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Item does not contain fulltext CONTEXT: Intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease. OBJECTIVE: To update the International Bladder Cancer Group (IBCG) guidance and provide practical recommendations on IR NMIBC management. EVIDENCE ACQUISITION: A collaborative review of published randomized clinical trials, meta-analyses, systematic reviews, and clinical practice guidance on IR NMIBC published before January 2022 was undertaken using PubMed/Medline. EVIDENCE SYNTHESIS: Variation exists between guidelines in defining IR NMIBC. The IBCG recommends defining IR NMIBC as any TaLG tumor that is either recurrent or multifocal or has size ≥3 cm, OR any T1LG tumor. If the 3 tier grading system is used, than any TaG2 tumor would also be considered IR diease regardless of whether new diagnosis or recurrent. Accurate grading and staging of tumor, particularly in ruling out HG/G3 disease and/or carcinoma in situ, are crucial. The IBCG recommends that management of IR NMIBC should be further based on the following risk factors: multifocal tumor (more than one), early recurrence (1/yr), tumor size (≥3 cm), and failure of prior intravesical treatment. Patients with no risk factors are best managed by one dose of postoperative intravesical chemotherapy. Patients with one to two risk factors should be offered additional adjuvant induction intravesical chemotherapy (or bacillus Calmette-Guérin (BCG) if prior chemotherapy has been used). Patients with three or more risk factors should be offered induction plus 1-yr maintenance BCG. Where BCG is not available or recurrent disease following BCG is present, alternative intravesical treatments such as chemotherapy (single agent, combination, or chemohyperthermia) or a clinical trial are recommended. CONCLUSIONS: Standardizing the definition of IR NMIBC is critical for appropriate management of patients and for allowing a comparison of outcomes across clinical trials. The IBCG recommends defining IR NMIBC as any TaLG tumor that is either recurrent or multifocal or ≥3 cm, OR any T1LG tumor. If the 3 tier grading system is used, than any TaG2 tumor would also be considered IR disease regardless of whether new diagnosis or recurrent. Adjunctive management should then be based on established risk factors. PATIENT SUMMARY: Standardizing the definition of intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC), which is a heterogeneous disease, is critical for appropriate management of patients. The International Bladder Cancer Group recommends classification of IR NMIBC tumors and personalized management based on the following risk factors: multifocal tumor (more than one), early recurrence (1/yr), tumor size (≥3 cm), and previous intravesical treatment.

To determine the geographic distribution of muscle-invasive bladder cancer mortality according to race in the United States (US). African Americans (AAs) have up to two times the risk of bladder cancer mortality compared to Caucasians. Bladder cancer mortality increases exponentially once it invades the muscle. Geographic heterogeneity in bladder cancer mortality according to race remains to be determined.Analysis of Surveillance, Epidemiology, and End Results (SEER)-Medicare data for 6,044 patients aged 66-85 diagnosed with clinical stage T2-T4 N0M0 bladder cancer from 1 January 2002 to 31 December 2011. Fine and Gray-competing risks regression models were used to assess the association of race with bladder cancer-specific mortality (BCSM) according to tumor registry.Out of 6,044 patients, 5,408 (89.5%) were Caucasian, 352 (5.82%) were non-Hispanic AA, 85 (1.4%) were Hispanic, and 199 (3.29%) were other. Of the 18 registries, AAs with bladder cancer were largely concentrated in Louisiana (19%), New Jersey (17.9%), and Georgia (17.6%). New Jersey was the only registry where AAs had increased risk of BCSM than Caucasians and only for stage T2 disease: (AHR, 1.74; 95% CI 1.22-2.47, p = 0.002). According to treatment, AAs in New Jersey had worse BCSM than Caucasians when they underwent radical cystectomy (AHR, 2.05; 95% CI 1.26-3.35, p = 0.0039) and radiotherapy or chemotherapy alone (AHR, 1.55; 95% CI 1.03-2.35, p = 0.0367).We observed geographic variation in bladder cancer mortality which impacted only one registry with one of the largest population of AAs. These findings support further investigation into the social determinants of race (i.e., socioeconomic status and distance to healthcare facility) and culturally centered healthcare decision making which may drive these results.

The morbidity associated with radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) has fueled investigations into the feasibility of bladder preservation strategies after a favorable clinical response to neoadjuvant therapy (NAT). Identifying optimal candidates for bladder preservation is predicated on our ability to identify tumors with inherent cisplatin sensitivity and accurately stage patients before and after NAT. In the present review, we evaluate the accuracy and limitations of contemporary staging modalities and investigate clinical outcomes in patients with MIBC who were managed with bladder preservation after NAT. Lastly, we discuss the predictive role of cisplatin-sensitizing DNA damage response (DDR) gene alterations as a foundational component to current prospective clinical trials evaluating bladder preservation in the setting of MIBC.

Background: We sought to determine whether differences in subtype distribution and differentially expressed genes exist between African Americans (AAs) and European Americans (EAs) in patients with high-risk nonmuscle-invasive bladder cancer (NMIBC). Methods: We performed a retrospective cohort study including 26 patients (14 AAs and 12 EAs) from the University of Texas Medical Branch and the Durham Veterans Affair Health Care System from 2010 to 2020 among treatment naïve, high-risk NMIBC. Profiled gene expressions were performed using the UROMOL classification system. Results: UROMOL racial subtype distributions were similar with class 2a being most common with 10 genes commonly upregulated in AAs compared to EAs including EFEMP1, S100A16, and MCL1 which are associated with progression to muscle-invasive bladder cancer, mitomycin C resistance, and bacillus Calmette-Guérin durability, respectively. We used single nuclei analysis to map the malignant cell heterogeneity in urothelial cancer which 5 distinct malignant epithelial subtypes whose presence has been associated with different therapeutic response prediction abilities. We mapped the expression of the 10 genes commonly upregulated by race as a function of the 5 malignant subtypes. This showed borderline (P = 0.056) difference among the subtypes suggesting AAs and EAs may be expected to have different therapeutic responses to treatments for bladder cancer. AAs were enriched with immune-related, inflammatory, and cellular regulation pathways compared to EAs, yet appeared to have reduced levels of the aggressive C3/CDH12 bladder tumor cell population. Conclusions: While premature, gene expression differed between AAs and EAs, supporting potential race-based etiologies for muscle-invasion, response to treatments, and transcriptome pathway regulations.

To examine differences in survival outcomes for muscle-invasive bladder cancer patients stratified by new mental health diagnosis.Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified patients diagnosed with muscle-invasive bladder cancer between 2008 and 2014. Our primary outcome was cancer-specific and overall hazards of mortality. As a secondary outcome, we reported predictors of developing a new mental health diagnosis after bladder cancer diagnosis. We used Cox proportional hazards models to determine the impact of palliative care and mental health diagnoses on survival outcomes after adjusting for grade, stage, comorbidity index, and baseline demographics.Of the 3794 patients who met inclusion criteria, 1193 (31%) were diagnosed with a mental health illness after their bladder cancer diagnosis during the 6 years in the study period. The most common diagnoses were depression (13%), alcohol and drug abuse (12%), and anxiety (11%). Patients with a post-bladder cancer mental health diagnosis had a 57% higher hazard of overall mortality (HR 1.57, P = .048) and an 80% higher hazard of bladder cancer-specific mortality (HR 1.81, P = .037) CONCLUSIONS: New mental health diagnoses are associated with worse survival in patients with muscle invasive bladder cancer. This suggests that a multimodal approach to bladder cancer treatment should include addressing the non-oncologic needs of the patient to optimize survival outcomes.

Purpose: To systematically review the literature to investigate racial disparities among bladder cancer clinical trial enrollees. Methods: A systematic review was conducted using Ovid, MEDLINE® to identify clinical trials between 1970 and 2020. Articles were reviewed and were included if they assessed race in their outcomes reporting among bladder cancer patients enrolled in clinical trials. The review was conducted in accordance with the PRISMA statement. Results: We identified 544 clinical trials meeting our initial search criteria, with only 24 (4.4%) studies reporting racial demographic data. Enrollees were largely Caucasian (81–98%), with a strikingly small proportion of enrolled patients consisting of African-Americans (2–8%) and Hispanics (2–5%). Only one of the studies reported results on the efficacy and safety/tolerability of the tested treatment separately for racial groups and performed analyses stratified by race. Conclusion: Race is poorly studied in bladder cancer clinical trials. Trial cohorts may not reflect multicultural populations. The potential association between race and efficacy, safety or tolerability of the tested interventions is unknown. Given the up to twofold increase in bladder cancer-specific death among African-Americans, further research is needed to address the impact of race in clinical trials, while encompassing socioeconomic factors and disease risk factor exposures.

BACKGROUND The objective of this study was to describe bladder cancer outcomes as a function of race among patients with high-risk non-muscle-invasive bladder cancer (NMIBC) in an equal-access setting. METHODS A total of 412 patients with high-risk NMIBC who received bacille Calmette-Guerin (BCG) from January 1, 2010, to December 31, 2015, were assessed. The authors used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine the association between race and recurrence, progression, disease-specific, and overall survival outcomes. RESULTS A total of 372 patients who had complete data were included in the analysis; 48 (13%) and 324 (87%) were Black and White, respectively. There was no difference in age, sex, smoking status, or Charlson Comorbidity Index by race. White patients had a higher socioeconomic status with a greater percentage of patients living above the poverty level in comparison with Black patients (median, 85% vs 77%; P < .001). A total of 360 patients (97%) received adequate induction BCG, and 145 patients (39%) received adequate maintenance BCG therapy. There was no significant difference in rates of adequate induction or maintenance BCG therapy according to race. There was no significant difference in recurrence (hazard ratio [HR], 1.53; 95% confidence interval [CI], 0.64-3.63), progression (HR, 0.77; 95% CI, 0.33-1.82), bladder cancer-specific survival (HR, 1.01; 95% CI, 0.30-3.46), or overall survival (HR, 0.97; 95% CI, 0.56-1.66) according to Black race versus White race. CONCLUSIONS In this small study from an equal-access setting, there was no difference in the receipt of BCG or any differences in bladder cancer outcomes according to race.

