bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunotherapy-related toxicities: A retrospective analysis of barriers to prompt detection and initiation of treatment in renal cell carcinoma.
Authors: Zeter Daniel , Patel Ina J 
Published: June 2023

e16547 Background: In 2021, there was an estimated 76,000 patients diagnosed with kidney cancer in the United States, and 90% of these patients were diagnosed with renal cell carcinoma (RCC). The current treatment for RCC is the use of immune checkpoint inhibitors (ICIs), which allow the body to naturally fight against cancer cells without impedance. A common side effect of this therapy, however, is immunotherapy-related adverse events (irAE), which are toxicities where the bodies overactive immune system attacks noncancerous organs. When irAEs arise, the patient’s immunotherapy is stopped, and a steroid regiment is begun to dampen the immune system before re-starting immunotherapy. Time is crucial when treating irAEs, and this study is aimed to identify barriers in the onset of steroid treatment and identify interventions that can help providers and patients identify toxicities and begin steroid treatment as soon as possible. Methods: We conducted a retrospective study analyzing adult patients (ages 18-75) being treated for RCC at UT Southwestern Medical Center and Moncrief Cancer Institute (MCI). We specifically looked at patients being treated with ipilimumab, nivolumab, and pembrolizumab. The first portion included a chart review to identify patients and identify barriers to prompt treatment, i.e. fear of worsening hyperglycemia in diabetics, access to healthcare, delay of re-initiating immunotherapy. The second portion of this study will be to identify and test a possible intervention for these patients to ensure timely recognition of toxicities and prompt initiation of steroids. Results: Upon review of 201 patients with RCC stage III/IV, the most common toxicity found was colitis (28.4%), followed by transaminitis (9.0%) and pneumonitis (9.0%). The most common method for identification of toxicities was routine lab work performed before immunotherapy administration (30.4%), check-ins at regularly scheduled appointments (21.7%), and after-hour physician telephone lines (19.6%). Additionally, the average time from irAE identification to steroid administration was 1.45 days. Excluding toxicities found either at office appointments or on routine lab work, the average time to steroids from identification was 3.55 days. Our data collection also demonstrated that routine labs were the most likely factor to identify immunotherapy toxicity in a timely manner. Conclusions: Continuation of current practices can lead to further decreases in time to steroid treatment. This study can be used as a blueprint and expanded to further investigate irAEs in other solid tumors as well as contribute to management of the ever-evolving immunotherapy landscape.
Updated analysis of real-world treatment outcomes of first-line axitinib plus pembrolizumab in patients with advanced renal cell carcinoma in the United States.
Authors: Zakharia Yousef , Vlahiotis Anna , Siu Gordon , Rao Dharanija , Teresi Rosemary , Eccleston Anthony 
Published: June 2023

e16553 Background: The combination of axitinib plus pembrolizumab (AXI+PEM) is a standard of care in the first-line (1L) treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Previous analyses described the demographic and clinical characteristics, as well as outcomes of patients receiving 1L AXI+PEM in a real-world setting. We report updated data with longer follow-up for this cohort. Methods: Electronic medical record data from the Flatiron Health, nationwide de-identified Database (280 cancer clinics across 800 sites in the US) were used to select patients with confirmed Stage IV/metastatic RCC and who initiated 1L AXI+PEM on or after 1/1/2018 to 7/31/2022. Analyses included best overall response to 1L therapy; real-world progression-free survival (rwPFS) and overall survival (rwOS) are reported as patients without a clinical event (rwPFS; progression/death; rwOS; death) at landmark time periods (3, 6, 9, 12, 18 and 24 months); denominators include censored patients. Other data are reported as medians (min, max) unless otherwise noted. Results: Three hundred and forty patients received 1L AXI+PEM, with an extended mean follow-up of 19.2 (0.1–41.6) months. Most patients were male (69.1%) and mean age of 64.1 (21.0–83.0) years. At diagnosis, 56.5% of patients had Stage IV RCC and 78.2% of patients had clear cell histology. IMDC Risk Score was favorable, intermediate, and poor in 24 (6.8%), 123 (34.4%), and 78 (22.1%) patients, respectively (unknown = 125 (36.8%)). At the time of analysis, 192 patients (56.5%) received only 1L therapy with AXI+PEM, while 148 patients (43.5%) received ≥1 subsequent line of treatment. Vascular endothelial growth factor receptor (VEGF-R) inhibitors were the most commonly used second-line (2L) treatment (109 patients, 73.6%), with cabozantinib being the most frequently used VEGF-R inhibitor (84 patients, 77.1%). Median rwPFS was 8.6 (CI: 7.2-9.7) months with 15.0% of patients achieving rwPFS at 2 years. Median rwOS was 29.4 (CI: 24.2-37.3) months with 38.5% of patients alive at 2 years. Best overall response rate to 1L was 54.1% (complete or partial response observed in 184/340 patients). 51.5% of patients required a dose hold, of which 58.3% required it due to an adverse event. Conclusions: This updated analysis supports the use of 1L AXI+PEM in patients with advanced RCC across all IMDC risk groups, providing further understanding of the clinical outcomes and treatment patterns of patients with advanced RCC in the US. [Table: see text]
Clinical-pathological features and treatment outcomes in Hispanic/Latino patients with advanced renal cell carcinoma at a single institution.
Authors: Ocejo Gallegos Jesus Antonio , Murray Abner , Jones Sandra , Frias Rosa Lizeth , Noy Jose , Campoverde Leticia , Merchan Jaime R. 
Published: June 2023

