Dopamine-driven Increase in IL-1ß in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV.

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1ß in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1ß in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1ß, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1ß. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1ß gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1ß signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1ß in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1ß, will be critical to effectively tailor medication regimens.

Genetic Testing in Men With Metastatic Castration-Resistant Prostate Cancer.

This cross-sectional study assesses homologous recombination repair mutation genetic testing and associated characteristics among men with metastatic castration-resistant prostate cancer (mCRPC).

Developing an educational "hub": impact of a distance-learning curriculum in a multinational cohort.

PURPOSE: To address a gap in radiation oncology education in low- and middle-income countries (LMICs), we sought to evaluate the effectiveness and generalizability of a refined curriculum on intensity modulated radiotherapy (IMRT) offered to existing radiation therapy (RT) clinics across Africa and Latin America (LATAM) at no cost. METHODS: A curriculum was created based on prior needs assessments and adapted for participating medical physicists, radiation oncologists, radiation therapists, and trainees in LMICs. English-speaking and Spanish-speaking teams of volunteer educators delivered 27 hour-long sessions 1-2 times weekly for 4 months using video conferencing to African and LATAM cohorts, respectively. Pre- and post-course multiple-choice examinations were administered to LATAM participants, and pre- and post-course self-confidence (1-5 Likert-scale) and open-ended feedback were collected from all participants. RESULTS: Twenty-five centers across Africa (13) and LATAM (12) participated, yielding a total of 332 enrolled participants (128 African, 204 LATAM). Sessions were delivered with a mean of 44 (22.5) and 85 (25.4) participants in the African and LATAM programs, respectively. Paired pre and post-course data demonstrated significant (p < 0.001) improvement in knowledge from 47.9 to 89.6% and self-confidence across four domains including foundations (+ 1.1), commissioning (+ 1.3), contouring (+ 1.7), and treatment planning (+ 1.0). Attendance was a significant predictor of change in self-confidence in "high attendance" participants only, suggesting a threshold effect. Qualitative data demonstrates that participants look forward to applying their knowledge in the clinical setting. CONCLUSION: A specialized radiation oncology curriculum adapted for LMIC audiences was effective for both African and LATAM participants. Participant feedback suggests that the refined IMRT course empowered clinics with knowledge and confidence to help train others. This feasible "Hub and Spokes" approach in which a distance-learning course establishes a hub to be leveraged by spokes (learners) may be generalizable to others aiming to reduce global health care disparities through training efforts.

Treatment outcomes in older patients with metastatic breast cancer receiving palbociclib plus an aromatase inhibitor: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This summary describes an article published in the medical journal Frontiers in Oncology in September 2023. The article reports results from a study that looked at breast cancer treatments for older patients aged 75 years or older. The study focused on a type of cancer called HR+/HER2- metastatic breast cancer. HR+/HER2- stands for hormone receptorpositive/human epidermal growth factor receptor 2-negative. This study evaluated whether older patients with this type of cancer benefited from the combination of two medicines - palbociclib and an aromatase inhibitor - compared with taking an aromatase inhibitor alone. HOW WAS THE STUDY IN THIS SUMMARY CARRIED OUT?: The Flatiron database contains medical records for people with cancer in the US. This study used deidentified health care information from this database. 'Deidentified' means that all information that could identify an individual was removed to protect individuals' privacy. People in this study received treatment in routine care and not in a clinical trial. WHAT DO THE RESULTS MEAN?: Older patients who took palbociclib plus an aromatase inhibitor lived longer than those who took an aromatase inhibitor alone. Older patients who took palbociclib plus an aromatase inhibitor also lived longer without their cancer getting worse and started chemotherapy later than those who took an aromatase inhibitor alone. These results support using palbociclib plus an aromatase inhibitor as the first treatment for patients aged 75 years or older with HR+/HER2- metastatic breast cancer.

This study evaluated outcomes in elderly patients with metastatic breast cancer treated in routine care. Overall, patients who took palbociclib plus an aromatase inhibitor (AI) lived longer, and lived longer without their cancer getting worse, than those who took an AI alone.

Prolonging the lives of African-Americans with metastatic breast cancer by adding palbociclib to an aromatase inhibitor in routine clinical practice: a plain language summary of a real-world database study.