OBJECTIVE Older patients diagnosed with cancer are at increased risk of physical and emotional distress; however, prescription utilization patterns largely remain to be elucidated. Our objective was to comprehensively assess prescription patterns and predictors in older patients with bladder cancer. METHODS A total of 10,516 older patients diagnosed with clinical stage T1-T4a, N0, M0 bladder urothelial carcinoma from 1 January 2008 to 31 December 2012 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare were analyzed. We used multivariable analysis to determine predictors associated with psychotropic prescription rates (one or more). Medication possession ratio (MPR) was used as an index to measure adherence in intervals of 3 months, 6 months, 1 year, and 2 years. Evaluation of psychotropic prescribing patterns and adherence across different drugs and demographic factors was done. RESULTS Of the 10,516 older patients, 5621 (53%) were prescribed psychotropic drugs following cancer diagnosis. Overall, 3972 (38%) patients had previous psychotropic prescriptions prior to cancer diagnosis, and these patients were much more likely to receive a post-cancer diagnosis prescription. Prescription rates for psychotropic medications were higher among patients with higher stage BC (p

Muscle-invasive bladder cancer (BC) often occurs in patients with competing mortality risks, while also being associated with the highest rate of second primary nonurothelial cancers (SNUC) of all solid malignancies. We investigated the incidence, risk factors, and timing of SNUC as a competing mortality risk factor in patients with BC who were treated with curative intent radical cystectomy (RC).We performed a retrospective cohort study assessing patients who underwent RC for cT2-4 N0M0 BC from January 1, 2005 to December 31, 2018 at a single, high volume tertiary care referral center. The Fine-Gray multivariable regression model was used to evaluate predictive factors for SNUC. Cumulative incidence of mortality (CIM) was estimated with modified Kaplan-Meier analysis.The median follow-up time for the 693 patients who underwent RC was 3.7 years (interquartile range [IQR] 1.9-5.9 years). SNUC developed in 85 (12.3%) patients at a median 3.0 years post-RC (IQR 1.2-5.5 years). On multivariable analysis, the only significant predictor for developing SNUC was freedom from BC recurrence or metastasis (HR 1.54, 95% CI 1.12-1.76, P = 0.019). The most common SNUCs were primary lung cancer (24, 3.2% of cohort) and colon cancer (9, 1.3% of cohort). BC surveillance imaging diagnosed SNUC in 35/52 (67.3%) patients with solid-organ visceral primaries. The overall mortality rate for any SNUC was 38.8%, with the 3 most lethal cancer types being pancreatic, lung, and colon (62.5%, 54.2%, and 44.4% mortality, respectively). The incidence of SNUC uniformly increased postoperatively, with a cumulative incidence of 22.1% (95% CI, 16.8-27.9%) at 12-years post-RC. 163 patients (23.5%) died from BC, 33 patients (4.8%) died from SNUC, and 94 patients (13.6%) died from other causes. While the CIM for BC plateaued around 5-years post-RC at 24%, the incidence of other-cause mortality uniformly rose throughout the postoperative period. By post-RC year 9 there was no significant difference in CIM between BC (CIM 27.2%, 95% CI, 23.5-31.1%) and other-causes (CIM 20.0%, 95% CI, 15.8-24.6%).The cumulative incidence of SNUC at 12-years post-RC was 22%, with the majority identified on BC surveillance imaging. While BC mortality plateaued around 5-years post-RC, mortality related to SNUC or other causes rose steadily in the postoperative period. These data have clinical significance with regards to patient counseling, survivorship and oncologic surveillance in the highly comorbid muscle-invasive BC population.

Bladder cancer (BC) represents a significant health problem due to the potential morbidity and mortality associated with disease burden, which has remained largely unaltered over time.To provide an expert collaborative review and describe the incidence, prevalence, and mortality of BC and to evaluate current evidence for BC screening and prevention.Data on the estimated incidence and mortality of BC for 2020 in 185 countries were derived from the International Agency for Research on Cancer GLOBOCAN database. A review of English-language articles published over the past 5 yr was conducted using PubMed/MEDLINE to identify risk factors in addition to contemporary evidence on BC screening and prevention.BC is the tenth most common cancer worldwide, with 573 278 cases in 2020. BC incidence is approximately fourfold higher in men than women. Tobacco smoking remains the principal risk factor, accounting for approximately 50% of cases. There is insufficient evidence to recommend routine BC screening. However, targeted screening of high-risk individuals (defined according to smoking history or occupational exposure) may reduce BC mortality and should be the focus of prospective randomized trials. In terms of disease prevention, smoking cessation represents the most important intervention, followed by a reduction in exposure to occupational and environmental carcinogens.BC confers a significant disease burden. An understanding of BC epidemiology and risk factors provides an optimal foundation for disease prevention and the care of affected patients.Bladder cancer is the tenth most common cancer worldwide and is approximately four times more common among men than among women. The main risk factors are tobacco smoking, followed by exposure to carcinogens in the workplace or the environment. Routine screening is not currently recommended, but may be beneficial in individuals at high risk, such as heavy smokers. Primary prevention is extremely important, and smoking cessation represents the most important action for reducing bladder cancer cases and deaths.

In 1997 an international group of scientists organized a meeting in Barcelona, Spain, to discuss the use of biomarkers in the management of patients with bladder cancer. This meeting was the offspring of an - initially informal - group that finally resulted in the foundation and incorporation of the International Bladder Cancer Network (IBCN) e.V. in 2005. Over the years the group has supported several research initiatives and generated several recommendations on the use of biomarkers in the diagnosis and treatment of bladder cancer. Meeting quality was generated by inviting experts presenting state-of-the-art lectures or work in progress reports, interdisciplinarity and the limited number of participants supporting an open and personal exchange resulted in a format increasingly attracting participants from all over the world. The recent limitations caused by the Covid-19 pandemic were partially met by organizing several well attended webinars. The future challenge is to maintain the IBCN meeting spirit despite an increasing interest of the scientific community and industrial partners to participate. However, the integration of and interaction between increasingly more specialized disciplines is a challenge that can be better catalyzed by an international multidisciplinary network than mostly national professional associations.

BACKGROUND: Disparity in mental health care among cancer patients remains understudied. METHODS: We conducted a large, retrospective, single tertiary-care institution cohort study based on de-identified electronic health record data of 54,852 adult cancer patients without prior mental health diagnosis (MHD) diagnosed at the University of California, San Francisco between 1/2012 and 9/2019. The exposure of interest was early onset MHD with or without psychotropic medication (PM) within 12 months of cancer diagnosis and primary outcome was all-cause mortality. RESULTS: 8.2% of patients received a new MHD at a median of 197 days (interquartile-range [IQR] 61-553) after incident cancer diagnosis, 31.0% received a PM prescription, and 3.7% a MHRV. 62.6% of patients were non-Hispanic white (NHW), 10.8% Asian, 9.8% Hispanic, and 3.8% Black. Compared to NHWs, minority cancer patients had reduced adjusted odds of MHDs, PM prescriptions, and MHRVs, particularly for generalized anxiety (Asian: odds ratio [OR] 0.66, 95% confidence interval 0.55-0.78; Black: OR 0.60, 0.45-0.79; Hispanic: OR 0.72, 0.61-0.85) and selective-serotonin-reuptake-inhibitors (SSRI; Asian: OR 0.43, 0.37-0.50; Black: OR 0.51, 0.40-0.61; Hispanic: OR 0.79, 0.70-0.89). New early MHD with PM was associated with elevated all-cause mortality (12-24 months: hazard ratio [HR] 1.43, 1.25-1.64) that waned by 24-36 months (HR 1.18, 0.95-1.45). CONCLUSIONS AND RELEVANCE: New mental health diagnosis with psychotropic medication was a marker of early mortality among cancer patients. Minority cancer patients were less likely to receive documentation of mental health diagnoses or treatment, which may represent missed opportunities to identify and treat cancer related mental health conditions.

Context Immune therapy has emerged as a powerful treatment of metastatic urothelial carcinoma. Over 20 ongoing studies are exploring this strategy in the neoadjuvant setting in patients with localized muscle-invasive bladder cancer. Objective To summarize the rationale and the clinical outcomes regarding the use of immune checkpoint blockade in the neoadjuvant setting before radical cystectomy. Evidence acquisition A systematic review of the literature in the MEDLINE database was performed. The central search strategy used the terms bladder cancer, urothelial carcinoma, mice, human, immunotherapy, neoadjuvant therapy, atezolizumab, pembrolizumab, durvalumab, nivolumab, avelumab, ipilimumab, and tremelimumab. The search was limited to publications between January 2008 and February 2020. Publicly available relevant abstracts from recent meetings were also included. Evidence synthesis Phase II trials investigating neoadjuvant immune checkpoint blockade as a single agent before radical cystectomy reported a rate of pathological complete response (CR), ranging from 31% with an anti–PD-L1 monoclonal antibody (mAb) atezolizumab (n = 27/88) to 37% with anti–PD-1 mAb pembrolizumab (n = 42/114). Overall, 92% (n = 87/95) and 98% (n = 112/114) of the patients underwent radical cystectomy. Neoadjuvant immune checkpoint blockade did not delay planned surgery. Checkpoint inhibitor monotherapy was well tolerated, with no unexpected toxicity in the presurgical setting. Early phase I/II trials investigating neoadjuvant combination chemotherapy strategies with immune checkpoint blockers reported enhanced antitumor efficacy, with a pathological CR ranging from 33% to 50%. Conclusions Although limited clinical data are available on long-term survival, neoadjuvant immune checkpoint blockade demonstrated effective antitumor efficacy for localized muscle-invasive bladder cancer. Phase III trials are currently investigating this strategy in the presurgical setting. Patient summary Immunotherapy prior to surgery has been evaluated for patients with muscle-invasive bladder cancer. Although long-term survival benefit is unknown, such treatment strategy revealed a promising antitumor response rate for patients who underwent radical cystectomy. Ongoing prospective clinical trials will define the potential advantage of this approach over current cisplatin-based chemotherapeutic regimens alone or in combination.

