bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidemiology of cholangiocarcinoma in Florida, and differences in risk factors between intra- and extra-hepatic cholangiocarcinoma.
Authors: Pinheiro Paulo S. , Cranford Hannah M. , Liu Qinran , Jones Patricia Denise 
Published: June 2023

e16329 Background: Albeit rare, cholangiocarcinoma (CC) is a poorly understood, highly fatal cancer with an incidence rate of less than 2.5 per 100,000 people. For most cases of CC, causes are not known. Here, we use population-based data from the diverse state of Florida to study the most recent incidence rates and trends for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and measure the prevalence of potential risk factors and preexisting conditions associated with liver cancer including biliary conditions, diabetes, obesity and dyslipidemia, hypertension, smoking, chronic hepatitis C (HCV) and hepatitis B (HBV) infections, alcohol-related disease, and auto-immunes diseases. Methods: We used the Florida Cancer Registry Data on all cases of cholangiocarcinoma (N = 5,096) diagnosed during 2010–2018 (2,930 intra-hepatic, 2,166 extra-hepatic). Data were linked with two other data sources: the Agency for Healthcare Administration and the Department of Viral Hepatitis. Age-adjusted rates by sex were computed, incidence trends using Joinpoint regression and 5-year age-adjusted survival, using lifetable methods, were estimated. Differences in prevalence of risk factors were tested using chi-square tests. Results: Both ICC rates, 1.7 (per 100,000) for males and 1.3 for females, and ECC rates, 1.0 in males and 0.7 in females are relatively low. ICC is currently the fastest increasing cancer at a rate of +7.2% per year in males and +6.5% in females, while ECC trends remain stable. The 5-year survival was 11.0% for ICC (95%CI: 9.2-12.8) and 12.9% (95%CI: 10.5-15.3) for ECC. Overall, conditions such as diabetes type 2 (29%), obesity and dyslipidemia (41%), and hypertension (61%) were highly but equally prevalent in both ICC and ECC. The presence of non-alcohol related cirrhosis (6.0% vs 2.8% for ICC and ECC, respectively), chronic HCV infection (6.6%, 2.0%), and smoking (52.7%, 48.5%) were significantly more prevalent in ICC, while cholangitis of any type (13.5%,26.0%), chronic pancreatitis, auto-immune diseases (all. Conclusions: Currently, ICC is the most rapidly increasing cancer in the US; though, the extent to which better recognition of ICC plays a role in this trend is unknown. ICC and ECC show similarities, but also, differences in the prevalence of specific risk factors and preexisting conditions. The commonly held perception that the increase in metabolic causes (diabetes and obesity), similarly present in both ICC and ECC, are responsible for the current trends is partially challenged by the stable trends in ECC. Given its dismal prognosis, cholangiocarcinoma, especially ICC, requires further research. Funding: This work was supported by Bankhead Coley Grant #20B16 from the Biomedical Research Program of the Department of Health State of Florida.
Gastrointestinal cancer trends in the Hispanic population: A SEER database population study (2000-2019).
Authors: Hechter Sharon , Nikiforov Ivan , Greenberg David B. 
Published: June 2023

e16331 Background: Cancer continues to be the leading cause of death in the Hispanic population. Gastrointestinal cancer surveillance data in Hispanic individuals has only recently become available in the last 3 decades. Differences in incidence rates among Hispanics and Non-Hispanic Whites (NHWs) need further elucidation. In this study, we analyzed trends in Hispanics and NHW populations across multiple gastrointestinal cancers. Methods: Gastrointestinal cancers (liver, colon and rectum, pancreas, esophagus, gallbladder, stomach, small intestine, anus, anal canal and anorectum) diagnosed between 2000-2019 were identified in the Surveillance, Epidemiology, and End Results Program (SEER) Database. We calculated incidence rates, confidence intervals and incidence rate ratios. Rates are per 100,000 and age adjusted to the 2000 US standard population. Rate ratios are the rounded rates in Hispanic individuals divided by the rounded rates in NHWs. Results: There was a higher incidence of liver, gallbladder, and stomach cancers among Hispanics when compared to NHWs between the years 2000-2019. Liver cancer incidence rate is (11.5 per 100,000) in Hispanics compared with (6.3 per 100, 000) in NHWs with an incidence rate ratio of 1.8. Gallbladder cancer incidence rate is (2.2 per 100,000) in Hispanics compared with (0.9 per 100,000) in NHWs with an incidence rate ratio of 2.4. Stomach cancer is (10.9 per 100,000) in Hispanics compared with (5.7 per 100,000) in NHWs with an incidence rate ratio of 1.9. The lowest incidence rate ratio was seen for anus, anal canal and anorectum cancers in Hispanics compared to NHWs. The incidence rate is (1.2 per 100,000) in Hispanics compared with (2.1 per 100,000) in NHWs with an incidence rate ratio of 0.6. Remaining cancers had incidence rate ratios less than 1.0 and were more likely to occur in NHWs. Conclusions: This study illustrates differing incidence rates of multiple gastrointestinal cancers among Hispanics compared to NHWs. Liver, gallbladder and stomach cancer incidence rates in Hispanics is double that of NHWs. Interestingly, the remaining gastrointestinal cancers had higher incidence rates among NHWs. Further research is warranted to understand the differences in cancer risk within the Hispanic population as well as healthcare access, language barriers and cultural differences that may play a role. [Table: see text]
The impact of ImmunoPrecision in small bowel adenocarcinoma.
Authors: Chiu Vi Kien , Belmonte Jessica , Osman Diaa , Gong Jun , Hendifar Andrew Eugene , Osipov Arsen , Lou Emil , Ziyeh Sharvina , Zaghiyan Karen , Nissen Nicholas 
Published: June 2023