WHAT IS THIS SUMMARY ABOUT?: This summary is about a study that was published in the medical journal The Oncologist in July 2023. The combination of palbociclib with an aromatase inhibitor (AI) was approved by the FDA in 2015 as a treatment for people with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). However, the effectiveness of palbociclib in African-Americans with MBC is not well studied. The goal of this study was to find out whether adding palbociclib to an AI helped African-Americans with HR+/HER2- MBC live longer. WHAT ARE THE KEY TAKEAWAYS?: This study used de-identified medical information from the Flatiron Database. This database contains healthcare information on people with cancer treated by doctors in the United States but personal information is removed to maintain privacy. Medical information for people who received certain treatments in routine clinical practice or real-world setting was included in the study.This study showed that in the real-world setting, African-Americans with HR+/HER2- MBC lived longer when receiving palbociclib with an AI than with an AI alone. Also, the study showed that African-Americans treated with palbociclib plus an AI lived longer without their cancer getting worse than those treated with an AI alone. WHAT WAS THE MAIN CONCLUSION REPORTED BY THE RESEARCHERS?: These results support the use of palbociclib with an AI as a first treatment for African-Americans with HR+/HER2- MBC.Clinical Trial Registration: NCT05361655 (ClinicalTrials.gov).

Effectiveness of palbociclib plus an aromatase inhibitor in African Americans with metastatic breast cancer in routine clinical practice: a plain language summary.

Real-world comparative effectiveness of palbociclib plus aromatase inhibitor in HR+/HER2- metastatic breast cancer.

Aim: Provide real-world data on palbociclib as evidence of effectiveness in patient populations from routine clinical practice. Methods: This was a retrospective, observational cohort study of patients with HR+/HER2- metastatic breast cancer treated with palbociclib plus aromatase inhibitor (AI) or AI alone as first-line therapy within the US Oncology Network. Results: Patients treated with palbociclib plus AI (n = 838) versus AI alone (n = 450) had a numerically longer median overall survival (42.1 vs 35.7 months; hazard ratio [HR] = 0.90 [95% CI: 0.75-1.07]; p = 0.117) and a significantly extended real-world progression-free survival (21.0 vs 15.7 months; HR = 0.75 [95% CI: 0.64-0.88]; p = 0.0002) after normalized inverse probability treatment weighting. Conclusion: These real-world results support the use of palbociclib plus AI as first-line treatment in routine clinical practice for patients with HR+/HER2- metastatic breast cancer.

What is this summary about? This summary describes how well palbociclib works when used with an aromatase inhibitor in the real-world setting for people with a certain type of breast cancer that has spread to other areas of the body. Palbociclib stops cancer cells from growing and dividing. An aromatase inhibitor prevents the body from making the hormone estrogen, which is needed for certain types of breast cancer cells to grow. Palbociclib with an aromatase inhibitor is a standard first treatment used for people with this type of breast cancer that needs estrogen to grow and has spread to other areas of the body. In clinics, doctors may not always prescribe the two treatments together. The study wanted to find out if using the two treatments together worked better than using an aromatase inhibitor alone in the real-world setting. What were the results? The results suggest that in this population of patients treated in a real-world setting, people with breast cancer that needs estrogen to grow and has spread to other areas of the body who were treated with palbociclib plus an aromatase inhibitor lived longer without their cancer getting worse than those treated with an aromatase inhibitor alone. What do the results of the study mean? The results support the use of palbociclib with an aromatase inhibitor as a first treatment for breast cancer that has spread to other areas of the body, rather than an aromatase inhibitor only.

Financial Toxicity among Patients with Breast Cancer during the COVID-19 Pandemic in the United States.

This study reported the prevalence of financial distress (financial toxicity (FT)) and COVID-19-related economic stress in patients with breast cancer (BC). Patients with BC were recruited from the Ciitizen platform, Breastcancer.org, and patient advocacy groups between 30 March and 6 July 2021. FT was assessed with the COmprehensive Score for financial Toxicity (COST) instrument. COVID-19-related economic stress was assessed with the COVID-19 Stress Scale. Among the 669 patients, the mean age was 51.6 years; 9.4% reported a COVID-19 diagnosis. The prevalence rates of mild and moderate/severe FT were 36.8% and 22.4%, respectively. FT was more prevalent in patients with metastatic versus early BC (p < 0.001). The factors associated with FT included income ≤ USD 49,999 (adjusted odds ratio (adj OR) 6.271, p < 0.0001) and USD 50,000-USD 149,999 (adj OR 2.722, p < 0.0001); aged <50 years (adj OR 3.061, p = 0.0012) and 50-64 years (adj OR 3.444, p = 0.0002); living alone (adj OR 1.603, p = 0.0476); and greater depression severity (adj OR 1.155, p < 0.0001). Black patients (adj OR 2.165, p = 0.0133), patients with income ≤ USD 49,999 (adj OR 1.921, p = 0.0432), or greater depression severity (adj OR 1.090, p < 0.0001) were more likely to experience COVID-19-related economic stress. FT was common in patients with BC, particularly metastatic disease, during COVID-19. Multiple factors, especially lower income and greater depression severity were associated with financial difficulties during COVID-19.