Context Urothelial carcinoma can exhibit a wide range of variant morphologies. Many variants present diagnostic challenges and carry clinical implications that inform prognosis and treatment decisions. Objective To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma. Evidence acquisition A PubMed/MEDLINE-based literature search was conducted using the key terms “urothelial carcinoma”, “variant histology”, “nested”, “micropapillary”, “microcystic”, “sarcomatoid”, “squamous differentiation”, “glandular differentiation”, “clear cell”, “plasmacytoid”, “lymphoepithelioma-like carcinoma”, “squamous cell carcinoma”, “small cell carcinoma”, “adenocarcinoma”, “radiotherapy”, “neoadjuvant chemotherapy”, and “adjuvant chemotherapy”. Evidence synthesis The incidence of variant histology is increasing due to improved recognition. Nonetheless, diagnosis can pose challenges due to sampling limitations and interobserver variability. Although associated with advanced disease at presentation, survival outcomes for most variants do not differ significantly compared with pure urothelial carcinoma of the same stage. Controversy exists regarding optimal management due to the low quality of available evidence. For most cases, radical cystectomy with pelvic lymph node dissection (with neoadjuvant chemotherapy when appropriate) represents the standard of care. Small cell carcinoma and lymphoepithelioma-like carcinoma appear to be particularly chemosensitive. Conclusions Accurate identification of variant histological subtypes is an important part of risk stratification, as these variants exhibit aggressive biological behaviour. Variant histology tumours are associated with advanced disease at presentation, which must be considered when counselling patients regarding survival outcomes. Optimal management remains to be defined but in most cases; neoadjuvant chemotherapy and radical cystectomy with pelvic lymph node dissection remains the mainstay of treatment. Patient summary It is important to recognise histological variants of urothelial carcinoma as they indicate aggressive disease. When compared with patients with pure urothelial carcinoma of the same disease stage, survival does not appear to be significantly worse. In most cases, patients with invasive variant histology should be treated with neoadjuvant chemotherapy and radical cystectomy. Take Home Messages Accurate identification of variant histology is important as it exhibits aggressive biological behaviour and affects treatment. Although associated with advanced disease at presentation, with appropriate treatment, survival outcomes are not significantly different compared with pure urothelial carcinoma of the same stage.

The tumor microenvironment is composed of highly heterogeneous structures and cell types that dynamically influence and communicate with each other. Although examination of singular biospecimens is sufficient for diagnostic purposes, it is inadequate and cost prohibitive when scaling for complex and overarching studies. Thus, high density multi-tumor tissue microarrays (TMAs) have been a practical and effective solution for high-throughput molecular analysis of tissues. Introduced more than a decade ago, TMAs have been instrumental in the recent study of tumor biology, the development of diagnostic tests, the establishment of quality control, and the investigation and identification of oncological biomarkers. Here, we demonstrate the pairing of the 10x Genomics Visium Cytassist Spatial Gene Expression Solution and Xenium In-Situ Platform on multi-tumor TMAs to screen for common biomarkers among a cohort of samples. Spatial transcriptomics technology has proven valuable in mapping the whole transcriptome with spatial context (Visium), whereas In Situ (Xenium) enables high-throughput cellular characterization at single-cell resolution. With the addition of our CytAssist platform, we expand on the pre-existing standard Visium solution by facilitating the retrieval of RNA transcriptomic information from tissues placed on standard or archival slides. On the other hand, the novel Xenium platform compliments whole transcriptome Visium data by unlocking the potential to assign transcripts to a particular cell with spatial context and subcellular resolution. The combination of spatial transcriptomics and targeted in situ data with FFPE TMAs promotes a high-throughput method to accelerate the uncovering of molecular signatures suitable to understanding the tumor microenvironment. We showcase the ability to spatially and comprehensively resolve individual oncogene and tumor suppressor genes associated with multiple tumors from a cohort of cancer patients and from multiple different tumor samples. In addition, these markers are mapped back to distinct morphological features within each tissue core, and use differential gene expression data to identify distinct cell types throughout the different patient tissues. By combining the throughput of TMA samples and depth of the Visium and Xenium platforms, the strategy enables greater insights into cell-type specifics while also expanding the spectrum of biospecimen types that can be analyzed. Citation Format: Syrus Mohabbat, Hardeep Singh, Stephen R. Williams, Lauren M M. Gutgesell, David J. Sukovich, Govinda M. Kamath, Hanyoup Kim, Amanda Janesick, Robert Shelansky, Ghezal Beliakoff, Augusto M. Tentori, Albert Kim, Cedric R. Uytingco, Sarah Taylor. Application of spatially resolved transcriptomics to screen multiple tumor biospecimens using tissue microarrays. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4708.

482 Background: Population-based studies evaluating outcomes exclusively for metastatic upper tract urothelial carcinoma (mUTUC) are sparse and often only capture patients with de novo (synchronous) metastases as opposed to those who progress to metastatic disease (metachronous). We sought to evaluate the outcomes and costs associated with mUTUC and employ a novel methodology to identify both synchronous and metachronous mUTUC patients using claims data. Additionally, we created a guideline-based quality score to improve quality of care in this space. Methods: Using the SEER-Medicare database we identified patients aged 66 years and older diagnosed with mUTUC between 2004 and 2012. Achievement of the following quality criteria was assessed: 1) cancer-specific survival greater than 12 months; 2) receipt of systemic therapy; 3) receipt of hospice/palliative care. Kaplan-Meier survival curves and Cox proportional hazard models were used to compare overall survival between quality scores (0 vs. ≥1) and synchronous vs. metachronous mUTUC. Total healthcare and Medicare Part D out-of-pocket costs within two years of diagnosis were evaluated. Regression analyses were performed to assess characteristics associated with quality criteria and total healthcare costs. Results: Of the 1,223 patients identified, 381 (31.2%) and 842 (68.8%) had synchronous and metachronous mUTUC, respectively. At least one quality criterion was met in 40.2% of patients. Notably, only 54 patients (4.4%) received palliative care services. On multivariable analysis, patients with synchronous mUTUC (OR:0.55, 95%CI:0.41–0.72), and at least 3 comorbidities (OR:0.68, 95%CI:0.47–0.98), were less likely to achieve at least one quality criterion. Patients meeting quality criteria had longer survival compared with patients who did not meet criteria (HR:0.52, 95%CI: 0.46–0.59). Meeting at least one quality criterion was independently associated with increased costs ($94,677, 95%CI: 87702–101652 vs. $63575, 95%CI: 59598–67552) on multivariable regression analysis. Conclusions: Less than half of mUTUC patients met at least one quality criterion. Quality score achievement was associated with longer overall survival at a modest increase in total healthcare spending. These findings not only provide guidance for future study of rare diseases using secondary data, but also highlight inadequacies in the current management of mUTUC.

461 Background: Prior studies suggest that white light cystoscopy (WLC) alone can fail to detect cases of non-muscle invasive bladder cancer (NMIBC) compared to blue light cystoscopy (BLC). We describe bladder cancer outcomes and the impact of BLC among NMIBC patients in an equal access setting. Methods: A total of 378 NMIBC patients within the Veterans Affairs system that had a CPT code for BLC from December 1, 2014 to December 31, 2020 were assessed. We determined recurrence rates and time to recurrence prior to BLC (i.e. after previous WLC if available) and following BLC. We used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine the association between race and recurrence, progression, and overall survival. Results: Of 378 patients with complete data, 43 (11%) were Black and 300 (79%) White. Median follow-up was 40.7 months from bladder cancer diagnosis. There were 194 (51%) patients with either TaHG or T1 without CIS; 52 (14%) had CIS with or without TaHG or T1; and 127 (34%) had TaLG only. A total of 239 (63%) patients received BCG at any point during the study. Median time to first recurrence following BLC was longer compared to WLC alone (40 (33-NE) vs. 26 (17-39) months). The risk of recurrence was significantly lower following BLC (Hazard Ratio (HR) 0.70; 95% Confidence Interval (CI) 0.54-0.90). There was no significant difference in recurrence (Hazard Ratio (HR) 0.83; 95% Confidence Interval (CI) 0.48-1.43), progression (HR 1.46; 95% CI 0.45-4.74), and overall survival (HR 0.69; 95% CI 0.29-1.65) following BLC by Black vs. White race. Conclusions: In this study from an equal access setting in the VA, we observed significantly decreased risk of recurrence and prolonged time interval to recurrence following BLC compared to WLC alone. There was no difference in any bladder cancer outcomes by race.

