Michael A. Liu

Background/Objectives: Enfortumab vedotin plus pembrolizumab (EV+pembro) is the standard first-line treatment for metastatic urothelial carcinoma (mUC), yet no validated on-treatment biomarker identifies patients deriving a durable benefit. We evaluated whether circulating tumor DNA (ctDNA) clearance is associated with response and survival with this regimen alone. Methods: This single-center retrospective study included 25 patients with mUC receiving first-line EV+pembro. A tumor-informed assay (Signatera) measured ctDNA longitudinally. Responses were assessed by RECIST 1.1. Progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs) were estimated by Cox regression and, to address immortal time bias, with clearance as a time-dependent covariate. Results: Fifteen of 25 patients (60%) achieved ctDNA clearance (ever undetectable). The objective response rate was 76% overall and 100% (15/15) with clearance versus 40% (4/10) without (p = 0.0012). Clearance was associated with longer PFS (HR 0.16, 95% CI 0.05–0.54; p = 0.003) and OS (HR 0.08, 95% CI 0.01–0.68; p = 0.021), with similar Firth penalized HRs (0.17 and 0.11). In the time-dependent analysis, the associations were attenuated (PFS HR 0.35, 95% CI 0.09–1.15, p = 0.085; OS HR 0.14, 95% CI 0.01–0.84, p = 0.029; profile likelihood CIs). A post-nadir ctDNA rise preceded progression or death by a median of 95 days in four patients (death in two). Conclusions: In this first-line EV+pembro cohort, all patients who cleared ctDNA responded, and clearance was associated with longer survival, although this association was attenuated in the time-dependent analysis. These hypothesis-generating findings support the prospective evaluation of ctDNA-guided monitoring.

Background: Research in residency supports career development, but improving research without compromising clinical training is challenging. Methods: At Brown Internal Medicine, we implemented an intern research day in 2016 with instruction in study design, IRB, and statistical guidance. We compared resident research characteristics between cohorts exposed to the program (2018-2020) versus those not exposed (2015-2017), using t-tests and chi-squared tests. Logistic regression was used to calculate the odds of manuscript publication or national conference presentation during residency. Results: Among 260 residents (100% response), lack of time was the most prevalent research barrier (83%), followed by lack of statistical support (53%), finding a mentor (50%), the IRB process (50%), lack of experience (41%), and lack of interest (27%). Peer-reviewed publications during residency increased from 57 in the pre-intervention cohort to 199 in the post-intervention cohort; national presentations increased from 40 to 140. Pre-residency clinical research experience was associated with greater odds of publication (OR 5.3, CI 2.9-9.5) and national presentation (OR 4.6, CI 2.5-8.4) during residency. The number of pre-residency publications was not significantly associated with the odds of residency publications or presentations. Research interest level was also associated with peer-reviewed publications (OR 3.2, CI 2.2-4.5) and national presentations (OR 2.2, CI 1.6-3.0) during residency. Conclusions: Implementation of an early research-training program was temporally associated with increased resident research productivity, although the observational pre-post design does not permit attribution of these changes specifically to the intervention. Understanding research barriers and facilitators may help guide efforts to increase scholarly activity.

Frontline systemic therapy for metastatic clear cell renal cell carcinoma (RCC) has evolved to include doublet immunotherapy (IO/IO) and immunotherapy-tyrosine kinase inhibitor combinations (IO/TKI), with selection typically guided by histology and risk stratification. However, optimal regimen selection remains undefined owing to limited head-to-head data. Subanalyses of landmark clinical trials and emerging real-world multicenter study data suggest differential treatment benefit derived by metastatic site, particularly for bone metastases. Evidence suggests that bone metastases promote an immunosuppressive tumor microenvironment and may preferentially upregulate genes encoding angiogenic factors, compared with other sites. Such biology-driven patterns provide a rationale for the hypothesis that IO/TKI may confer greater activity in bone-predominant disease. Liver metastases may also exhibit similar site-specific patterns due to harboring an immunosuppressive and vascular environment, but RCC-specific data remain scarce. This overview summarizes the mechanistic rationale, clinical evidence, and practical implications of tailoring treatment by disease site, highlighting critical gaps as well as future research priorities.

PURPOSE: Androgen receptor signaling inhibitors (ARSIs) are mainstay treatments for metastatic prostate cancer. Hyperglycemia is a common side effect, but limited data exist on outcomes such as acute care use among patients on these medications. This study aimed to assess the impact of diabetes on acute care use in older patients with metastatic prostate cancer on ARSIs. METHODS: We used SEER-Medicare data for patients 66 years and older with de novo metastatic prostate cancer who were prescribed abiraterone, enzalutamide, or apalutamide from 2010 to 2017. Negative binomial regression calculated incidence rate ratios of acute care use (total hospital or emergency admissions divided by total time at risk) for each model covariate among diabetic and nondiabetic patients after initiation of ARSI. RESULTS: A total of 2,697 patients were included, of which 17.4% had diabetes. The average age was 75.0 years, and most were White (80.3%). Most (85.3%) patients received androgen deprivation therapy before ARSI. Acute care use within 6 months occurred in 29.5% of patients, with 39.9% in the diabetes group and 27.4% in the nondiabetes group ( P < .0001). Adjusted for covariates, patients with diabetes had an increased rate of acute care use (Incidence rate ratio [IRR] = 1.38 [95% CI, 1.11 to 1.70]; P = .003) compared with those without diabetes. In addition, compared with those who were prescribed only enzalutamide or apalutamide, patients who were prescribed abiraterone had an increased rate of acute care use (IRR, 1.43 [95% CI, 1.12 to 1.82]; P = .005). CONCLUSION: Acute care use was common among patients with metastatic prostate cancer on ARSIs. Patients with diabetes experienced higher rates of acute care use compared with those without diabetes among all ARSI types. Future studies should assess potential interventions in older patients with diabetes on ARSIs.

