Evaluation and management of sport-related concussions in adolescent athletes.

Sport-related concussions in young athletes are common, generally under reported and often go unrecognized. Concussion in sport may result either from a direct impact to the head or from indirect forces transmitted to the brain from impact elsewhere on the body. Concussions may also result from sudden acceleration, deceleration or rotational forces to the brain. The key features of concussion include confusion, impaired memory and reduced speed of information processing. Recovery may occur from a few days to several weeks or months. Both physical and cognitive rests are recommended for recovery. Long-term cognitive and behavioral complications are a concern. Preventive strategies include education, modification of sport rules, use of equipment such as headgears, face masks and mouth guards, and neck muscle training. Evidence is limited to support effectiveness of these preventive measures with the exception of rule modification in some sports. Laws have been enacted that require medical evaluation and clearance prior to return to play; however, evidence thus far does not show that laws have been effective in reducing the incidence of concussions in sport. More research is needed in all areas of preventive measures. Sports participation is a complex personal decision on the part of adolescent and his or her family. They should be provided with all information on inherent risks so that they can make an informed decision.

Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6.

PURPOSE: The emerging need for rational combination treatment approaches led us to test the concept that cotargeting MEK and CDK4/6 would prove efficacious in KRAS-mutant (KRAS(mt)) colorectal cancers, where upregulated CDK4 and hyperphosphorylated retinoblastoma (RB) typify the vast majority of tumors. EXPERIMENTAL DESIGN: Initial testing was carried out in the HCT-116 tumor model, which is known to harbor a KRAS mutation. Efficacy studies were then performed with five RB(+) patient-derived colorectal xenograft models, genomically diverse with respect to KRAS, BRAF, and PIK3CA mutational status. Tolerance, efficacy, and pharmacodynamic evaluation of target modulation were evaluated in response to daily dosing with either agent alone or concurrent coadministration. RESULTS: Synergy was observed in vitro when HCT-116 cells were treated over a broad range of doses of trametinib and palbociclib. Subsequent in vivo evaluation of this model showed a higher degree of antitumor activity resulting from the combination compared to that achievable with single-agent treatment. Testing of colorectal patient-derived xenograft (PDX) models further showed that combination of trametinib and palbociclib was well tolerated and resulted in objective responses in all KRAS(mt) models tested. Stasis was observed in a KRAS/BRAF wild-type and a BRAF(mt) model. CONCLUSIONS: Combination of trametinib and palbociclib was well tolerated and highly efficacious in all three KRAS-mutant colorectal cancer PDX models tested. Promising preclinical activity seen here supports clinical evaluation of this treatment approach to improve therapeutic outcome for patients with metastatic colorectal cancer.

Cancer stem cell marker phenotypes are reversible and functionally homogeneous in a preclinical model of pancreatic cancer.

Survival rates associated with pancreatic cancer remain dismal despite advancements in detection and experimental treatment strategies. Genetically engineered mouse models of pancreatic tumorigenesis have gained considerable attention based on their ability to recapitulate key clinical features of human disease including chemotherapeutic resistance and fibrosis. However, it is unclear if transgenic systems exemplified by the Kras(G12D)/Trp53(R172H)/Pdx-1-Cre (KPC) mouse model recapitulate the functional heterogeneity of human pancreatic tumors harboring distinct cells with tumorigenic properties. To facilitate tracking of heterogeneous tumor cell populations, we incorporated a luciferase-based tag into the genetic background of the KPC mouse model. We isolated pancreatic cancer cells from multiple independent tumor lines and found that roughly 1 out of 87 cells exhibited tumorigenic capability. Notably, this frequency is significantly higher than reported for human pancreatic adenocarcinomas. Cancer stem cell (CSC) markers, including CD133, CD24, Sca-1, and functional Aldefluor activity, were unable to discriminate tumorigenic from nontumorigenic cells in syngeneic transplants. Furthermore, three-dimensional spheroid cultures originating from KPC tumors did not enrich for cells with stem-like characteristics and were not significantly more tumorigenic than cells cultured as monolayers. Additionally, we did not observe significant differences in response to gemcitabine or salinomycin in several isolated subpopulations. Taken together, these studies show that the hierarchical organization of CSCs in human disease is not recapitulated in a commonly used mouse model of pancreatic cancer and therefore provide a new view of the phenotypic and functional heterogeneity of tumor cells.