BackgroundThe tumor microenvironment (TME) is composed of highly heterogeneous extracellular structures and cell types such as endothelial cells, immune cells, and fibroblasts that dynamically influence and communicate with each other. The constant interaction between a tumor and its microenvironment plays a critical role in cancer development and progression and can significantly affect a tumor’s response to therapy and capacity for multi-drug resistance. High resolution analyses of gene and protein expression with spatial context can provide deeper insights into the interactions between tumor cells and surrounding cells within the TME, where a better understanding of the underlying biology can improve treatment efficacy and patient outcomes. Here, we demonstrated the ability to perform streamlined multi-omic tumor analyses by utilizing the 10X Genomics Visium Spatial Gene Expression Solution for FFPE with multiplex protein enablement. This technique simultaneously assesses gene and protein expression to elucidate the immunological profile and microenvironment of different breast cancer samples in conjunction with standard pathological methods.MethodsSerial (5 µm) sections of FFPE human breast cancer samples were placed on Visium Gene Expression (GEX) slides. The Visium GEX slides incorporate ~5,000 molecularly barcoded, spatially encoded capture spots onto which tissue sections are placed, stained, and imaged. Following incubation with a human whole transcriptome, probe-based RNA panel and an immuno-oncology oligo-tagged antibody panel, developed with Abcam conjugated antibodies, the tissues are permeabilized and the representative probes are captured. Paired GEX and protein libraries are generated for each section and then sequenced on an Illumina NovaSeq at a depth of ~50,000 reads per spot. Resulting reads from both libraries are aligned and overlaid with H&E-stained tissue images, enabling analysis of both mRNA and protein expression. Additional analyses and data visualizations were performed on the Loupe Browser v4.1 desktop software.ConclusionsSpatial transcriptomics technology complements pathological examination by combining histological assessment with the throughput and deep biological insight of highly-multiplexed protein detection and RNA-seq. Taken together, our work demonstrated that Visium Spatial technology provides a spatially-resolved, multi-analyte view of the tumor microenvironment, where a greater understanding of cellular behavior in and around tumors can help drive discovery of new biomarkers and therapeutic targets.

Background Upper tract urothelial carcinoma (UTUC) is a heterogeneous disease that presents a clinical management challenge for the urologic surgeon. We assessed treatment patterns, costs, and survival outcomes among patients with nonmetastatic UTUC. Methods We identified 4114 patients diagnosed with nonmetastatic UTUC from 2004 to 2013 in the Survival Epidemiology, and End Results–Medicare population-based database. Patients were stratified into low- or high-risk disease groups. Median total costs from 30 days prior to diagnosis through 365 days after diagnosis were compared between groups. Overall and cancer-specific survival were evaluated using Cox proportional hazards regression. All statistical tests were 2-sided. Results After risk stratification, 1027 (24.9%) and 3087 (75.0%) patients were classified into low- vs high-risk UTUC groups. Most patients underwent at least 1 surgical intervention (95.1%); 68.4% underwent at least 1 endoscopic intervention. Patients diagnosed with high- vs low-risk UTUC were more likely to undergo nephroureterectomy (83.6% vs 72.0%; P Conclusions UTUC continues to be managed primarily with nephroureterectomy, regardless of risk stratification, and patients with high-risk UTUC have worse overall and cancer-specific survival. Substantial costs are associated with management of low- and high-risk UTUC, with the latter being more costly up to 1 year from diagnosis.

This editorial highlights submissions to part II of the 3rd IBCN Seminars Series particularly focusing on the tools required for conduction of translational research in bladder cancer. One of the submissions describe the ex vivo culture of primary tumor cells from N-methyl-N-nitrosourea-induced bladder tumors in rats and subsequent establishment of an immortalized cell line. In a next step the authors thoroughly characterize this cell line. They conclude that differentiation marker expression patterns observed in the original tumors are largely retained in the spheroids. Although new cancer models, such as organoid tissue cultures, hold great promise for studying cancer progression and might have a potential for development and selection of an optimal treatment, their limitations must be kept in mind. The second submission, therefore, critically questions the current role of organoid tissue culture as a predictive tool in urothelial cancer patients. The third manuscript of this series provides a broader overview of post-translational modification in bladder cancer is presented and how PTMs can be exploited as potential therapeutic targets. The 3 manuscripts featured in this issue demonstrate especially how basic research is being channeled to inform clinically actionable discoveries.

Objective Length of hospital stay for patients following radical cystectomy is an important determinant for improved quality of care. We sought to develop and validate a predictive model for length of hospital stay following radical cystectomy. Methods Patients aged 66 to 90 years diagnosed with clinical stage T2-4a muscle-invasive bladder cancer who underwent radical cystectomy were included from January 1, 2002 through December 31, 2011 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Linear regression analyses were used to develop and validate a predictive model for length of hospital stay. Results A total of 2,448 patients met inclusion criteria. After random assignment, 1,224 patients were included in the discovery cohort and 1,224 patients included in the validation cohort. The cohorts were well balanced with no significant difference in any of the preoperative variables. A best model was developed using marital status, Surveillance, Epidemiology, and End Results (SEER) region, clinical stage, Charlson comorbidity index, logarithm of hospital cystectomy volume, and use of neoadjuvant chemotherapy in a backward selection to predict the length of stay. There was robust internal validation (sum square error (SSE): 258.1 vs. predicted sum of squares (PRESS): 264.0 at SLS = 0.10), consistent with the external validation (average square error (ASE): discovery (0.248) vs. validation (0.258)) cohort. The strength of the model in predicting length of stay for the entire cohort was (R2 = 0.048). Conclusion In this large population-based study, we developed and validated a model to predict length of hospital stay following radical cystectomy. Identification of at-risk patients for prolonged hospital stay may aid in targeted interventions to reduce length of stay, improve quality of care, and decrease healthcare costs.

BACKGROUND Although skeletal-related events (SREs) are linked with a reduced quality of life and worse outcomes, to the authors' knowledge the factors that predict SREs are minimally understood. The objective of the current study was to identify predictors of SREs and all-cause mortality among men with metastatic castration-resistant prostate cancer (mCRPC). METHODS Data were collected on 837 men with bone mCRPC at 8 Veterans Affairs medical centers within the Shared Equal Access Regional Cancer Hospital (SEARCH) database from 2000 through 2017. Patients were followed to assess development of SREs (pathological fracture, radiotherapy to bone, spinal cord compression, or surgery to bone). Cox proportional hazards models were used to evaluate predictors of SREs and mortality. RESULTS Of the 837 men with bone mCRPC, 287 developed a SRE and 740 men died (median follow-up, 26 months). Bone pain was found to be the strongest predictor of SREs (hazard ratio [HR], 2.96; 95% CI, 2.25-3.89). A shorter time from CRPC to the development of metastasis (HR, 0.92; 95% CI, 0.85-0.99), shorter progression to CRPC (HR, 0.94; 95% CI, 0.91-0.98), and visceral metastasis at the time of diagnosis of bone metastasis (HR, 1.91; 95% CI, 1.18-3.09) were associated with an increased risk of SREs. Ten or more bone metastases (HR, 2.17; 95% CI, 1.72-2.74), undergoing radical prostatectomy (HR, 0.73; 95% CI, 0.61-0.89), shorter progression to CRPC (HR, 0.97; 95% CI, 0.94-0.99), older age (HR, 1.03; 95% CI, 1.02-1.04), higher prostate-specific antigen level at the time of diagnosis of metastasis (HR, 1.21; 95% CI, 1.14-1.28), bone pain (HR, 1.44; 95% CI, 1.23-1.70), and visceral metastasis (HR, 1.72; 95% CI, 1.23-2.39) were associated with an increased mortality risk. CONCLUSIONS Among men with bone mCRPC, bone pain was found to be the strongest predictor of SREs and the number of bone metastases was a strong predictor of mortality. If validated, these factors potentially may be used for risk stratification and for SRE prevention strategies.

Clinical factors and barriers affecting adoption of active surveillance (AS) for low-risk prostate cancer (PCa) remain poorly understood. We performed a national survey of radiation oncologists (RO) and urologists (URO) about the perceptions and recommendations of AS for low-risk PCa.In 2017, we surveyed 915 RO and 940 URO about AS for low-risk PCa in the United States. Survey items queried respondents about their attitudes toward AS and recommendations of AS for low-risk PCa. Pearson chi-square and multivariable logistic regression identified clinical and physician factors related toward AS for low-risk PCa.Overall, the response rate was 37.3% (n = 691) and was similar for RO and URO (35.7% vs. 38.7%; P = .18). RO were less likely to consider AS effective for low-risk PCa (86.5% vs. 92.0%; P = .04) and more likely to rate higher patient anxiety on AS (49.5% vs. 29.5%; P .001) than URO. Recommendations of AS varied modestly on the basis of age, prostate-specific antigen (PSA), and number of cores positive for Gleason 3 + 3 PCa. For a 55-year-old man with PSA 8 with 6 cores of Gleason 6 PCa, both RO and URO infrequently recommended AS (4.4% vs. 5.2%; adjusted odds ratio = 0.6; P = .28). For a 75-year-old patient with PSA 4 with 2 cores of Gleason 6 PCa, URO and RO most often recommended AS (89.6% vs. 83.4%; adjusted odds ratio = 0.5; P = .07).RO and URO consider AS to be effective in the clinical management of low-risk PCa, but this varies by clinical and physician factors.

