In 2015, ramucirumab and TAS-102 became the 10th and 11th drugs approved by the Food and Drug administration for the treatment of patients with colorectal cancer, not counting leucovorin, and yet only 3 agents, 5-fluorouracil, capecitabine, and oxaliplatin, have proven benefit in adjuvant treatment. In fact, there have been no additions (and 1 subtraction levamisole) to our arsenal of therapies for patients with stages II and III colon cancer for more than a decade. How did we get here? Are we stuck? And how do we move forward?

PURPOSE OF REVIEW

There are evolving epidemiological and biological data to support an association between the gene encoding apolipoprotein-L1 (APOL1) and progressive chronic kidney disease (CKD) among African-Americans.

RECENT FINDINGS

Individuals with two APOL1 risk alleles are at greater risk of incident albuminuria, CKD, and progression to end-stage renal disease despite optimal blood pressure management and use of angiotensin-converting enzyme inhibitors. These variants also appear to influence outcomes in donor and recipients in kidney transplantation. Recent studies have also variably shown a potential role of APOL1 variants in cardiovascular disease. A number of studies have addressed genetic and environmental factors such as HIV but most do not modify the course of APOL1-related kidney disease. Although the exact mechanism remains unclear, functional studies have demonstrated the effect of APOL1 and related protein on innate immunity and cytotoxicity.

SUMMARY

APOL1 is an important genetic risk factor for kidney disease among African-Americans. With approximately one in 10 African-Americans at risk, further studies are warranted to identify underlying biological mechanisms and other potential modifiers leading to CKD. Moreover, studies that clarify the association of APOL1 variants with cardiovascular disease, independent of CKD, are also needed.

IMPORTANCE

Despite guidelines recommending against prostate-specific antigen (PSA) screening in elderly men with limited life expectancy, PSA screening remains common.

OBJECTIVE

To identify clinician characteristics associated with PSA screening rates in older veterans stratified by life expectancy.

DESIGN, SETTING, AND PARTICIPANTS

Cross-sectional study of 826 286 veterans 65 years or older eligible for PSA screening who had VA laboratory tests performed in 2011 in the VA health care system.

MAIN OUTCOMES AND MEASURES

The primary outcome was the percentage of men with a screening PSA test in 2011. Limited life expectancy was defined as age of at least 85 years with Charlson comorbidity score of 1 or greater or age of at least 65 years with Charlson comorbidity score of 4 or greater. Primary predictors were clinician characteristics including degree-training level, specialty, age, and sex. We performed log-linear Poisson regression models for the association between each clinician characteristic and PSA screening stratified by patient life expectancy and adjusted for patient demographics and clinician clustering.

RESULTS

In 2011, 466 017 (56%) of older veterans received PSA screening, including 39% of the 203 717 men with limited life expectancy. After adjusting for patient demographics, higher PSA screening rates in patients with limited life expectancy was associated with having a clinician who was an older man and was no longer in training. The PSA screening rates ranged from 27% for men with a physician trainee to 42% for men with an attending physician (P < .001); 22% for men with a geriatrician to 82% for men with a urologist as their clinician (P < .001); 29% for men with a clinician 35 years or younger to 41% for those with a clinician 56 years or older (P < .001); and 38% for men with a female clinician older than 55 years vs 43% for men with a male clinician older than 55 years (P < .001).

CONCLUSIONS AND RELEVANCE

More than one-third of men with limited life expectancy received PSA screening. Men whose clinician was a physician trainee had substantially lower PSA screening rates than those with an attending physician, nurse practitioner, or physician assistant. Interventions to reduce PSA screening rates in older men with limited life expectancy should be designed and targeted to high-screening clinicians- older male, nontrainee clinicians-for greatest impact.

The single leading cause of mortality on hemodialysis is sudden cardiac death. Whether measures of electrophysiologic substrate independently associate with mortality is unknown. We examined measures of electrophysiologic substrate in a prospective cohort of 571 patients on incident hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease Study. A total of 358 participants completed both baseline 5-minute and 12-lead electrocardiogram recordings on a nondialysis day. Measures of electrophysiologic substrate included ventricular late potentials by the signal-averaged electrocardiogram and spatial mean QRS-T angle measured on the averaged beat recorded within a median of 106 days (interquartile range, 78-151 days) from dialysis initiation. The cohort was 59% men, and 73% were black, with a mean±SD age of 55±13 years. Transthoracic echocardiography revealed a mean±SD ejection fraction of 65.5%±12.0% and a mean±SD left ventricular mass index of 66.6±22.3 g/m During 864.6 person-years of follow-up, 77 patients died; 35 died from cardiovascular causes, of which 15 were sudden cardiac deaths. By Cox regression analysis, QRS-T angle ≥75° significantly associated with increased risk of cardiovascular mortality (hazard ratio, 2.99; 95% confidence interval, 1.31 to 6.82) and sudden cardiac death (hazard ratio, 4.52; 95% confidence interval, 1.17 to 17.40) after multivariable adjustment for demographic, cardiovascular, and dialysis factors. Abnormal signal-averaged electrocardiogram measures did not associate with mortality. In conclusion, spatial QRS-T angle but not abnormal signal-averaged electrocardiogram significantly associates with cardiovascular mortality and sudden cardiac death independent of traditional risk factors in patients starting hemodialysis.

Liver metastasis is the major cause of death from colorectal cancer (CRC). Understanding its mechanisms is necessary for timely diagnosis and development of effective therapies. Interleukin-33 (IL-33) is an IL-1 cytokine family member that uniquely functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or an early danger signal. Its role in invoking type 2 immune response has been established; however, it has contrasting roles in tumor development and metastasis. We identified IL-33 as a potently upregulated cytokine in a highly metastatic murine CRC cell line and examined its role in tumor growth and metastasis to the liver. IL-33 was transgenically expressed in murine and human adenocarcinoma and carcinoma cell lines and their growth and spontaneous metastasis to the liver were assessed in orthotopic models of CRC in wild-type C57Bl/6 and Il33 knockout mice. The results showed that increased expression of IL-33 in CRC cells enhanced their tumor take, growth, and liver metastasis. Tumor- rather than host-derived IL-33 induced the enhanced recruitment of CD11b GR1 and CD11b F4/80 myeloid cells to remodel the tumor microenvironment by increased expression of mobilizing cytokines, and tumor angiogenesis by activating endothelial cells. IL-33 expression was elevated in patient tumor tissues, induced early in adenoma development, and activated by pro-inflammatory cytokines derived from the tumor microenvironment. The data suggest that tumor-derived IL-33 modulates the tumor microenvironment to potently promote colon carcinogenesis and liver metastasis, underscoring its potential as a therapeutic target. © 2016 Wiley Periodicals, Inc.