Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.

PURPOSE: Increased ß-adrenergic receptor (ß-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly ß2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective ß-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. PATIENTS AND METHODS: A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months. RESULTS: Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders. CONCLUSIONS: Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.

Growth of the Spanish-speaking workforce in the Northeast dairy industry.

The Spanish-speaking proportion of the Northeast dairy industry workforce is believed to be increasing. This study quantifies the extent of this increase over time in New York, Pennsylvania, and Vermont, and compares demographics between English- and Spanish-speaking workers. A total of 293 farms were followed for 21 months via telephone. The proportion of the Spanish-speaking dairy workforce was measured. Differences in demographic characteristics were assessed. The proportion of Spanish-speaking workers increased linearly for both large and small farms. The rate of increase was much greater on large farms. Linear models predicted that 53.2% of the large and 18.1% of the small farm workforce would be Spanish speaking within 5 years. Spanish-speaking workers worked significantly longer weeks than their English-speaking counterparts. The Occupational Safety and Health Administration (OSHA) monitoring cutoff for number of employees is currently 10. Consequently, the increase in the proportion of Spanish-speaking workers in dairy, who have been shown to work more hours per week, is likely to result in fewer workers per farm. This could have implications for farms currently under OSHA regulations based on having 10 or more workers, because farms with workers working longer hours per week will employ fewer workers overall. In addition, according to section 330 of the Public Health Service Act, these workers do not currently meet the migrant farmworker definition that would qualify them to receive primary health services from federally funded migrant health centers. New legislation is needed to formally qualify this growing indigent population to receive healthcare via channels that are currently available to migrant and seasonal farmworkers.

Spanish-speaking dairy workers in New York, Pennsylvania, and Vermont: results from a survey of farm owners.

A New York Center for Agricultural Medicine and Health (NYCAMH) study surveyed 294 dairy farms in New York, Pennsylvania, and Vermont. The study utilized a quarterly telephone survey to assess the proportion of Spanish-speaking workers on these farms, and also to contrast the hazard level of work tasks and prevalence of lost work time between Spanish- and English-speaking workers. The total workforce followed in the study was comprised of 14.4 percent Spanish-speaking workers, with larger farms having a higher proportion than smaller farms (19.9% versus 4.6%, respectively). Of the 294 farms, 22.5 percent had at least one Spanish-speaking worker, which differed, greatly between larger and smaller farms (51.5% versus 7.3%). Spanish workers were significantly younger, worked significantly longer hours and had significantly fewer years of employment than their English-speaking counterparts. Work hour differences were more pronounced on the larger farms. Lost work time, due to on-farm injuries, did not differ between the Hispanic workers and the non-Hispanic workers. After correcting for both age and length of farm employment, Spanish-speaking workers were far less likely to perform managerial functions than their English-speaking counterparts (OR = . 22 p < .01).