Background Among patients with cancer, prior research suggests that patients with mental illness may have reduced survival. The objective was to assess the impact of psychiatric utilisation (PU) prior to cancer diagnosis on survival outcomes. Methods All residents of Ontario diagnosed with one of the top 10 malignancies (1997–2014) were included. The primary exposure was psychiatric utilisation gradient (PUG) score in 5 years prior to cancer: 0: none, 1: outpatient, 2: emergency department, 3: hospital admission. A multivariable, cause-specific hazard model was used to assess the effect of PUG score on cancer-specific mortality (CSM), and a Cox proportional hazard model for effect on all-cause mortality (ACM). Results A toal of 676,125 patients were included: 359,465 (53.2%) with PUG 0, 304,559 (45.0%) PUG 1, 7901 (1.2%) PUG 2, and 4200 (0.6%) PUG 3. Increasing PUG score was independently associated with worse CSM, with an effect gradient across the intensity of pre-diagnosis PU (vs PUG 0): PUG 1 h 1.05 (95% CI 1.04–1.06), PUG 2 h 1.36 (95% CI 1.30–1.42), and PUG 3 h 1.73 (95% CI 1.63–1.84). Increasing PUG score was also associated with worse ACM. Conclusions Pre-cancer diagnosis PU is independently associated with worse CSM and ACM following diagnosis among patients with solid organ malignancies.

Context Despite established guidelines for the treatment of muscle-invasive bladder cancer, it has been reported that radical cystectomy (RC) is markedly underused, especially among patients of advanced age and those with higher comorbidity burden and lower access to care. Understanding the interactions between patient, provider, and hospital factors may inform targeted interventions to optimize RC utilization. Objective To systematically review the literature regarding factors associated with RC utilization. Evidence acquisition A systematic search was conducted using Ovid and Medline according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify studies between 1970 and 2017 reporting on RC utilization. Prospective and retrospective studies were included. Evidence synthesis There are no published randomized control trials on RC utilization. Variations in study quality and design precluded a formal statistical meta-analysis. RC receipt significantly depended on patient, provider, and hospital factors. Patient factors associated with lower RC use included advanced age, African American and Hispanic race/ethnicity, higher comorbidity burden, unmarried marital status, higher tumor stage and grade, and lower socioeconomic status. Provider factors associated with underutilization included lower surgeon volume and a metropolitan location. Finally, hospital factors associated with lower RC use included low hospital volume, nonacademic affiliation, and hospital location in the Midwest. Conclusions RC is reportedly underutilized. We found that age, race, marital status, socioeconomic factors, cancer severity, comorbidity burden, surgeon volume, and facility type and location significantly determined RC receipt. Improved understanding of the varying contributions of the risk factors according to patient, provider, and hospital determinants may assist in developing targeted interventions to improve RC utilization. Patient summary In this review we explored the clinical evidence for factors predicting the utilization of radical cystectomy for muscle-invasive bladder cancer. Many factors related to the patient, provider, and hospital determine whether patients receive this guideline-recommended treatment. However, there remains a lack of understanding on characterization and targeted interventions according to these levels, which may improve use.

Objective To determine the estimated budget impact to practices that incorporate blue light cystoscopy (BLC) with hexaminolevulinate HCl (HAL) for the surveillance of non-muscle-invasive bladder cancer (NMIBC) in the clinic setting. With the introduction of advanced technologies in the clinic setting such as HAL, further cost comparative research is needed to justify HAL as a high value option. Material and methods A budget impact model was developed from the facility perspective assessing projected costs at 2 years for a simulated facility with 50 newly diagnosed bladder cancer patients. Treatment and surveillance cystoscopy intervals were based on clinical guidelines. Clinical inputs, including tumor stage and grade at diagnosis, rates of recurrence and relative risk reduction when using BLC with HAL, were derived from published studies. Cost inputs were based on Medicare reimbursement rates and facility costs. Results Use of BLC identified 9 additional recurrences over two years compared to white light cystoscopy alone. Use of flexible BLC for surveillance marginally increased costs to the practice, with a net difference of $0.76 per cystoscopy over 2 years. Conclusions From the office/clinic perspective, the model suggests that the use of flexible BLC for the surveillance of NMIBC may not impact cost per cystoscopy and identifies 9 recurrences over 2 years that would be missed using white light cystoscopy alone. These findings could have important implications in the management of NIMBC and help guide clinical practice guidelines that promote cost-effective care and improved patient outcomes.

To describe overall and categorical cost components in the management of patients with non-metastatic upper tract urothelial carcinoma (UTUC) according to treatment.We identified 4,114 patients diagnosed with non-metastatic UTUC from 2004 to 2013 in the Survival Epidemiology and End Results-Medicare linked database. Patients were stratified into renal preservation (RP) vs. radical nephroureterectomy (NU) groups. Total Medicare costs within 1 year of diagnosis were compared for patients managed with RP vs. NU using inverse probability of treatment-weighted propensity score models.A total of 1,085 (26%) and 3,029 (74%) patients underwent RP and NU, respectively. Median costs were significantly lower for RP vs. NU at 90 days (median difference -$4,428, Hodges-Lehmann [H-L] 95% confidence interval [CI], -$7,236 to -$1,619) and 365 days (median difference -$7,430, H-L 95% CI, -$13,166 to -$1,695), respectively. Median costs according to categories of services were significantly less for RP vs. NU patients by hospitalization, office visits, emergency room/critical care, consultations, and anesthesia. The only category which was significantly higher for RP vs. NU was inpatient visits ($1,699 vs. $1,532; median difference $152; HL 95% CI, $19-$286).Median costs were significantly lower for RP vs. NU up to 1-year and by hospitalization, office visits, emergency room/critical care, consultations, and anesthesia costs. In appropriately selected patients, such as patients with low-risk disease, these findings suggest the utility of RP as a suitable high-value management option in UTUC.

Mesothelioma is an aggressive tumor with very poor prognosis. The limited availability of therapeutic options for mesothelioma patients suggests the need for a better understanding of mesothelioma biology and the identification of novel therapeutic targets. Progranulin is a pluripotent growth factor whose dysregulation is implicated in several human pathologies including cancer. The pro-tumorigenic activity of progranulin depends on the activation of its functional receptor EphA2. Indeed, in bladder cancer, progranulin promotes EphA2 phosphorylation at Ser897 and triggers EphA2 oncogenic action resulting in increased tumor cell migration, invasion and in vivo tumor growth. Both progranulin and EphA2 are expressed in mesothelioma, with progranulin promoting tumor angiogenesis in a VEGF-independent manner and EphA2 being often mutated or overexpressed. However, in mesothelioma, the potential functional interaction between progranulin and EphA2 is unexplored. Using a panel of mesothelioma cell lines covering all mesothelioma subtypes, we observed increased levels of phosphorylated EphA2 at Ser897 when compared to immortalized normal mesothelial cells, and the levels of phosphorylation positively correlated with progranulin expression. Progranulin-dependent activation of EphA2 in mesothelioma cells promoted the activation of the MAPK and AKT pathways and ERK1/2-dependent EphA2 phosphorylation at Ser897. Transient depletion of progranulin by siRNA approaches as well as GRN gene knock-out by CRISP/Cas9 strategies in mesothelioma cells reduced the activation of the AKT signaling pathway and inhibited the migratory and invasive capabilities of progranulin-depleted cells when compared to parental cells, suggesting that the progranulin/EphA2 axis is oncogenic in mesothelioma. However, EphA2 genetic ablation resulted in an increased basal activation of AKT and MAPK and in progranulin-evoked EphA2-independet AKT/MAPK activation, indicating that alternative membrane receptors might compensate for EphA2 loss and sustain progranulin action in mesothelioma. Using several pharmacological and genetic approaches, we uncovered a role for EGFR and FAK in compensating for EphA2 loss by triggering progranulin-dependent oncogenic signaling in mesothelioma, highlighting a complex functional cross-talk between EphA2, EGFR and FAK in mediating progranulin-dependent tumorigenesis. Thus, these results suggest the need for combinatorial therapeutic approaches to blunt progranulin oncogenic action in mesothelioma. Citation Format: Elisa Ventura, Simone Buraschi, Stephen J. Williams, Antonino Belfiore, Renato V. Iozzo, Antonio Giordano, Andrea Morrione. Mechanisms of action and regulation of the progranulin/EphA2 axis in mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 97.

The ability of cancer cells to alter their metabolism is one of the major mechanisms underlying rapid tumor progression and/or therapeutic resistance in solid tumors, including the hard-to-treat triple-negative breast cancer (TNBC) subtype. Here, we assessed the contribution of the tumor suppressor, Annexin A6 (AnxA6) in the metabolic adaptation of rapidly growing versus invasive TNBC cells as well as in Lapatinib resistant (Lap-R) TNBC cells. AnxA6 expression in cultured TNBC cell lines, Lap-R cells and in crude isolates of mitochondria was determined by Western blotting and/or immunofluorescence assays. The oxygen consumption rates (OCR), extracellular acidification rates (ECAR) and mitochondria activity were assessed using the Seahorse XF Analyzer. Intracellular metabolites were detected by 1H-NMR analysis. Using model proliferative basal-like and invasive mesenchymal-like TNBC cell lines, we show that TNBC cells also exhibit metabolic heterogeneity. Down regulation of AnxA6 in TNBC cells attenuated mitochondrial respiration, glycolytic flux, and cellular ATP production capacity, resulting in a quiescent cellular energy phenotype. We further show that AnxA6-depletion was associated with decreased lipid droplet accumulation and the lipolytic phenotype by enhancing the uptake and mitochondrial fatty acid oxidation for ATP production. Chronic Lapatinib-induced up regulation of AnxA6 in AnxA6-low TNBC cells reversed their lipolytic to a more lipogenic/glycolytic metabolic phenotype with gluconeogenic precursors as additional metabolites. Collectively, these data suggest that the expression status of AnxA6 in TNBC cells underlies significant metabolic adaptation during stress and/or chronic Lapatinib treatment and provide additional insights into the potential of AnxA6 as a biomarker for not only therapeutic intervention but also the metabolic subtyping of TNBC subsets. Citation Format: Stephen D. Williams, Sarrah E. Widatalla, Amos M. Sakwe. Reduced expression of annexin-a6 induces metabolic reprogramming that favors rapid fatty acid oxidation in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB127.