e16333 Background: Although approaches to treating adenoCA of the small bowel (SBA) are extrapolated from those of the colon, SBA has distinct pathogenesis, clinical presentation and poorer prognosis. We examine the impact of SBA treatment by ImmunoPrecision, which combines Immunotherapy and Precision genomic targeting. Methods: SBA pts were identified retrospectively from Cedars-Sinai electronic health record (2000 – 2022) on an IRB-approved protocol. Microsatellite status and genomic testing were done in CLIA-certified, CAP-accredited labs. Pt characteristics, pathology, in-depth clinical history and genomics were summarized with descriptive statistics. Endpoint of median OS was estimated by Kaplan-Meier and calculated from pre-treatment imaging to last event. Treatment groups were compared using log-rank test. Results: Between Jan 2003 – Dec 2022, 137 stage 1 – 4 SBA pts (93 duodenal; 44 jejunal/ileal) were identified. Median age was 67 (range 22 – 95). Microsatellite status and genomic testing data were done or known for 72 pts (53%). In 35 pts who had metastases at initial presentation, 15 pts had NGS genomics, which identified actionable targets: 20% Her2amp/mut, 13% FGFR1amp/mut, 7% ALKfusion, 7% KRAS G12C, and 7% ATM R35*. 40% of 10 metastatic pts tested for microsatellite status were MSI/TMB-High, and only 1 pt received immunotherapy. In pts with metastases, median OS was 9.5 mo in duodenal adenoCA (51 pts) vs 13.0 mo in jejunal/ileum adenoCA (23 pts) (p = 0.46). There was a non-significant improvement in median OS to 20.5 mo in metastatic duodenal adenoCA pts who received targeted inhibition of actionable genomics or had MSI/TMB-High status (p = .51). Conclusions: Our real-world cohort of metastatic duodenal adenoCA shows a trend toward improved median OS from ImmunoPrecision targeting of frequent MSI/TMB-High status and actionable genomics. ImmunoPrecision clinical trial investigation is warranted in this rare SBA population. [Table: see text]
Single-cell analysis of CD8+ T-cells by sex in renal cell carcinoma.
Authors: Kang Ning 
Published: June 2023

e16501 Background: Although sex bias has been reported in the development and progression of renal cell carcinoma (RCC), the underlying mechanisms remain enigmatic. Here, we investigated the sex differences in the tumor microenvironment (TME) of RCC patients and explored a promising combination drug regimen to enhance the efficacy of immunotherapy. Methods: Single-cell RNA sequencing (scRNA-seq) data from four published datasets were analyzed to investigate the sex differences in RCC patients, and tumor tissues were collected to validate the sex differences using multiplex immunofluorescence (MxIF) and flow cytometry (FCM). The function of the androgen-androgen receptor axis in sex differences was explored in vivo and in vitro experiments. Results: By analyzing the scRNA-seq data of 220,156 cells and MxIF and FCM assays, we found that CD8+ T-cells infiltrated highly in the TME of male RCC, but mainly presented an exhausted and dysfunctional state. In vitro and in vivo experiments indicated that the dysfunction and exhaustion of CD8+ T-cells in male TME were induced by androgen. Clinically, higher serum androgen was significantly associated with a worse prognosis in male RCC patients receiving immunotherapy. Androgen receptor inhibitors could activate tumor-infiltrating CD8+ T-cells and enhance the efficacy of immunotherapy of RCC in vivo. Conclusions: We delineated the difference in TME between male and female patients with RCC, and demonstrated that the androgen-androgen receptor axis plays an important role in immunosuppression in male RCC. Clinically, androgen receptor inhibitors plus immunotherapy can be a promising combination regimen in RCC patients.
Detection of progression and regression of genitourinary cancers by circulating tumor DNA (ctDNA).
Authors: Karki Ujjwal , Ghimire Bipin , Herrman Emma , Chisti Mohammad Muhsin 
Published: June 2023