Background: Prostate cancer is the most common malignancy in men and may often result in psychiatric symptoms due to the direct disease effects, hormonal treatments, functional losses, and psychological responses of patients to the cancer. Positive psychology interventions have shown promise in alleviating psychological symptoms in patients with chronic diseases but are infrequently studied in patients with prostate cancer. Aims: Our systematic review aimed to examine the benefits of positive psychology interventions for patients with prostate cancer. Methods and Results: We searched the PubMed/Medline, Embase, and PsycInfo databases yielding 1078 initial studies, 10 of which met inclusion criteria. The methodological quality of included studies was formally assessed. Positive psychology interventions consisted of mindfulness‐based therapies, meditation, hope and resilience therapies, and well‐being therapies. Most studies showed a positive effect on outcomes for patients with early to advanced stage prostate cancers, including psychological distress, mood disorders, anxiety, quality of life, happiness, and life satisfaction. However, most studies were limited by small sample size, qualitative findings, and loss to follow‐up. Conclusion: This systematic review demonstrates that positive psychology approaches may have benefit in patients with prostate cancer. Hormonal changes and inflammatory biomarkers are potential pathways through which positive psychology interventions influence this population.

Background: Management of metastatic prostate cancer often requires combining androgen deprivation therapy (ADT) with novel androgen receptor signaling inhibitors (ARSIs). Although these agents improve survival, older patients may face acute care utilization from medication burden, reflected in polypharmacy and nonadherence. Methods: Using SEER‐Medicare data, the authors identified patients ≥66 years old with de novo metastatic prostate cancer prescribed abiraterone, enzalutamide, or apalutamide (2010–2017). Polypharmacy was defined by the Youden index (≥8 medications). ARSI adherence was measured by medication possession ratio (≥0.8) from initiation to discontinuation, assessed over 6 months. Acute care use was defined as any inpatient hospitalization or emergency visit within 6 months. Demographic characteristics were compared by t ‐tests/χ ² . Negative binomial regression estimated incidence rate ratios (IRRs) for acute care use. Results: Among 2697 patients (mean age, 75 years), most were White (80.3%), married (63.1%), and received prior ADT (85.3%). Polypharmacy was present in 50.6% of patients before ARSI initiation, whereas ARSI nonadherence in the 6 months post‐initiation was 34.0%. Polypharmacy and adherence were not significantly associated. In adjusted analyses controlling for demographic, clinical, and treatment factors, both polypharmacy (IRR, 1.59; 95% confidence interval [CI], 1.28–1.98) and ARSI nonadherence (IRR 2.50; 95% CI, 2.00–3.03) independently prognosticated higher acute care use. Conclusions: Medication burden, as characterized by suboptimal adherence and polypharmacy, is an independent risk factor for acute care use among older adults initiating ARSI treatment for metastatic prostate cancer. These findings highlight an opportunity for potential interventions to reduce downstream acute care use.

High-intensity end-of-life (EoL) care for patients with cancer often includes multiple transitions to the hospital and intensive care unit (ICU) and is associated with adverse outcomes, such as declines in patient functional abilities

Purpose: Medicare patients who die from cancer are responsible for about 30% of annual Medicare spending, most of which occurs during the last 30 days of life. Yet, there are significant and persisting knowledge gaps regarding which factors contribute to this high-intensity EoL spending. To that end, we conducted a retrospective analysis of SEER-Medicare data to identify risk factors associated with high-intensity EoL spending among older adults who died of breast, prostate, lung, or colorectal cancer. Methods: We used multivariable linear regression to identify clinical, demographic, socioeconomic, and geographic characteristics associated with total inflation-adjusted Medicare spending in the last 30 days of life, including reimbursements for services provided in the inpatient and outpatient settings. Study subjects included U.S. Medicare beneficiaries aged 65 and older who died of breast, prostate, lung, or colorectal cancer between 2011 and 2015. Results: Among 59,355 decedents (49.2% female; 21.2% of non-White race/ethnicity), factors associated with greater EoL spending were increased comorbidity burden, female sex, Black race, other race/ethnicity, stage III and IV disease, living in a more populated county, and state subsidization of patient Medicare premiums. EoL spending was lower among older patients, patients living in the Midwest, South, and West, patients living in more rural areas, and patients with poor performance status. Results were largely consistent across cancer types. Conclusion: Our findings can inform targeted intervention development for patients with cancer who are at higher risk of high-intensity EoL spending, such as decision-support tools that facilitate referrals to palliative care for high-risk patients.