Despite years of prostate cancer-related research, balancing the risk of treatment-derived complications with tumor progression risk remains a challenge. The inability to dissect heterogeneous tumor microenvironments (TME) and immune compartments partly contribute to this knowledge gap. Spatially resolved molecular tumor profiling can enhance our understanding of these complexities and bring us closer to personalized treatment; however, deploying such methods in oncology workflows is challenging as the prevalent tissue preservation technique of formalin fixation and paraffin embedding (FFPE) leads to RNA degradation.We used tissue-wide whole transcriptome analysis with 10x Genomics Visium Spatial Gene Expression Solution for FFPE tissue to resolve the tumor microenvironment of two prostate cancer samples. This assay incorporates ~5,000 molecularly barcoded, spatially encoded capture probes in spots over which the tissue is placed, imaged, and permeabilized. Imaging and sequencing data are processed together for spatially resolved transcriptional readout. We analyzed, and resolved whole transcriptome tumorigenic profiles in sections of normal, stage III invasive adenocarcinoma, and stage IV acinar cell carcinoma FFPE human prostate tissues. Computational clustering of the whole-transcriptome data automatically identified spatial gene expression patterns that aligned well with pathologist annotations. Well known prostate gland and prostate cancer markers were over-expressed in the corresponding healthy and cancerous tumor tissue, validating this method. The data showed that basal cells and luminal cells are spatially organized in healthy tissue while this pattern is lost in tumor samples as the luminal cells encroach the invasive carcinoma region and do not colocalize with basal cells. Moreover, T lymphocytes are dispersed throughout the whole tissue in the adenocarcinoma, while plasma B cells are in the peritumoral region which could impact prognosis. Using computational methods to infer CNV profiles, we identified aneuploidy regions and specific loci that may be driving the underlying genomic profile of the cancerous regions. We demonstrated that spatial whole transcriptome analysis can successfully resolve FFPE prostate samples. Whole-transcriptome data can rapidly confirm known patterns of cell type and tumor region-specific gene expression while giving a better understanding of the TME for drug target identification or biomarker discovery that may lead to patient-tailored therapies and improved patient stratification. Citation Format: Stephen Richardson Williams, Valeria Giangarra, Naishitha Anaparthy, Mesruh Turkekul, Paulius Mielinis, Caroline Gallant, Neil I. Weisenfeld, Sarah E. Taylor, James Chell. Spatial whole transcriptome profiling of the tumor microenvironment in FFPE prostate carcinoma using the Visium platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3812.

The tumor microenvironment (TME) is composed of highly heterogeneous structures and cell types that dynamically influence and communicate with each other. The constant interaction between a tumor and its microenvironment plays a critical role in how the cancer develops, progresses, and responds to therapies. Traditionally, Hematoxylin and Eosin (H&E) staining has been used to annotate and characterize tissues and associated pathologies. Recent single analyte approaches spatially interrogate targeted or transcriptome-wide expression of RNA in tissue sections, while others capture phenotypes using a limited number of protein markers. However, for a more comprehensive understanding of the unique characteristics of cell types, cell states, and cell-cell interactions within the TME, multiple layers of information are needed and must be studied together. Here we demonstrate a novel, streamlined multiomic spatial assay that integrates histological staining and imaging with simultaneous transcriptome-wide gene expression and highly multiplexed protein expression profiling from the same formalin-fixed paraffin embedded (FFPE) tissue section. In short, tissue sections from archived FFPE samples were placed on slides containing arrayed capture oligos with unique positional barcodes. The H&E or immunofluorescence stained tissues were then imaged, followed by incubation with transcriptome-wide probes and a high-plex DNA-barcoded antibody panel containing intra- and extracellular markers. Transcriptome probes and antibody-barcodes were then spatially captured on the slide and converted into sequencing-ready libraries. Our data analysis and interactive visualization software enable interrogation of all data layers (H&E/immunofluorescence, RNA, protein) from the same tissue section. We apply this method to simultaneously measure gene and protein expression within the TME of human breast cancer and melanoma FFPE samples using whole transcriptome probes and an immune-oncology antibody panel. The data enables comparison and correlation of multiple analytes and their patterns within the same sample section. In addition, this simultaneous detection enables marker-guided regional selection and differential gene expression analysis on the defined regions. Taken together, our data demonstrates that a spatially resolved, multiomic approach provides a more comprehensive understanding of cellular behavior in and around tumors, yielding new insights into disease progression, predictive biomarkers, drug response and resistance, and therapeutic development. Citation Format: Cedric Uytingco, Jennifer Chew, Naishitha Anaparthy, Jun D. Chiang, Christina Galonska, Karthik Ganapathy, Ryo Hatori, Alexander Hermes, Layla Katiraee, Anna-Maria Katsori, William Nitsch, Patrick Roelli, Joe Shuga, Rapolas Spalinskas, Mesruh Turkekul, Benton Veire, Dan Walker, Neil Weisenfeld, Stephen R. Williams, Zachary Bent, Marlon Stoeckius. Multiomic characterization of the tumor microenvironment in FFPE tissue by simultaneous protein and gene expression profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3814.

Earlier studies on the cost of muscle-invasive bladder cancer treatments are limited to short-term costs of care. We determined the 2- and 5-year costs associated with trimodal therapy (TMT) vs. radical cystectomy (RC).We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Total Medicare costs at 2 and 5 years following RC vs. TMT were compared using inverse probability of treatment-weighted propensity score models.A total of 2,537 patients aged 66 to 85 years were diagnosed with clinical stage T2-4a muscle-invasive bladder cancer. Total median costs for patients that received no definitive treatment(s) were $73,780 and $88,275 at 2-and 5-years. Costs were significantly higher for TMT than RC at 2-years ($372,839 vs. $191,363, Median Difference $127,815, Hodges-Lehmann Estimate (H-L) 95% Confidence Interval (CI), $112,663-$142,966) and 5-years ($424,570 vs. $253,651, Median Difference $124,466, H-L 95% CI, $105,711-$143,221). TMT had higher outpatient costs than RC (2-years: $318,221 vs. $100,900; 5-years: $367,092 vs. $146,561) with significantly higher costs with radiology, medications, pathology/laboratory, and other professional services. RC had higher inpatient costs than TMT (2-years: $62,240 vs. $33,631, Median Difference $-29,174, H-L 95% CI, $-32,364-$-25,984; 5-years: $75,499 vs. $45,223, Median Difference $-29,843, H-L 95% CI, $-33,905-$-25,781).The excess spending associated with trimodal therapy vs. radical cystectomy was largely driven by outpatient expenditures. The relatively high long-term trimodal therapy costs are prime targets for cost containment strategies to optimize future value-based care.

Bladder cancer is a heterogeneous disease with vastly differing levels of risk to the patient. Low-risk non-invasive disease poses little to no threat to a patient’s survival, whereas invasive disease is rapidly fatal without intervention. This chapter aims to address the more recent developments in risk stratification tools available in assessing patients with non-muscle invasive bladder cancer and muscle invasive bladder cancer.

Background Multiple single-arm clinical trials showed promising pathologic complete response rates with neoadjuvant immune checkpoint inhibitors (ICIs) in muscle-invasive bladder cancer. We conducted a cost-effectiveness analysis comparing neoadjuvant ICIs with cisplatin-based chemotherapy (CBC). Methods We applied a decision analytic simulation model with a health care payer perspective to compare neoadjuvant ICIs vs. CBC. For the primary analysis we compared pembrolizumab with ddMVAC. We performed a secondary analysis with gemcitabine/cisplatin as CBC and exploratory analyses with atezolizumab or nivolumab/ipilimumab as ICI. We input pathologic complete response rates from trials or meta-analysis and costs from average sales price. Outcomes of interest included costs, 2-year recurrence-free survival (RFS), and incremental cost-effectiveness ratio (ICER) of cost per 2-year RFS. A threshold analysis estimated a price reduction for ICI to be cost-effective and one-way and probabilistic sensitivity analyses were performed. Results The incremental cost of pembrolizumab compared with ddMVAC was $8,041 resulting in an incremental improvement of 1.5% in 2-year RFS for an ICER of $522,143 per 2-year RFS. A 21% reduction in cost of pembrolizumab would render it more cost-effective with an ICER of $100,000 per 2-year RFS. GC required an 89% pembrolizumab cost reduction to achieve an ICER of $100,000 per 2-year RFS. Atezolizumab appeared to be more cost-effective than ddMVAC. Conclusions ICIs were not cost-effective as neoadjuvant therapies, except when atezolizumab was compared with ddMVAC. Randomized clinical trials, larger sample sizes and longer follow-up are required to better understand the value of ICIs as neoadjuvant treatments.

