Exploring the Molecular Tumor Microenvironment and Translational Biomarkers in Brain Metastases of Non-Small-Cell Lung Cancer.

Brain metastases represent a significant clinical challenge in the treatment of non-small-cell lung cancer (NSCLC), often leading to a severe decline in patient prognosis and survival. Recent advances in imaging and systemic treatments have increased the detection rates of brain metastases, yet clinical outcomes remain dismal due to the complexity of the metastatic tumor microenvironment (TME) and the lack of specific biomarkers for early detection and targeted therapy. The intricate interplay between NSCLC tumor cells and the surrounding TME in brain metastases is pivotal, influencing tumor progression, immune evasion, and response to therapy. This underscores the necessity for a deeper understanding of the molecular underpinnings of brain metastases, tumor microenvironment, and the identification of actionable biomarkers that can inform multimodal treatment approaches. The goal of this review is to synthesize current insights into the TME and elucidate molecular mechanisms in NSCLC brain metastases. Furthermore, we will explore the promising horizon of emerging biomarkers, both tissue- and liquid-based, that hold the potential to radically transform the treatment strategies and the enhancement of patient outcomes.

Clinical Trial Protocol for "Replace Cysto": Replacing Invasive Cystoscopy with Urine Testing for Non-muscle-invasive Bladder Cancer Surveillance-A Multicenter, Randomized, Phase 2 Healthcare Delivery Trial Comparing Quality of Life During Cancer Surveillance with Xpert Bladder Cancer Monitor or Bladder EpiCheck Urine Testing Versus Frequent Cystoscopy.

"Replace Cysto" is a multisite randomized phase 2 trial including 240 participants with low-grade intermediate-risk non-muscle-invasive bladder cancer, in which participants will be randomized 1:1:1 to one of two urine marker-based approaches alternating a urine marker test (Xpert Bladder Cancer Monitor or Bladder EpiCheck) with cystoscopy or to frequent scheduled cystoscopy. The primary objective is to determine whether urinary quality of life after surveillance is significantly improved in the urine marker arms. The primary outcome will be the patient-reported urinary quality of life domain score of the validated QLQ-NMIBC24 instrument, measured 1-3 d after surveillance. Exploratory outcomes include discomfort after surveillance, the number of invasive procedures that participants undergo per 1000 person years, complications from these procedures per 1000 person years, nonurinary quality of life, acceptability of surveillance, and bladder cancer recurrence and progression. Comparators include surveillance using (1) the Xpert Bladder Cancer Monitor test, (2) the Bladder EpiCheck urinary marker, or (3) frequent cystoscopy alone. After a negative cystoscopy ≤4 mo following bladder tumor resection, all the participants will undergo surveillance at 6, 12, 18, and 24 mo (with time zero defined as the date of the most recent bladder tumor resection). In the urine marker arms, surveillance at 6 and 18 mo will be performed with the marker. Regardless of the arm, participants will undergo cystoscopy at 12 and 24 mo. End of study for each participant will be their 24-mo cystoscopy. Overall trial duration is estimated at 5 yr from when the study opens to enrollment until completion of data analyses. The trial is registered at clinicaltrials.gov (NCT05796375).

Accurate Documentation Contributes to Guideline-concordant Surveillance of Nonmuscle Invasive Bladder Cancer: A Multisite Department of Veterans Affairs Study.

OBJECTIVE: To determine if accurate documentation of bladder cancer risk was associated with a clinician surveillance recommendation that is concordant with AUA guidelines among patients with nonmuscle invasive bladder cancer (NMIBC). METHODS: We prospectively collected data from cystoscopy encounter notes from four Department of Veterans Affairs (VA) sites to ascertain whether they included accurate documentation of bladder cancer risk and a recommendation for a guideline-concordant surveillance interval. Accurate documentation was a clinician-recorded risk classification matching a gold standard assigned by the research team. Clinician recommendations were guideline-concordant if the clinician recorded a surveillance interval that was in line with the AUA guideline. RESULTS: Among 296 encounters, 75 were for low-, 98 for intermediate-, and 123 for high-risk NMIBC. 52% of encounters had accurate documentation of NMIBC risk. Accurate documentation of risk was less common among encounters for low-risk bladder cancer (36% vs 52% for intermediate- and 62% for high-risk, P < .05). Guideline-concordant surveillance recommendations were also less common in patients with low-risk bladder cancer (67% vs 89% for intermediate- and 94% for high-risk, P < .05). Accurate documentation was associated with a 29% and 15% increase in guideline-concordant surveillance recommendations for low- and intermediate-risk disease, respectively (P < .05). CONCLUSION: Accurate risk documentation was associated with more guideline-concordant surveillance recommendations among low- and intermediate-risk patients. Implementation strategies facilitating assessment and documentation of risk may be useful to reduce overuse of surveillance in this group and to prevent unnecessary cost, anxiety, and procedural harms.

Using electronic health records to streamline provider recruitment for implementation science studies.