e16508 Background: Circulating tumor DNA (ctDNA) are short DNA sequences shed by tumor cells into systemic circulation. The sensitivity and specificity of single ctDNA test to predict relapse or recurrence in solid tumor vary widely and the utility of monitoring serial ctDNA trends has not been well-described in genitourinary cancers. Methods: We conducted a retrospective study including adult patients with genitourinary cancers at the hematology-oncology clinic at William Beaumont - Royal Oak and Troy Hospitals, Michigan from, August 2021 to May 2022, who had ctDNA testing done with imaging available for comparison. We evaluated the correlation between ctDNA test, both single test as well as dynamic trends in value over time, with imaging findings. We also calculated lead time for uptrending ctDNA to detect disease progression compared to imaging. Results: 21 total ctDNA test results from eight patient were included in the study; five had renal cell cancer, two had urothelial cancer and one had prostate cancer. The median age at diagnosis was 62 years (Range: 45-82); 90% were Caucasian and 50% were female. Majority (87.5%) had Stage III or IV disease. Out of the 21 total ctDNA samples, all 16 positive ctDNA results had evidence of disease on corresponding imaging: 13 showed progression while 3 showed regression with residual disease compared to prior imaging. Of the 5 negative ctDNA test results, 2 showed no evidence of disease and 3 showed regression with residual disease on corresponding imaging. Sensitivity and specificity of a single positive ctDNA test to detect evidence of disease on imaging was 84.2% and 100%, respectively. Six patients had multiple ctDNA test results with 12 pairs of serial ctDNA values, of which 9 were up-trending, and 3 were down-trending. Both sensitivity and specificity of up-trending ctDNA values to detect progression and down-trending ctDNA values to detect regression on imaging were 100%. Uptrending ctDNA values predicted disease progression with a median lead time of 55.5 days compared to imaging. Conclusions: Given the high sensitivity and specificity of serial ctDNA monitoring to detect disease progression and regression in our study, we conclude that this may be a valid way to reliably monitor for changes in disease status in genitourinary cancers before they become evident on imaging studies. Further clinical studies are needed to prove its utility in detecting immediate changes in disease status and guide therapeutic intervention in genitourinary cancers. [Table: see text] [Table: see text]
Nivolumab as second-line treatment of patients with metastatic renal cell carcinoma with high or normal fibrinogen levels: A prospective, cohort study.
Authors: Tsimafeyeu Ilya , Volkova Maria , Utyashev Igor A. , Gerk Ivan , Zakurdaeva Kristina 
Published: June 2023

e16510 Background: In a number of coagulation-related studies, elevated fibrinogen levels were found in patients with renal cell carcinoma (RCC) and correlated with more advanced disease. The impact of hyperfibrinogenemia on the clinical outcomes of immunotherapy remains uncertain. Methods: In this prospective cohort study, fibrinogen levels were measured one week prior to the second-line nivolumab therapy (240 mg or 480 mg every 2 or 4 weeks) and then monthly until disease progression or unacceptable toxicity. High fibrinogen level was defined as ≤5 g/L. Key eligibility criteria included metastatic clear cell RCC resistant to the first-line targeted therapy, ≤3 MSKCC risk factors, ECOG PS 0-2, platelet count <400×10(9)/L, no heart diseases, no anticoagulation therapy, and age 40-65 years. The primary endpoint was overall survival (OS) in cohorts with high (H) and normal (N) fibrinogen levels. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and fibrinogen levels during therapy. Results: Between November 2018 and January 2021, 82 patients were enrolled, of whom 41 and 41, respectively, were recruited in H and N cohorts. The groups were well balanced at baseline. The median follow-up time was 32.4 months. Compared to patients in N cohort, patients in H cohort had shorter OS (P=0.001), shorter PFS (P<0.01), and lower ORR (P=0.012). In H cohort, a below-median fibrinogen level was associated with longer observed OS (median, 23.7 vs. 19.4 months; P=0.03). In N cohort, 6 (15%) patients with stable disease had an increase in fibrinogen levels during nivolumab therapy. Patient characteristics and clinical outcomes are summarized. Conclusions: High fibrinogen levels affect the clinical outcomes in patients with metastatic renal cell carcinoma treated with second-line nivolumab. These findings require large-scale prospective validation. Clinical trial information: KCRB0181209 . [Table: see text]
Uncovering LAG-3 related tumor immunology in renal cell carcinoma and pan-cancer evaluation.
Authors: Takamatsu Kimiharu , Tanaka Nobuyuki , Matsumoto Kazuhiro , Kosaka Takeo , Mizuno Ryuichi , Oya Mototsugu 
Published: June 2023