African Americans endure a nearly two-fold greater risk of suffering a stroke and are 2–3 times more likely to die from stroke compared to those of European ancestry. African Americans also have a greater risk of recurrent stroke and vascular events, which are deadlier and more disabling than incident stroke. Stroke is a multifactorial disease with both heritable and environmental risk factors. We conducted an integrative, multi-omic study on 922 plasma metabolites, 473,864 DNA methylation loci, and 556 variants from 50 African American participants of the Vitamin Intervention for Stroke Prevention clinical trial to help elucidate biomarkers contributing to recurrent stroke rates in this high risk population. Sixteen metabolites, including cotinine, N-delta-acetylornithine, and sphingomyelin (d17:1/24:1) were identified in t-tests of recurrent stroke outcome or baseline smoking status. Serum tricosanoyl sphingomyelin (d18:1/23:0) levels were significantly associated with recurrent stroke after adjusting for covariates in Cox Proportional Hazards models. Weighted Gene Co-expression Network Analysis identified moderate correlations between sphingolipid markers and clinical traits including days to recurrent stroke. Integrative analyses between genetic variants in sphingolipid pathway genes identified 29 nominal associations with metabolite levels in a one-way analysis of variance, while epigenomic analyses identified xenobiotics, predominately smoking-associated metabolites and pharmaceutical drugs, associated with methylation profiles. Taken together, our results suggest that metabolites, specifically those associated with sphingolipid metabolism, are potential plasma biomarkers for stroke recurrence in African Americans. Furthermore, genetic variation and DNA methylation may play a role in the regulation of these metabolites.

BACKGROUND Postchemotherapy retroperitoneal lymphadenectomy (PC-RPLND) is an essential, yet potentially morbid, therapy for the management of patients with advanced germ cell tumors. In the current study, the authors sought to define the complication profile of PC-RPLND using validated grading systems for intraoperative adverse events (iAEs) and early postoperative complications. METHODS Between 2000 and 2018, all patients who underwent PC-RPLND were analyzed for iAEs and early postoperative complications using the Kaafarani and Clavien-Dindo classifications, respectively. Logistic regression models were conducted to assess patient and tumor factors associated with iAEs and postoperative complications. RESULTS Of the 453 patients identified, 115 patients (25%) and 252 patients (56%), respectively, experienced an iAE and postoperative complication. Major iAEs (grade ≥3) were observed in 15 patients (3%) and major postoperative complications (grade ≥3) were noted in 80 patients (18%). The most common iAE was vascular injury (112 of 132 events; 85%), which occurred in 92 patients (20%), and the most frequent postoperative complication was ileus, which occurred in 121 patients (27%). Original and postchemotherapy retroperitoneal mass size, nonretroperitoneal metastases, intermediate and/or poor International Germ Cell Cancer Collaborative Group classification, previous RPLND, elevated tumor markers at the time of RPLND, and anticipated adjuvant surgical procedures increased the risk of both iAEs and postoperative complications. Patients who experienced an iAE were significantly more likely to experience a postoperative complication (odds ratio, 2.50; 95% confidence interval, 1.58-3.97 [P

Occupational exposure to benzene at levels of 10 ppm or more has been associated with increased risk of acute myeloid leukaemia (AML). The mode of action (MOA) for AML development leading to mortality is anticipated to include multiple earlier key events, which can be observed in hematotoxicity and genetic toxicity in peripheral blood of exposed workers. Prevention of these early events would lead to prevention of the apical, adverse outcomes, the morbidity and mortality caused by the myelodysplastic syndrome (MDS) and AML.. Incorporation of key event information should modify the risk model, but few modification approaches have been suggested. To that end, two approaches to risk model modification are described that use sub-linear and segmented linear increases in risk below key events, while maintaining a linear increase in AML mortality risk beginning at 2 ppm, the lowest observed adverse effect concentration (LOAEC) identified for hemato- and geno- toxicity in high quality studies of human occupational exposure. Below 2 ppm two different modification approaches to quantitative risk models were applied: a continuously decreasing slope model and a segmented modification in slope. These two approaches provide greater flexibility to incorporate MOA information in risk model development and selection.

Introduction Prior studies noted substantial costs associated with radical cystectomy, however, they lack surgical comparison to a less costly partial cystectomy. We compared costs associated with radical versus partial cystectomy. Methods A total of 2,305 patients aged 66-85 years diagnosed with clinical stage T2-4a muscle-invasive bladder cancer from January 1, 2002 through December 31, 2011 were included. Total Medicare costs within one year of diagnosis following radical versus partial cystectomy were compared using inverse probability of treatment-weighted propensity score models. Cox regression and competing risks analysis were used to determine overall and cancer-specific survival, respectively. Results Median total costs were not significantly different for radical than partial cystectomy in 90 days ($73,907 vs. $65,721; median difference $16,796, 95% CI $10,038 to $23,558), 180 days ($113,288 vs. $82,840; median difference $36,369, 95% CI $25,744 to $47,392), and 365 days ($143,831 vs. $107,359; median difference $34,628, 95% CI $17,819 to $53,558), respectively. Hospitalization, surgery, pathology/laboratory, pharmacy, and skilled nursing facility costs contributed largely to costs associated with either treatment. Patients who underwent partial cystectomy had similar overall survival but had worse cancer-specific survival (Hazard Ratio (HR) 1.45, 95% Confidence Interval (CI), 1.34-1.58, p Conclusions While treatments for bladder cancer are associated with substantial costs, we showed radical cystectomy had similar total costs when compared to partial cystectomy among patients with muscle-invasive bladder cancer. However, partial cystectomy resulted in worse cancer-specific survival further supporting radical cystectomy as a high-value surgical procedure for muscle-invasive bladder cancer.

Insulin receptor overexpression is a common event in human cancer. Its overexpression is associated with a relative increase in the expression of its isoform A (IRA), a shorter variant lacking 11 aa in the extracellular domain, conferring high affinity for the binding of IGF-II along with added intracellular signaling specificity for this ligand. Since IGF-II is secreted by the vast majority of malignant solid cancers, where it establishes autocrine stimuli, the co-expression of IGF-II and IRA in cancer provides specific advantages such as apoptosis escape, growth, and proliferation to those cancers bearing such a co-expression pattern. However, little is known about the exact role of this autocrine ligand−receptor system in sustaining cancer malignant features such as angiogenesis, invasion, and metastasis. The recent finding that the overexpression of angiogenic receptor kinase EphB4 along with VEGF-A is tightly dependent on the IGF-II/IRA autocrine system independently of IGFIR provided new perspectives for all malignant IGF2omas (those aggressive solid cancers secreting IGF-II). The present review provides an updated view of the IGF system in cancer, focusing on the biology of the autocrine IGF-II/IRA ligand−receptor axis and supporting its underscored role as a malignant-switch checkpoint target.

455 Background: Earlier studies on the cost of muscle-invasive bladder cancer treatments are limited to short-term periods of cost. Our study objective is to compare the 2- and 5-year costs associated with trimodal therapy (TMT) versus radical cystectomy (RC) benchmarked against costs for patients who received no curative treatment. Methods: This cohort study used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Medicare expenditures were summed from inpatient, outpatient, and physician services within 2 and 5 years of diagnosis to determine total costs Total Medicare costs at 2-and 5-years following TMT versus RC were compared using inverse probability of treatment-weighted (IPTW) propensity score models. Results: A total of 2,537 patients aged 66-85 years diagnosed with clinical stage T2-4a muscle-invasive bladder cancer from January 1, 2002 through December 31, 2009. Total median costs for patients that received no definitive/systemic treatments (RC, TMT, radiotherapy alone, or chemotherapy alone) were $73,780 vs. $88,275 at 2-and 5-years respectively. Total median costs were significantly higher for TMT than RC at 2-years ($372,839 vs. $191,363, p

527 Background: Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) have heterogeneous outcomes with African Americans (AAs) having worse survival than European Americans (EAs). It is unknown whether race-based biological differences contribute to this disparity. Methods: We performed a retrospective cohort study including patients from the University of Texas Medical Branch (UTMB) and the Durham VA Health Care System (DVAHCS) from 2010-2020 among treatment naïve, high-risk NMIBC. Profiled gene expressions of high-risk NMIBC by race were performed using the UROMOL classification system. Results: A total of 26 patients (14 AAs and 12 EAs) matched on age and sex were included with no significant difference in clinical stage group (CIS +/- T1 or TaHG vs. TaHG or T1, no CIS), smoking status, or progression. We found a similar racial UROMOL subtype distribution with class 2a being most common. A total of 10 genes were discovered to be commonly upregulated differentially expressed genes (up-DEGs) in AAs vs EAs. EFEMP1, which has been associated with progression to muscle-invasive bladder cancer (MIBC) in vitro, and S100A16 gene expression, which has been implicated with mitomycin C resistance in bladder cancer in vitro, was significantly more common among AAs. We used single nuclei analysis to map the malignant cell heterogeneity in urothelial cancer which five distinct malignant epithelial subtypes whose presence has been associated with different therapeutic response prediction ability. We mapped the expression of the 10 genes commonly up-DEGs by race as a function of the five malignant subtypes. This showed borderline (p = 0.056) differences among the subtypes suggesting AA and EA patients may be expected to have different therapeutic responses to treatments for BC. AAs were enriched with immune-related, inflammatory, and cellular regulation pathways compared to EAs, yet appeared to have reduced levels of the aggressive C3 bladder tumor cell population. Conclusions: In this small sample, we found similar subtype distribution among high-risk NMIBC patients according to race. However, gene expression differs by race, supporting potential novel race-based etiologies for differences in muscle-invasion, response to treatments, and transcriptome pathway regulations. Further biological studies in NMIBC molecular sub-stratification, associated treatment(s), and prognoses in a larger cohort are needed to support these hypotheses.