e16554 Background: Annually, there are over 400,000 new renal cell carcinoma (RCC) cases and more than 170,000 deaths worldwide. RCC is one of the top ten more prevalent malignancies in the United States, with 76,000 new cases each year and almost 14,000 deaths. Over the past half-century, RCC has more than doubled in incidence. Studies demonstrate histologic differences and outcome disparities among Hispanic and Latino patients diagnosed with RCC. Research to date describes earlier and more advanced diseases at diagnosis, higher rates of obesity at presentation, and higher mortality among these cohorts. However, there is limited data on clinical, pathological, molecular, and treatment outcomes in this patient population. This study aims to characterize clinical features and treatment outcomes in this patient population in South Florida. Methods: We conducted a retrospective cohort study to describe the characteristics and rates of recurrence of RCC among patients treated at Sylvester Comprehensive Cancer Center in Miami (which serves four counties in South Florida) between June 2010 to June 2022. An IRB-approved advanced RCC database was developed on RedCap, where clinical, laboratory, pathological, treatment, and response information were captured. Ethnicity was determined as Hispanic/Latino (HL) or non-Hispanic/Latino (NHL). Clinical groups were classified based on the last encounter as local RCC after nephrectomy, recurrent metastatic RCC after nephrectomy, and metastatic RCC at diagnosis/de novo. Results: We analyzed a total of 2048 patients aged 18 and older diagnosed with RCC, from which 1008 patients (47.70%) were identified as NHL and 963 (47.92%) as HL. RCC was in over a 2:1 ratio of men to women in both HLs and NHLs. A subtotal of 435 patients (22.87%) had metastatic RCC at diagnosis/de novo, from which 245 (55.59%) were NHL, and 175 (40.32%) were HL. A subtotal of 1613 patients (78.76%) were diagnosed with local RCC and underwent nephrectomy, from which 763 (45.46%) were identified as NHL and 788 (50.15%) as HL. From the NHL group that underwent nephrectomy, 222 patients (28.21%) had recurrent disease, and 541 patients (71.79%) did not. From the HL group, 175 patients (21.69%) had recurrent disease, and 613 (78.31%) did not. Overall, 408 patients had metastasis after nephrectomy, of which 175 (44.31%) were HL, and 203 (52.24%) were NHL. Conclusions: In this cohort of patients with RCC, over 40% of patients diagnosed with metastasis were HL. NHL appeared to have more disease recurrence after nephrectomy and higher rates of metastatic disease at diagnosis compared to Hispanics. Further histopathological differences, clinical outcomes, genomic characterization, and rates of clinical trial participation between the NHL and HL cohorts will be presented at the meeting, along with comparisons between US and foreign-born HLs.
Incidence and risk of peripheral sensory neuropathy with enfortumab vedotin in patients with advanced urothelial cancer: A systematic review and meta-analysis.
Authors: Shah Yousuf , Sher Amna Falak , Wu Shenhong 
Published: June 2023