e16517 Background: LAG-3 (lymphocyte activation gene 3) is of interest as a target molecule for next-generation immune checkpoint inhibitors in several solid tumors, including renal cell carcinoma (RCC). The aim of this study is uncovering the tumor immune microenvironment (TIME) of the LAG-3-dominant RCC. Methods: Firstly, we performed an automated single-cell count for immunolabelled LAG-3, TIM-3 and TIGIT and TIME evaluation panel molecules (CD3, CD8, CD39, PD1, PDL1, Ctla4, CD68, CD163, CD47, Ki67, CD73, IDO1, GLUT1, CD34 and D2-40) to 105 primary ccRCC tumor samples and created the new classification model. The TIME and clinical value of LAG-3-dominant RCC were evaluated. Secondly, The TIME features of LAG-3 dominant RCC in metastatic sites was evaluated in 47 metastatic samples. Lastly, mRNA seq data from the public cohort and clinical trial data (RCC, n = 1144, other solid cancers, n = 3691) was analyzed with the digital cytometry and evaluated whether the TIME features of LAG-3 dominant RCC are RCC-specific or applicable to other solid tumors. Results: In our cohort and our validated cohort (n = 96), the LAG-3 group had significantly shorter OS (p = 0.037 and p = 0.003). The LAG-3 high expression RCC also showed shorter OS in the TCGA RCC cohort (p = 0.016). As the result of TIME evaluation, LAG-3 dominant RCCs had statistically high level of CD8, high CD39+CD8+, and high M2 macrophages. In metastasis samples, LAG-3 dominant RCCs preserved high level of CD8, high CD39+CD8+. In public mRNA seq analysis, LAG-3 dominant RCCs showed high level of CD8, high CD8+Tregs and high M2 macrophages. High Tregs in LAG-3 dominant tumor were seen in melanoma, HCC and prostate cancer. High M2 macrophage TIME in LAG-3 dominant tumor was unique to RCC, not seen in other solid cancer. Conclusions: LAG-3 dominant RCC had poor prognosis and could exhibit a unique, immunosuppressive TIME.
Outcomes and safety of subsequent treatments after immune- and anti-VEGF therapy in patients with metastatic clear-cell renal cell carcinoma: Outcomes from a tertiary referral hospital.
Authors: Tapia Jose Carlos , Toms Charlotte , Wang Yishen , Jovaisaite Agne , Young Matthew Nicholas , Jackson-Spence Francesca , Powles Thomas , Szabados Bernadett 
Published: June 2023

e16533 Background: Immune checkpoint inhibitors (ICIs) and anti-VEGFs, either in combination or sequentially, are the standard of care in first- and second-line (2L) setting for metastatic clear-cell renal cell carcinoma (mRCC); however, there is uncertainty about the subsequent lines. We describe real-world outcomes and safety of using anti-VEGFs such as cabozantinib (CABO), axitinib (AXI), and sunitinib (SUN) after ICIs and anti-VEGF therapies in patients (pts) with mRCC. Methods: A retrospective audit was performed on pts with mRCC treated between June 2014 and June 2022 at the St Bartholomew’s Hospital, London, UK. Baseline patient and treatment characteristics, best response, dose modifications and survival outcomes were collected. Kaplan-Meier methods were used to evaluate the progression-free survival (PFS) and overall survival (OS). Results: Overall, 188 pts with mRCC were treated. We analysed 69 pts of whom 45 (65%), 16 (23%) and 8 (12%) pts received CABO, AXI, and SUN, respectively, as subsequent treatment after prior ICIs and anti-VEG. Baseline characteristics are described. Median follow-up was 36 months (95% CI: 31.6 - 55.3). Overall, the partial response (PR) and stable disease (SD) rates were 9% and 45%, respectively. Eleven percent, 12% and 0% pts achieved PR and 53%, 25% and 31% achieved SD on CABO, SUN and AXI, respectively. In general, the median PFS was 9.9 months (95% CI: 6.5-14.2) and the median OS was 16.5 months (95% CI: 11.6-23.5). One-year PFS and 1-year OS was 36% and 51%, respectively. PFS and OS by treatment are reported. The number of pts who experienced toxicities that required dose reductions was higher with CABO (58%) and SUN (37%) than with AXI (6%). The median time to dose reduction was 2.4, 1.4, and 1.4 months for CABO, SUN and AXI. Conclusions: In our centre, CABO was the most common subsequent treatment after previous ICIs and anti-VEGF. Taking into account the retrospective and single-centre nature of the collected data these results support the activity of CABO, AXI and SUN in this setting. AXI was well tolerated with less dose modifications. [Table: see text]
Efficacy of subsequent immunotherapy-tyrosine kinase inhibitor combinations after TKI monotherapy failure in patients with intermediate/poor risk metastatic clear cell renal cell carcinoma: A real-world retrospective study.
Authors: Wu Jie , Qu Wang , Hu Linjun , Zhou Aiping , Shou Jianzhong 
Published: June 2023