447 Background: Mortality from bladder cancer (BC) increases exponentially once it invades the muscle. At the population level, accurate delineation of these patients is challenging. Methods: To develop and validate a natural language processing (NLP) model for automatically identifying muscle-invasive BC (MIBC) patients, aiding in population-based BC research. All patients with a CPT code for transurethral resection of bladder tumor (TURBT) (N = 76,060) were selected from the Department of Veterans Affairs (VA) Corporate Data Warehouse database. A sample of 600 patients (with 2,337 full-text notes) who had TURBT and confirmed pathology results were selected for NLP model development (500 patients) and validation (100 patients). Muscle-invasion (yes/no), unknown, or no cancer, were confirmed by detailed chart review of pathology notes. The NLP performance was assessed by calculating the sensitivity, positive predictive value (PPV), and overall accuracy at the individual note and patient levels. Results: In the validation cohort, the NLP model had overall accuracy of 88% and 92% at the note and patient levels. Specifically, PPV and specificity for predicting muscle-invasion on note level were 83% and 70%, respectively. The model classified non-muscle invasive BC (NMIBC) with 98% sensitivity at both the note and patient levels. Although the sensitivity for MIBC was 70% for note-level determination, the sensitivity was 86% when evaluated at the patient level. When applying the model to 71,200 patients VA-wide, the model classified 13,642 (19%) as having MIBC and 47,595 (66%) as NMIBC. The NLP model was able to identify invasion status for 96% TURBT patients at the population level. Inherent limitations include relatively small training set given the size of the VA population. Conclusions: This NLP model for identifying muscle-invasion at the population level had high accuracy. The NLP model may be a practical and accurate tool for efficiently identifying BC invasion status and may potentially aid in population-based BC research in the VA.

The reasons for low clinical adoption of active surveillance (AS) for low-risk prostate cancer (PCa) remain poorly understood. Thus, we conducted a national survey of radiation oncologists (ROs) and urologists (UROs) to elucidate perceived barriers to AS for low-risk PCa. In 2017, we undertook a four-wave mail survey of 1855 ROs and UROs. The survey instrument assessed attitudes about possible barriers towards AS for low-risk PCa. We used Pearson Chi square and multivariable logistic regression analyses to identify physician characteristics associated with attitudes about AS. We received 691 completed surveys for an overall response rate of 37.3%. A majority of respondents indicated that they felt comfortable recommending AS (90.0%), agreed that high-level evidence supports it (82.3%), and considered AS equally effective for survival compared with surgery and radiation therapy (84.4%). UROs were less likely to agree that patients were not interested in AS for low-risk PCa compared with ROs (16.5 vs. 48.9%; adjusted odds ratio [OR] 0.18, p

Context Radical cystectomy continues to be associated with a significant risk of morbidity and all-cause mortality (ACM). Practice pattern data demonstrating underuse of surgery for patients with muscle-invasive and high-risk non–muscle invasive bladder cancer (BC) have been linked to the advanced age and higher comorbidity status of such patients, which suggests that rates of ACM as well as cancer-specific mortality should be incorporated into patient counseling and guideline recommendations. Objective To review the literature on risk assessment tools for preoperative comorbidity in BC that may aid in treatment decision-making. Evidence acquisition A systematic search was conducted using Ovid and Medline according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify studies between 1970 and 2017 reporting on comorbidity risk assessment (CRA) tools for BC. Prospective and retrospective studies were included. Evidence synthesis There are no published randomized control trials comparing CRA tools for BC. Patients undergoing radical cystectomy with combined high-risk comorbidity and performance scores may face up to a sevenfold greater risk of other-cause mortality compared to those with low scores. The Charlson Comorbidity Index is one of the most widely studied indices for 90-d perioperative mortality and overall and cancer-specific survival, with an area under the receiver operating characteristic curve of up to 0.810. Prospective studies of CRA tools for BC have consistently shown that patients with higher comorbidity have worse outcomes. While not specific for BC, comorbidity indices provide useful assessment of competing risks. Competing-risks assessment tools are lacking, with limited studies assessing the impact of these tools on treatment decision-making by patients and providers. We provide the impetus for incorporation of comorbidity risks into practice guidelines when discussing treatment options with patients. Conclusions CRA tools should be incorporated into preoperative treatment counseling and the assessment of postoperative outcomes. While retrospective evidence supports the use of CRA tools for BC, further comparative studies evaluating the effectiveness of these tools and identifying the patients most likely to benefit from a treatment according to competing-risks assessment are needed. Patient summary In this review we explored the clinical evidence for comorbidity risk assessment tools in bladder cancer. We found evidence to support incorporation of comorbidity risks into practice guidelines when discussing treatment options with patients.

Introduction This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC). Patients and Methods We enrolled 77 patients who had received no prior chemotherapy for CRPC between 1998 and 2000; a total of 74 subjects were eligible for the study. Each 8-week cycle included paclitaxel 90 mg/m2 provided intravenously weekly for 6 weeks, followed by 2 weeks off therapy and oral estramustine 280 mg twice daily for 3 days beginning 24 hours before the first dose of paclitaxel. The primary end point was rate of objective or prostate-specific antigen (PSA) response at 16 weeks. A 50% response rate was considered of further interest. Results Eligible patients received a median of 3 cycles (range, 1-10 cycles). The response rate among patients with measurable disease was 34% (95% confidence interval [CI], 19-52). The PSA response rate was 58% (95% CI, 47-70). Clinical benefit rate was 45% (95% CI, 33-57). The median progression-free survival was 5.9 months (95% CI, 4.4-6.7). The median overall survival was 17.6 months (95% CI, 14.6-20.8). The most common clinical grade 3/4 toxicities were fatigue (14%) and sensory neuropathy (7%). Grade 3/4 hematologic toxicities included lymphopenia (21%) and anemia (9%). There was one toxicity-related death. Quality-of-life scores improved by week 8, but the change was not statistically significant. Conclusion The combination has activity defined by PSA declines in CRPC but did not meet the protocol-specified end point for efficacy as defined by objective response rate. Since this study was conducted, more effective, better-tolerated regimens have been developed.

Background This study was designed to adapt the Elixhauser comorbidity index for 4 cancer-specific populations (breast, prostate, lung, and colorectal) and compare 3 versions of the Elixhauser comorbidity score (individual comorbidities, summary comorbidity score, and cancer-specific summary comorbidity score) with 3 versions of the Charlson comorbidity score for predicting 2-year survival with 4 types of cancer. Methods This cohort study used Texas Cancer Registry-linked Medicare data from 2005 to 2011 for older patients diagnosed with breast (n = 19,082), prostate (n = 23,044), lung (n = 26,047), or colorectal cancer (n = 16,693). For each cancer cohort, the data were split into training and validation cohorts. In the training cohort, competing risk regression was used to model the association of Elixhauser comorbidities with 2-year noncancer mortality, and cancer-specific weights were derived for each comorbidity. In the validation cohort, competing risk regression was used to compare 3 versions of the Elixhauser comorbidity score with 3 versions of the Charlson comorbidity score. Model performance was evaluated with c statistics. Results The 2-year noncancer mortality rates were 14.5% (lung cancer), 11.5% (colorectal cancer), 5.7% (breast cancer), and 4.1% (prostate cancer). Cancer-specific Elixhauser comorbidity scores (c = 0.773 for breast cancer, c = 0.772 for prostate cancer, c = 0.579 for lung cancer, and c = 0.680 for colorectal cancer) performed slightly better than cancer-specific Charlson comorbidity scores (ie, the National Cancer Institute combined index; c = 0.762 for breast cancer, c = 0.767 for prostate cancer, c = 0.578 for lung cancer, and c = 0.674 for colorectal cancer). Individual Elixhauser comorbidities performed best (c = 0.779 for breast cancer, c = 0.783 for prostate cancer, c = 0.587 for lung cancer, and c = 0.687 for colorectal cancer). Conclusions The cancer-specific Elixhauser comorbidity score performed as well as or slightly better than the cancer-specific Charlson comorbidity score in predicting 2-year survival. If the sample size permits, using individual Elixhauser comorbidities may be the best way to control for confounding in cancer outcomes research. Cancer 2018;124:2018-25. © 2018 American Cancer Society.

Urothelial carcinoma of the bladder (UCB) is a common cancer worldwide with over 430,000 new cases in 2012 and 165,000 deaths and is currently the most expensive cancer per capita to treat in the U...

Triple-negative breast cancer (TNBC), which accounts for up to 17% of all breast cancer cases in the Unites States, disproportionately affects premenopausal African American and Hispanic women. Here, we report the synergistic function of the tumor suppressor annexin-A6 (AnxA6) and Lapatinib-resistance (Lap-R) in the context of cellular bioenergetics. Metabolic profiling of TNBC cell lines show extensive diversity amongst basal-like (BSL) vs mesenchymal-like (MSL) molecular subtypes. Down regulation of AnxA6 in AnxA6- expressing and Lap-R cell lines attenuated mitochondrial respiration, glycolytic function, and cellular ATP production capacity, decreasing the overall metabolic plasticity of the cell. Additionally, AnxA6-depletion altered lipid metabolism by enhancing the mitochondrial uptake of cytosolic fatty acids for β-oxidation. NMR-based metabolomics revealed that AnxA6 depleted and/or Lap-R TNBC cells have a greater dependency on gluconeogenic precursors including glycine, alanine, lactic acid, and oxaloacetic acid as survival mechanisms. Taken together, this study proposes that altered expression of AnxA6 is accompanied by significant bioenergetic adaptations and hence provide novel insights into the failure of EGFR-targeted therapies as therapeutic options and disease progression in patients with triple-negative breast cancer. Citation Format: Stephen D. Williams, Sarrah E. Widatalla, Amos M. Sakwe. The role of annexin A6 in triple-negative breast cancer metabolism and disease progression [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-148.