e16556 Background: Enfortumab Vedotin (EV), a first-in-class antibody-drug conjugate directed against Nectin-4, is associated with peripheral sensory neuropathy (SN) in the treatment of advanced urothelial cancers. A systematic literature review and meta-analysis were conducted to assess the overall incidence and risk of SN in patients receiving EV. Methods: A systematic search through mid-2022 of PubMed, Cochrane Library, and recent ASCO annual and genitourinary meetings was conducted to identify relevant studies. Eligible studies were clinical trials of patients with urothelial cancer receiving single-drug EV at the standard dose with data on SN available. Incidence and relative risk (RR) of SN were calculated using both a fixed-effects and a random-effects model. Results: Of the 93 initial publications identified, there were 5 trials that met the eligibility criteria and included a total 996 patients with 630 patients receiving EV at the standard dose. The summary incidence of all-grade SN was 42.3% (95% CI: 38.5-46.2%) with the incidence of high-grade SN being 3.1% (95% CI: 1.9-4.9%). In comparison with standard chemotherapy, there was no significant difference for EV in all-grade SN (RR = 0.95, 95% CI: 0.77-1.18, p = 0.66) and high-grade SN (RR = 1.69, 95% CI: 0.40-7.21, p = 0.48). In some cases, SN also led to discontinuation of EV (4.4%, 95% CI: 2.1-6.7%). Conclusions: EV is associated with a substantial toxicity of peripheral sensory neuropathy, and its risk may be comparable to that of standard chemotherapy. Further studies are needed to assess and reduce the risk of severe neuropathy.
Real-world use, dose intensity, and adherence to enfortumab vedotin (EV) in locally advanced or metastatic urothelial cancer (la/mUC).
Authors: Tsingas Konstantinos , Parikh Ravi Bharat , Elsouda Dina , Mucha Lisa , Fuldeore Rupali , Hubbard Rebecca A. , Mamtani Ronac 
Published: June 2023

e16567 Background: EV, the first antibody drug conjugate approved for la/mUC, received accelerated approval in the US in 2019 as later-line therapy (post-immunotherapy and platinum-chemotherapy) and regular approval in 2021 with label expansion to include earlier-line therapy (cisplatin-ineligible, ≥1 prior therapy). Because EV delivery per current labelling (1.25 mg/kg, D1, 8, 15 of a 28D cycle) may differ from routine practice, we examined real-world EV use, dose intensity and adherence across 280 US cancer clinics. Methods: This descriptive post-marketing retrospective cohort study used the Flatiron Health longitudinal database derived from EHR records of US patients with la/mUC initiating EV on or after December 19, 2019. We summarized EV use, including but not limited to: % cisplatin-ineligible, and median duration of use and number of cycles administered. We computed metrics of dose intensity: average treatment rate (mean number of treatments per patient-month), dosing frequency (mean number of treatments per cycle), dose (mean dose, mg/kg), and % change in dose (mg) from baseline (difference in dose between last recorded treatment in last cycle and first recorded treatment in first cycle). Finally, we measured treatment adherence, defined as % of cycles across all patients where a patient had > 2 treatments per 28D cycle. Results: Among patients with la/mUC, we identified 416 EV users (mean [SD] age 71 [9] years, 27.4% female, 24.8% non-white, 70.2% prior smokers, 17.5% ECOG 2+, 81.5% from community sites). EV use, dose intensity, and adherence are shown (table). Most were cisplatin-ineligible (55%). Average dosing frequency (2.4 [0.5] treatments per cycle) and dose (1.1 [0.2] mg/kg) were lower than label indication guidelines; 58.8% received > 2 treatments per 28D cycle. Conclusions: Among la/mUC patients treated with EV in contemporary practice, treatment frequency and dosing were lower than recommended in the product labelling. Further research is required to understand clinical factors and outcomes associated with the differences observed. [Table: see text]
Identification of biomarkers for early progression in muscle invasive bladder cancer (MIBC) using real-world data.
Authors: Singh Neeraj , George Rohini , Agrawal Smita 
Published: June 2023