e16537 Background: The randomized phase 3 trials KEYNOTE-426, CheckMate 9ER, and CLEAR have demonstrated the efficiency of immunotherapy-based drug combinations as first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC). Immunotherapy-tyrosine kinase inhibitor (IO-TKI) has shown significant benefits over sunitinib monotherapy with respect to overall survival in mccRCC patients with intermediate/poor international metastatic database consortium (IMDC risk group). However, most of the patients received second-line TKI or immune checkpoint inhibitors therapy after TKI monotherapy failure in those clinical trials. The role of IO-TKI after disease progression in sunitinib monotherapy cohort was not fully investigated. We sought to evaluate the efficacy of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk who had previously received at least one line of TKI monotherapy. Methods: We conducted retrospective analysis of IMDC intermediate/poor risk mccRCC patients treated with IO-TKI during any treatment line at our center from June 2019 to April 2022. Demographic, clinicopathological, and systemic therapy data were collected. The primary end point was overall survival (OS), defined as the time from initiation of treatment to death from any cause or last follow-up. The secondary end point was progression-free survival (PFS), defined as the time to the first documented disease progression. Results: Overall, 81 IMDC intermediate/poor risk mccRCC patients were enrolled, with a median follow-up of 17 months. 49 patients received first-line IO-TKI therapy, 32 patients who had previously received at least one line of TKI monotherapy received second-line IO-TKI after disease progression. The objective response rate (ORR) and median PFS of second-line IO-TKI after TKI monotherapy failure was 28.6% and 9 months, respectively. OS between first-line IO-TKI therapy and second-line IO-TKI after TKI monotherapy failure was not statistic significant (30 months vs. 26 months, p = 0.630). Conclusions: In this real-world retrospective study, we observed antitumor activity of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk after disease progression. Notably, first-line IO-TKI therapy did not have superior OS when TKI monotherapy patients received second-line IO-TKI therapy. Randomized trials are needed to evaluate optimal combination strategies and sequencing of therapies in mccRCC.
Urine-based epigenetic profiling for detection of clear cell renal cell carcinoma: A prospective study.
Authors: Kong Wen , Zhang Jin , Dong Hang , Tang Haoran , Du Pan , Jia Shidong 
Published: June 2023

e16545 Background: Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that poses a significant challenge in early detection and differentiation from other subtypes in clinical practice. Liquid biopsy using epigenomic signatures represents a potential solution for non-invasive cancer detection and disease surveillance. Methods: In this prospective study, aiming to collect matched tissue-plasma-urine samples from 200 ccRCC patients and 50 non-tumor donors, we enrolled 14 patients with ccRCC and 10 patients with benign kidney lesions. Matched samples (tissue, blood, and urine) were collected and analyzed using the DNA methylation assay, PredicineEPIC. An in-house developed bioinformatics algorithm was used to investigate the genome-wide epigenomic profiles, and a machine-learning model was built for tumor prediction based on tumor-specific methylation patterns. Further enrollment is ongoing. Results: In the exploratory cohort, tissue-based differential methylated regions (DMRs) profiling differentiated tumors from normal renal tissues with high accuracy. The ccRCC-specific methylation patterns were constructed with 637 optimized methylation features, and the machine learning classifier was trained. The prediction efficacy was tested in a larger-scale TCGA-KIRC dataset, which demonstrated high sensitivity and specificity (AUC = 0.985). Compared with the use of blood, urinary cell-free DNA-based methylation profiling allowed for the differentiation of ccRCC patients from healthy controls and patients with benign kidney lesions. Conclusions: The current preliminary study demonstrates the technical feasibility of urine-based methylation study in the identification of patients with ccRCC. Our findings highlight the potential of urine-based methylation profiling in kidney cancer detection and disease surveillance.