that CREB and MKK1 regulate spine geometry in opposite ways. MKK1 is required to reduce spine head size when spine density is high, whereas CREB is required to enlarge spines when spine density is low. Our data suggest that CREB and MKK1 might function as complementary negative feedback mechanisms to maintain synaptic drive within bounds.

Regulation of the CREB signaling cascade in the visual cortex by visual experience and neuronal activity.

The cAMP-responsive element (CRE) regulatory pathway has been studied as a model of signal-regulated transcription and is critical for some forms of learning and adaptation. In cell culture systems, the extracellular-regulated kinase (ERK) and ribosomal S6 kinase (RSK) couple synaptic signals to CRE-mediated gene expression by modulating CRE-binding protein (CREB) phosphorylation. However, it is not known whether sensory experience regulates gene expression in the brain by this mechanism. In this study, we ask: Are activated forms of ERK, RSK, and CREB colocalized in the cortex and are they coordinately regulated by synaptic signals? We find that these three signaling components are regulated in distinct ways. First, cells that show CRE-lacZ reporter expression, primarily excitatory neurons, do not colocalize with cells containing phospho-ERK. Second, while phosphorylation of ERK and RSK are modulated by visual experience, phosphorylation of CREB at serines 133, 142, or 143 is detected constitutively and is unaffected by experience. This finding suggests that neural activity might not regulate CREB phosphorylation in vivo. To test this hypothesis, we blocked action potentials by injection of tetrodotoxin and found no effect on CREB phosphorylation. These in vivo data show that, in contrast to cell culture systems, cortical synaptic activity controls CRE-mediated gene expression without affecting CREB phosphorylation, possibly by modification of RSK and CREB-associated coregulators.

Swept contrast visual evoked potentials and their plasticity following monocular deprivation in mice.

The swept contrast visual evoked potential technique is a quasi-psychophysical method that can help bridge the gap between cell biology and visual performance in studies of ocular dominance plasticity. In mice we found that four days of monocular deprivation diminished the amplitude of evoked potentials from the deprived eye relative to the non-deprived eye. This ocular dominance plasticity was nearly as great in adult mice as in juveniles. The monocular deprivation effect was mediated, at least in part, by enhancement of responses evoked from the non-deprived eye, rather than by depression of responses from the deprived eye.

A semi-persistent adult ocular dominance plasticity in visual cortex is stabilized by activated CREB.

The adult cerebral cortex can adapt to environmental change. Using monocular deprivation as a paradigm, we find that rapid experience-dependent plasticity exists even in the mature primary visual cortex. However, adult cortical plasticity differs from developmental plasticity in two important ways. First, the effect of adult, but not juvenile monocular deprivation is strongly suppressed by administration of barbiturate just prior to recording visual evoked potentials, suggesting that the effect of adult experience can be inactivated acutely. Second, the effect of deprivation is less persistent over time in adults than in juveniles. This correlates with the known decline in CREB function during maturation of the visual cortex. To compensate for this decline in CREB function, we expressed persistently active VP16-CREB and find that it causes adult plasticity to become persistent. These results suggest that in development and adulthood, the regulation of a trans-synaptic signaling pathway controls the adaptive potential of cortical circuits.