e16568 Background: MIBC accounts for ~25% of all newly diagnosed bladder cancers and is associated with a high rate of recurrence despite radical treatment. The time to progression (TTP) can vary significantly between patients and can affect their prognosis. We leveraged a real world clinico-genomics database to classify patients as early vs late progressors, understand its impact on their outcomes and identify genetic drivers of early progression. Methods: This retrospective study was executed using the deeply curated ConcertAI Genome360 bladder cancer dataset. Only patients with confirmed MIBC status with reported tumor progression after initial treatment were considered. Based on the distribution of TTP from MIBC diagnosis of this patient cohort, we subdivided the patients into early vs late progressors. Overall survival (OS) and progression free survival (PFS) analyses were performed between these 2 cohorts. The underlying deleterious genomic mutations were identified in each cohort and differential genomic enrichment analysis was performed to identify statistically significant biomarkers correlated with early progression (p-value < = 0.05). Additionally, identified biomarkers were analyzed in the context of administered therapies. Results: The TTP exhibited a bimodal distribution with a break at around 500 days, so we chose this as the cut-off to define early (N = 203) vs late progressors (N = 51). As expected, there was a significant difference in the median PFS of early vs late progressors (0.62 vs 2.41 years (p < 1e-6)). The OS was also significantly different (1.98 vs 4.36 years (p = 6e-6)). We further identified mutations in 6 biomarkers which were enriched in early vs late progressors. These were CDK12 (p = 0.05), EGFR (p = 0.034), LRP1B (p = 0.05), MET (p = 0.045), PTEN (p = 0.026) and SMAD4 (p = 0.047). These patients were primarily treated with platinum-based therapies +/- gemcitabine/PD-L1 therapies in-line with MIBC treatment guidelines. The identified driver genes activate PI3K-AKT-MTOR, JAK-STAT3, b-catenin and ERK pathways which are known to interfere with the mechanism of action of platinum-based therapies, thus potentially forming the basis of early progression. Conclusions: Using our Genome360 bladder dataset, we have identified prognostic biomarkers for early progression in MIBC. This may provide clinicians with a tool to identify and modify treatment for a subset of MIBC patients who are at risk of early progression on standard of care therapies.
Effects of treatment and patterns of metastases in upper tract and bladder urothelial cancer and non-urothelial cancer based on the national cancer database (NCDB) analysis.
Authors: Yu Eun-mi , Wang Hongkun , Aragon-Ching Jeanny B. 
Published: June 2023

e16571 Background: Upper tract Urothelial cancer (UTUC) and bladder urothelial and non-urothelial cancers can have varying patterns of metastases and response to treatment. Given worse response of visceral metastases to current immune checkpoint inhibitors (ICI) and worse outcomes of non-urothelial cancers, understanding the incidence, characteristics and survival for different metastatic presentation would be informative. Methods: The primary objective is to describe characteristics, treatment patterns, evaluate trends and differences in metastatic presentation and survival according to NCDB between upper tract urothelial cancers (UTUC) versus non-urothelial (nUTUC) histologies (squamous, sarcomatoid, small cell or neuroendocrine, adenocarcinoma) and bladder urothelial cancer (UC) and bladder non-urothelial cancer (nUC). Results: Extraction of data from diagnosis between year 2004 – 2017 from the NCDB was performed. A total of 649939 cases of whom UC = 630423 and nUC = 19516 for both bladder and upper tract cancers, respectively, were identified. Median age was 71.4 years (UC) and 70.1 years (nUC), with majority made up of men (62% of UTUC and 75% of bladder UC). Stage distribution at diagnosis was higher in nUC with Stage III at 1711 (8.8%, nUC) compared to 15725 (2.5%, UC) and Stage IV the nUC group (21.9%) compared to UC at 4.6%. Overall survival (OS) was worse with nUC for stage IV cancers with median OS (mOS) of 6.14 mos (95% CI 5.78-6.47) for nUC vs 7.92 mos (95% CI 7.75-8.08) for UC; logrank p < 0.001. Metastatic sites evaluated included bone, brain, liver, lung, and distant lymph nodes. mOS of Patients with visceral metastatic sites of disease are as follows: distant lymph nodes: UC: 7.59 mos (95% CI 6.6- 8.8); nUC: 5.62 mos (95% CI 4.1-7); log-rank p = 0.0372; liver: UC: 3.5 mos (95% CI 2.89-4.1); nUC: 4.1 mos (95% CI 2.6-6.83); p = 0.1874; lung: UC: 5.7 mos (95% CI 5.09-6.37); nUC: 4.27 mos (95% CI 2.99-6.74); p = 0.1567; Brain: UC: 3.06 mos (95% CI 2.1-4.24); nUC: 2.34 (95% CI 1.1-5.3), p = 0.5464. Use of chemotherapy resulted in improved OS in the UC group with mOS of 73.53 mos (95% CI 72.61-74.41) compared to nUC at 17.28 mos (95% CI 16.59-17.87), p < 0.0001 and use of ICI similarly yielded improvement in the UC group with mOS of 115.98 mos (95% CI 114.33-117.65) compared to nUC at 64.49 mos (95% CI 45.67-88.51); p < 0.0001 although radiation therapy resulted in less profound treatment effect with UC at 16.39 mos (95% CI 16.07-16.69) and nUC: 13.01 (95% CI 12.32-13.63); p < 0.0001. Conclusions: While treatment using chemotherapy and ICI has led to improvement in OS in higher stages of disease, patterns of metastases reveals visceral presentation portends a poor prognosis in both urothelial and non-urothelial cancers with slightly better mOS in those with distant lymph nodes as main presentation of metastases.
CDH12 and the development of the neuronal subtype in MIBC.
Authors: Chen Xingyu , Basu Mukta , Knott Simon , Theodorescu Dan 
Published: June 2023