BACKGROUND: Healthcare providers are often targeted as research participants, especially for implementation science studies evaluating provider- or system-level issues. Frequently, provider eligibility is based on both provider and patient factors. Manual chart review and self-report are common provider screening strategies but require substantial time, effort, and resources. The automated use of electronic health record (EHR) data may streamline provider identification for implementation science research. Here, we describe an approach to provider screening for a Veterans Health Administration (VHA)-funded study focused on implementing risk-aligned surveillance for bladder cancer patients. METHODS: Our goal was to identify providers at 6 pre-specified facilities who performed ≥10 surveillance cystoscopy procedures among bladder cancer patients in the 12 months prior to recruitment start on January 16, 2020, and who were currently practicing at 1 of 6 pre-specified facilities. Using VHA EHR data (using CPT, ICD10 procedure, and ICD10 diagnosis codes), we identified cystoscopy procedures performed after an initial bladder cancer diagnosis (i.e., surveillance procedures). Procedures were linked to VHA staff data to determine the provider of record, the number of cystoscopies they performed, and their current location of practice. To validate this approach, we performed a chart review of 105 procedures performed by a random sample of identified providers. The proportion of correctly identified procedures was calculated (Positive Predictive Value (PPV)), along with binomial 95% confidence intervals (CI). FINDINGS: We identified 1,917,856 cystoscopies performed on 703,324 patients from October 1, 1999-January 16, 2020, across the nationwide VHA. Of those procedures, 40% were done on patients who had a prior record of bladder cancer and were completed by 15,065 distinct providers. Of those, 61 performed ≥ 10 procedures and were currently practicing at 1 of the 6 facilities of interest in the 1 year prior to study recruitment. The random chart review of 7 providers found 101 of 105 procedures (PPV: 96%; 95% CI: 91% to 99%) were surveillance procedures and were performed by the selected provider on the recorded date. IMPLICATIONS: These results show that EHR data can be used for accurate identification of healthcare providers as research participants when inclusion criteria consist of both patient- (temporal relationship between diagnosis and procedure) and provider-level (frequency of procedure and location of current practice) factors. As administrative codes and provider identifiers are collected in most, if not all, EHRs for billing purposes this approach can be translated from provider recruitment in VHA to other healthcare systems. Implementation studies should consider this method of screening providers.

Data-driven approach to implementation mapping for the selection of implementation strategies: a case example for risk-aligned bladder cancer surveillance.

BACKGROUND: Implementation Mapping is an organized method to select implementation strategies. However, there are 73 Expert Recommendations for Implementing Change (ERIC) strategies. Thus, it is difficult for implementation scientists to map all potential strategies to the determinants of their chosen implementation science framework. Prior work using Implementation Mapping employed advisory panels to select implementation strategies. This article presents a data-driven approach to implementation mapping, in which we systematically evaluated all 73 ERIC strategies using the Tailored Implementation for Chronic Diseases (TICD) framework. We illustrate our approach using implementation of risk-aligned bladder cancer surveillance as a case example. METHODS: We developed objectives based on previously collected qualitative data organized by TICD determinants, i.e., what needs to be changed to achieve more risk-aligned surveillance. Next, we evaluated all 73 ERIC strategies, excluding those that were not applicable to our clinical setting. The remaining strategies were mapped to the objectives using data visualization techniques to make sense of the large matrices. Finally, we selected strategies with high impact, based on (1) broad scope, defined as a strategy addressing more than the median number of objectives, (2) requiring low or moderate time commitment from clinical teams, and (3) evidence of effectiveness from the literature. RESULTS: We identified 63 unique objectives. Of the 73 ERIC strategies, 45 were excluded because they were not applicable to our clinical setting (e.g., not feasible within the confines of the setting, not appropriate for the context). Thus, 28 ERIC strategies were mapped to the 63 objectives. Strategies addressed 0 to 26 objectives (median 10.5). Of the 28 ERIC strategies, 10 required low and 8 moderate time commitments from clinical teams. We selected 9 strategies based on high impact, each with a clearly documented rationale for selection. CONCLUSIONS: We enhanced Implementation Mapping via a data-driven approach to the selection of implementation strategies. Our approach provides a practical method for other implementation scientists to use when selecting implementation strategies and has the advantage of favoring data-driven strategy selection over expert opinion.

Determinants of Risk-Aligned Bladder Cancer Surveillance-Mixed-Methods Evaluation Using the Tailored Implementation for Chronic Diseases Framework.

PURPOSE: For many patients with cancer, the frequency of surveillance after primary treatment depends on the risk for cancer recurrence or progression. Lack of risk-aligned surveillance means too many unnecessary surveillance procedures for low-risk patients and not enough for high-risk patients. Using bladder cancer as an example, we examined whether practice determinants differ between Department of Veterans Affairs sites where risk-aligned surveillance was more (risk-aligned sites) or less common (need improvement sites). METHODS: We used our prior quantitative data to identify two risk-aligned sites and four need improvement sites. We performed semistructured interviews with 40 Veterans Affairs staff guided by the Tailored Implementation for Chronic Diseases framework that were deductively coded. We integrated quantitative data (risk-aligned site v need improvement site) and qualitative data from interviews, cross-tabulating salient determinants by site type. RESULTS: There were 14 participants from risk-aligned sites and 26 participants from need improvement sites. Irrespective of site type, we found a lack of knowledge on guideline recommendations. Additional salient determinants at need improvement sites were a lack of resources ("the next available without overbooking is probably seven to eight weeks out") and an absence of routines to incorporate risk-aligned surveillance ("I have my own guidelines that I've been using for 35 years"). CONCLUSION: Knowledge, resources, and lack of routines were salient barriers to risk-aligned bladder cancer surveillance. Implementation strategies addressing knowledge and resources can likely contribute to more risk-aligned surveillance. In addition, reminders for providers to incorporate risk into their surveillance plans may improve their routines.