Citations

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8–26.9) and 6.9 (5.0–9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6–2.9] for screening colonoscopy and 2.5 [1.8–3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8–18.5] and 2.9 [2.1–3.9], respectively) than HSgFOBT (20.8 [15.8–28.1] and 3.9 [2.9–5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68–0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable—as observed in the National Colonoscopy Study—offering screening colonoscopy can increase screening effectiveness.

Abstract Infectious diseases (ID) research is vital for global public health, typically led by physician-scientists. This Perspective addresses challenges in the ID workforce and suggests solutions. Physician-scientists have made key discoveries that have significantly impacted human health. The importance of ID research in understanding diseases, leading to treatments and vaccines, is emphasized, along with the need to address persistent and new infections, antimicrobial resistance, and threats like HIV and influenza. The paper analyzes the physician-scientist workforce's struggles, including funding, training, and research-practice integration gaps. We suggest increased funding, better training, and mentorship, more collaborative and interdisciplinary research, and improved recognition systems. The article stresses the urgency of supporting physician-scientists in ID, advocating for proactive prevention and preparedness, and calls for immediate action to enhance ID research and care.

AbstractPredicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population‐based cohort of 3525 patients with advanced cutaneous melanoma treated with anti‐PD‐1‐based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal–external cross‐validation. Included patients received anti‐PD‐1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence—all at start of ICI—, and location and type of primary melanoma, the presence of satellites and/or in‐transit metastases at primary diagnosis and sex. The over‐optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64–0.66). The range of predicted response probabilities was 7%–81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression‐free survival (20.0 vs 2.8 months; P < .001) and median overall survival (62.0 vs 8.0 months; P < .001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis.

572 Background: Bladder preservation with trimodal therapy (TMT), which consists of maximal transurethral resection of bladder tumors followed by chemoradiation, is now included in guidelines with radical cystectomy (RC) as options for definitive management of muscle-invasive bladder cancer (MIBC). Prospective randomized controlled trial data to help guide treatment selection are lacking, and prior efforts to bridge this knowledge gap have failed primarily due to poor accrual. A recent retrospective analysis comparing TMT to RC reported similar oncologic outcomes between these treatments when performed in highly selected patients. However, treatment toxicities and costs vary significantly between these management options. To investigate the impact of these outcomes on relative treatment value, we evaluated the comparative cost-effectiveness of TMT and RC for treatment of MIBC. Methods: Cost-effectiveness was compared between TMT and RC for patients with a solitary, muscle-invasive tumor less than 7cm, no or unilateral hydronephrosis, limited carcinoma in situ, and adequate bladder function (criteria utilized in a recent retrospective comparative series) using a microsimulation model with a 5-year horizon from a Medicare payer perspective. Additionally, a 10-year lifetime horizon was evaluated to better understand the impact of long-term outcome uncertainty on cost-effectiveness. Based on recently published multicenter retrospective propensity score matched data, metastatic progression and survival probabilities were assumed to be equivalent between treatments. Utility values and additional probabilities, including both short and long-term treatment toxicities, were obtained from published literature. Primary outcomes of interest included effectiveness measured in quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER) using a willingness-to-pay threshold of $100,000/QALY. One-way and probabilistic sensitivity analyses were performed to assess the robustness of the model. Results: At 5 years, the average cost was $32,286.35 higher for TMT versus RC. The average QALYs were 3.88 and 3.96 for RC and TMT respectively. TMT was not cost-effective at 5-year (ICER: $379,917.21/QALY) or 10-year (ICER: $222,704.78/QALY) time horizons. On one-way sensitivity analyses, TMT would become cost effective if: 1) TMT costs were less than $16,152; or 2) TMT resulted in a 13.3% improvement in metastasis free survival relative to RC. Conclusions: Although it resulted in similar quality and duration of life, TMT was not cost-effective relative to RC at 5 and 10 years given higher treatment costs. These findings support the role of both TMT and RC in management of MIBC and highlight the need for continued efforts to reduce healthcare costs associated with TMT.

320 Background: sRT is used in men with prostate cancer (PC) recurrence following radical prostatectomy (RP) signaled by a persistent or delayed elevation in PSA. It was previously reported that the use of AAT with RT improved cancer control and overall survival (OS). Long-term follow-up (FU) results are presented here. Methods: From 1998to 2003, 760 eligible post-RP patients with Stage pT3N0 or with pT2N0 and positive margins and PSA from 0.2 to 4.0 ng/mL were randomly assigned on a double-blinded, placebo-controlled trial of RT + placebo vs. RT + anti-androgen therapy (AAT) (24 months of bicalutamide, 150mg daily) during and after RT (64.8 Gy in 36 fractions prostate bed). The primary endpoint was OS estimated using Kaplan-Meier method. Time to PC death and metastatic PC (competing risk of death without an event) was estimated using cumulative incidence. The hazard ratio (HR) was obtained using Cox models (OS) and subdistribution HRs (sHRs) used the Fine-Gray model (time to PC death and metastatic PC). All tests are one-sided based on study design. Results: Median FU for surviving patients was 19 years. OS at 18 years was 53% [95% confidence interval (CI): 47-58%] for RT + AAT and 43% [95% CI: 38-48%] for RT + placebo (adjusted HR 0.82 [95% CI: 0.67-1.00], p = 0.025). The 18-year incidence of centrally reviewed PC deaths were 18% [95% CI: 14-22%] RT + AAT and 28% [95% CI: 23-32%] RT + placebo (adjusted sHR = 0.57 [95% CI: 0.42-0.78], p<0.001). The 18-year incidence of metastatic PC was 22% [95% CI: 18-26%] and 31% [95% CI: 26-35%] for AAT and placebo arms respectively with adjusted sHR = 0.59 [95% CI: 0.44-0.80, p<0.001]. Subgroup analyses is shown in the Table. Conclusions: Long term results of 24-month duration AAT during and after sRT are consistent with the primary report with significantly improved long-term OS, reduced incidence of metastatic PC and PC death for RT+AAT. Statistically significant metastatic PC was noted for Gleason score 8-10, study entry PSA>1.5 and margin positive patients and borderline significance was observed in patients with study entry PSA 0.7-1.5. Clinical trial information: NCT00002874 . [Table: see text]