e16579 Background: We discovered a novel cell epithelial cell population we termed “C3” in muscle-invasive bladder cancer (MIBC) that is negatively prognostic for surgery and chemotherapy. This cell population shares similarities with the neuronal subtype MIBC (NEBC) which has limited treatment options and is driven by unclear molecular mechanisms. The objective of the study was to determine if NEBC is driven by some of the genes that are overexpressed in C3 cells. A top overexpressed and C3 cell specific gene that is also enriched in normal neuronal tissue is Cadherin 12 (N-Cadherin 2, CDH12). Hence, we initiated a study of this gene. Methods: We overexpressed CDH12 in two murine MIBC cell lines (NA13 and MB49) and then inoculated them into mice. Tumor growth kinetics were studied, and single-nucleus RNA sequencing (snRNA-seq) and bulk RNA sequencing were then used to evaluate the tumors. Tissue samples from patients with MIBC were also analyzed using snRNA-seq and Co-detection by Indexing (CODEX) multiplexed immunofluorescence, and our bioinformatics analysis combined transcriptomic profiles from > 2000 MIBC samples from published datasets, to characterize the transcriptional programs induced by enforcing CDH12 expression. Results:Enforced expression of CDH12 led to enhanced tumor growth and the appearance of the neuroendocrine tumor phenotype. NEBC from human samples showed the highest expression of CDH12, and snRNA-seq results showed that NEBC also has the highest proportion of CDH12 epithelial cells and demonstrated co-expression of CDH12 and neuronal markers (NCAM1, CHGA, and SYP). RNA velocity analysis in murine and human tumors implicated CDH12 as a driver for the development of the neuronal subtype. Conclusions: To our knowledge, this study provides the first identification of a genetic driver leading to NEBC and implicates a novel gene, CDH12 in this process.
Prediction of 6-year risk of bladder cancer using the HUNT Lung Cancer Risk Model in ever-smokers: A HUNT study.
Authors: Røe Oluf D. , Nguyen Olav Toai Duc , Fotopoulos Yannis , Lagani Vincenzo , Tsamardinos Ioannis 
Published: June 2023

e16581 Background: Bladder cancer is the 6th most common cancer in men and 17th most common cancer in women and the mortality is high when detected in advanced stage. Previous or current cigarette smoke is the main risk factor. There is no screening program for bladder cancer. Given the pathophysiological similarity with lung cancer, we postulated that a lung cancer risk model could work for bladder cancer. The validated HUNT Lung Cancer Risk Model (HUNT LCM) predicts lung cancer in 6 years with an area under the ROC curve (AUC) of 0.87. Here we aimed to test the performance of the HUNT LCM in the prospective HUNT2 cohort for a 6-year prediction of bladder cancer. Methods: The HUNT2 cohort from Norway, a prospective population study of 65 200 individuals 19-100 years of age, was followed up for a median of 15 years. This population was linked with the Norwegian Cancer Registry and all cases diagnosed with bladder cancer were registered. The HUNT Lung Cancer Model was used to predict risk of bladder cancer within 6 years. Results: In the HUNT2 cohort 38 846 ever-smokers were identified. 82.6% of those developing bladder cancer were ever-smokers. 31 269 had all the variables needed for the model and of those, 191 developed bladder cancer in six years. The HUNT Lung Cancer Model prediction of bladder cancer in 6 years AUC was 0.751. Conclusions: To our knowledge, this is the first time a lung cancer risk prediction model has been applied to predict bladder cancer. The performance of the model is lower than for lung cancer but still has a good performance. This may open a path for screening and early detection of bladder cancer.