Current and Emerging Treatment Paradigms in Colorectal Cancer: Integrating Hallmarks of Cancer.

The treatment of unresectable metastatic colorectal cancer has evolved over the last two decades, as knowledge of cancer biology has broadened and new targets have emerged. 'The Hallmarks of Cancer' illustrate the crucial capabilities acquired by cells to become malignant and represent the evolution of knowledge of tumor biology. This review integrates these novel targets and therapies into selected hallmarks: sustaining proliferative signaling, inducing vasculature, avoiding immune destruction, genome instability and mutation, reprogramming cellular metabolism, and resisting cell death. The different strategies and combinations under study are based on treatments with anti-EGFR, anti-VEGF, and anti-HER2 agents, KRAS G12C inhibitors, BRAF and MEK inhibitors, and immune checkpoint inhibitors. However, new approaches are emerging, including vaccines, WEE1 inhibitors, and PARP inhibitors, among others. The further deciphering of cancer biology will unravel new targets, develop novel therapies, and improve patients' outcomes.

Trajectories of parental and peer supply of alcohol in adolescence and associations with later alcohol consumption and harms: A prospective cohort study.

BACKGROUND: Supply of alcohol to adolescents is associated with increased alcohol consumption and harms including alcohol use disorder (AUD). We aimed to identify: (1) trajectories of alcohol supply to adolescents; (2) sociodemographic characteristics associated with supply trajectory; (3) patterns of alcohol consumption by supply trajectory; and (4) supply trajectory associations with adverse alcohol outcomes. METHODS: We used Australian longitudinal survey data (N = 1813) to model latent trajectories of parent and peer alcohol supply over five annual follow-ups (Waves 2-6; Mage 13.9-17.8 years). Regression models assessed associations between supply trajectories and Wave 1 (Mage=12.9 years) sociodemographic factors and associations between supply trajectories and Wave 7 (Mage=18.8 years) alcohol outcomes. RESULTS: We identified five alcohol supply classes: (1) minimal supply (n = 739, 40.8%); (2) early parent sips, late peer/parent whole drinks (n = 254, 14.0%); (3) late peer/parent whole drinks (n = 419, 23.1%); (4) early parent sips, mid peer/parent whole drinks (n = 293, 16.2%); (5) early peer/parent whole drinks (n = 108, 6.0%). Compared to minimal supply, the other classes were 2.7-12.9 times as likely to binge drink, 1.6-3.0 times as likely to experience alcohol-related harms, and 2.1-8.6 times as likely to report AUD symptoms at age 19. CONCLUSION: Earlier supply of whole drinks, particularly from peers, was associated with increased risk of early adulthood adverse alcohol outcomes. While minimal supply represented the lowest risk, supplying sips only in early-mid adolescence and delaying supply of whole drinks until late adolescence is likely to be less risky than earlier supply of whole drinks.

Adolescent Alcohol Use Trajectories: Risk Factors and Adult Outcomes.

OBJECTIVES: Adolescents often display heterogenous trajectories of alcohol use. Initiation and escalation of drinking may be important predictors of later harms, including alcohol use disorder (AUD). Previous conceptualizations of these trajectories lacked adjustment for known confounders of adolescent drinking, which we aimed to address by modeling dynamic changes in drinking throughout adolescence while adjusting for covariates. METHODS: Survey data from a longitudinal cohort of Australian adolescents (n = 1813) were used to model latent class alcohol use trajectories over 5 annual follow-ups (mean age = 13.9 until 17.8 years). Regression models were used to determine whether child, parent, and peer factors at baseline (mean age = 12.9 years) predicted trajectory membership and whether trajectories predicted self-reported symptoms of AUD at the final follow-up (mean age = 18.8 years). RESULTS: We identified 4 classes: abstaining (n = 352); late-onset moderate drinking (n = 503); early-onset moderate drinking (n = 663); and early-onset heavy drinking (n = 295). Having more alcohol-specific household rules reduced risk of early-onset heavy drinking compared with late-onset moderate drinking (relative risk ratio: 0.31; 99.5% confidence interval [CI]: 0.11-0.83), whereas having more substance-using peers increased this risk (relative risk ratio: 3.43; 99.5% CI: 2.10-5.62). Early-onset heavy drinking increased odds of meeting criteria for AUD in early adulthood (odds ratio: 7.68; 99.5% CI: 2.41-24.47). CONCLUSIONS: Our study provides evidence that parenting factors and peer influences in early adolescence should be considered to reduce risk of later alcohol-related harm. Early initiation and heavy alcohol use throughout adolescence are associated with increased risk of alcohol-related harm compared with recommended maximum levels of consumption (late-onset, moderate drinking).

Parental supply of sips and whole drinks of alcohol to adolescents and associations with binge drinking and alcohol-related harms: A prospective cohort study.

BACKGROUND: Parents frequently supply alcohol to their children, often only sips. We investigated whether supply of sips and whole drinks, from parents and other sources, are differentially associated with subsequent drinking outcomes. METHODS: A cohort of 1910 adolescents (mean age 12.9yrs) were surveyed annually over seven years from 2010-11. We examined prospective, adjusted associations between the quantity of supply from parental and non-parental sources in the preceding 12 months and five outcomes in the subsequent year, over several consecutive years: binge drinking; alcohol-related harms; symptoms of alcohol abuse, dependence and alcohol use disorder (AUD). RESULTS: In early waves, most parental supply comprised sips, while supply of whole drinks increased in later waves. Among those not receiving alcohol from other sources, parental supply of sips was associated with increased odds of binge drinking (OR: 1.85; 99.5 % CI: 1.17-2.91) and alcohol-related harms (OR: 1.70; 99.5 % CI: 1.20-2.42), but not with reporting symptoms of alcohol abuse, dependence or AUD, compared with no supply. Relative to no supply, supply of sips from other sources was associated with increased odds of binge drinking (OR: 2.04; 99.5 % CI: 1.14-3.67) only. Compared with supply of sips, supply of whole drinks by parents or others had higher odds of binge drinking, alcohol-related harms, symptoms of dependence and of AUD. Secondary analysis demonstrated that supply of larger quantities was associated with an increased risk of all outcomes. CONCLUSION: Parental provision of sips is associated with increased risks and the supply of greater quantities was associated with an increasing risk of adverse outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT02280551).