INTRODUCTION: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations. METHODS: NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear cells (PBMCs) from controls (n = 16), AP/RAP (n = 17), and CP (n = 15) were measured by cytometry by time-of-flight. RESULTS: Plasma NGAL was elevated in subjects with CP compared with controls (area under the curve [AUC] = 0.777) or AP/RAP (AUC = 0.754) in univariate and multivariate analyses with sex, age, body mass index, and smoking (control AUC = 0.874; AP/RAP AUC = 0.819). NGAL was elevated in CP and diabetes compared with CP without diabetes ( P < 0.001). NGAL + PBMC populations distinguished CP from controls (AUC = 0.950) or AP/RAP (AUC = 0.941). Linoleic acid was lower, whereas dihomo-γ-linolenic and adrenic acids were elevated in CP ( P < 0.05). Linoleic acid was elevated in CP with diabetes compared with CP subjects without diabetes ( P = 0.0471). DISCUSSION: Elevated plasma NGAL and differences in NGAL + PBMCs indicate an immune response shift that may serve as biomarkers of CP. The potential interaction of FAs and NGAL levels provide insights into the metabolic pathophysiology and improve diagnostic classification of CP.

Achieving health equity in populations with congenital heart disease (CHD) requires recognizing existing disparities throughout the lifespan that negatively and disproportionately impact specific groups of individuals. These disparities occur at individual, institutional, or system levels and often result in increased morbidity and mortality for marginalized or racially minoritized populations (population subgroups (e.g., ethnic, racial, social, religious) with differential power compared to those deemed to hold the majority power in the population). Creating actionable strategies and solutions to address these health disparities in patients with CHD requires critically examining multilevel factors and health policies that continue to drive health inequities, including varying social determinants of health (SDOH), systemic inequities, and structural racism. In this comprehensive review article, we focus on health equity solutions and health policy considerations for minoritized and marginalized populations with CHD throughout their lifespan in the United States. We review unique challenges that these populations may face and strategies for mitigating disparities in lifelong CHD care. We assess ways to deliver culturally competent CHD care and to help lower-health-literacy populations navigate CHD care. Finally, we review system-level health policies that impact reimbursement and research funding, as well as institutional policies that impact leadership diversity and representation in the workforce.

67 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality among men and women combined in the United States (US). Although the national screening rate has increased over the years, it remains below the target of 80% recommended by the National Colorectal Cancer Roundtable for improved CRC outcomes. In most recent years, and particularly during COVID-19, screening-eligible individuals preferred at-home, non-invasive screening options over invasive tests such as colonoscopy due to convenience and accessibility. The objective of this study was to understand the CRC screening trends over the last two decades, and the impact of various screening modalities on the overall CRC screening rate. Methods: Using National Health Interview Survey (NHIS) data from 2005 onwards, we examined CRC screening (colonoscopy, mt-sDNA, FIT/FOBT, and sigmoidoscopy) rates among adults aged 50-75 years. A pseudo-time-series cross-sectional (pseudo TSCS) analysis was conducted including random effects Generalized Least Square (GLS) regression model to estimate the relative impact of each modality on the overall increase in CRC rates from 2018 to 2021. Results: Among 50-75 years old individuals, the estimated CRC screening use increased by 32% from 2005 to 2021 (47.7% to 69.9%). Between 2018 to 2021, the rates increased from 64% to 70%, driven largely by increased use of mt-sDNA, a 62.1% increase from 2018 to 2021 (2.5% to 6.6%). During this time period, colonoscopy utilization increased by 4.4% (61.2% to 64.0%), while FOBT/FIT utilization increased by 3.6% (5.3% to 5.5%). A pseudo-TSCS analysis showed that mt-sDNA contributed substantially to the overall CRC screening rate increase during years 2018-2021 (77.3%; p < 0.0001). Conclusions: While CRC screening rates are increasing, they remain below the national goal of 80%. Mt-sDNA as a home-based, non-invasive screening, recommended at a 3-year interval, has been leveraged to improve overall CRC screening rates, particularly to address the screening backlog created during the COVID-19 pandemic. A collaborative approach between healthcare providers and screening-eligible individuals is needed to empower patients with choice for their CRC screening modality to achieve the national goal.