bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of adrenergic receptor antagonists on clinical outcomes in metastatic renal cell carcinoma.
Authors: Ganta Teja , Tsao Che-Kai 
Published: June 2022

e16520 Background: Adrenergic receptors (ADR) have a well-established role in kidney physiology, suggesting a possible role of ADR signaling in renal cell carcinoma (RCC). Preclinical studies have shown a possible anti-tumor effect of both alpha-adrenergic blockers (AB) and beta-adrenergic blockers (BB) on renal cancer cells. However, the literature is conflicting regarding the effect on clinical outcomes. In addition, there is no comprehensive analysis of what role these medications have specifically in RCC patients with metastatic disease. In this single health system retrospective study, we evaluate the effect of AB or BB prescription on cancer-specific outcomes in patients with metastatic RCC. Methods: Clinical data was abstracted from the electronic health record and the institutional cancer registry at The Mount Sinai Health System to include patients with RCC diagnosed with metastatic disease ( de novo or relapsed) between 2016-2020. Follow up data was recorded until a data lock of 4/1/2021. Multivariate Cox regression was used to evaluate the association of AB and BB prescription on overall survival (OS) for the entire cohort and progression free survival (PFS) for patients who received any first line therapy. Multivariate logistic regression was used to evaluate association of these medications with overall response rate (ORR) of first line therapies with available data on initial response. Analyses were controlled for clinical risk factors including age at diagnosis, sex, race, treatment plan including immunotherapy, and medical history of benign prostatic hyperplasia, hypertension, or heart failure. Data was analyzed using R version 4.1.0. Results: 133 patients were identified for inclusion in the study. 61% of cases are de novo metastatic and 39% are relapsed from previously resected disease. 71% are clear cell histology, 3.8 % are papillary, and the rest are unspecified/other. 84 patients (63%) received at least a 1st line systemic therapy. AB or BB prescription alone is not associated with OS, PFS, or ORR. However, prescription of both AB and BB is associated with worse OS (HR 2.94 95% CI 1.13-7.68), worse PFS (HR 7.70 95% CI 1.80-33.0), and decreased odds of responding to 1st line therapy (OR 0.06 95% CI 0.00-0.55) on multivariate analysis. Conclusions: The data suggests that the concurrent use of both an AB and BB in patients with metastatic RCC leads to worse clinical outcomes. What remains unclear is if there is a negative synergistic effect of these medications on RCC pathophysiology or if the prescription of these medications is associated with another negative confounding clinical factor. Since these medications are commonly utilized for cardiovascular disease, multivariate analyses attempted to control for these comorbidities. Future studies may add to this data by cataloging the severity of heart failure and doses of AB and BB medications used in a RCC cohort.
Fumarate hydratase-deficient renal cell carcinoma: The real-world experience at Dana-Farber Cancer Institute and Moores Cancer Center.
Authors: Saliby Renee Maria , Labaki Chris , Xie Wanling , Nonato Taylor , Schmidt Andrew Lachlan , Bakouny Ziad , Xu Wenxin , Ravi Praful , Braun David A. , Hirsch Michelle S. , McKay Rana R. , Choueiri Toni K. , McGregor Bradley Alexander 
Published: June 2022

e16522 Background: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare and aggressive tumor with limited clinical trials dedicated to therapeutics for this disease. This retrospective study aimed to report a multi-center experience in the systemic treatment of FH-deficient RCC. Methods: The medical records of patients undergoing systemic therapy for advanced or metastatic FH-deficient RCC at Dana-Farber Cancer Institute and Moores Cancer Center were reviewed from 2012 to 2021. Demographic, histologic, molecular, and survival parameters were collected. Response was assessed using RECIST 1.1 criteria. A confirmative initial diagnosis of FH-RCC was made utilizing FH/2SC immunohistochemistry (n = 12) and/or the presence of an FH mutation (n = 6). The primary endpoint of this study was to characterize patients with FH-deficient RCC in the modern era. Results: 18 patients were included; median age at diagnosis was 45 (interquartile range [IQR]: 40-55) years. All patients had a Karnofsky Performance Status (KPS) ≥ 80. Among 14 patients with evaluable IMDC criteria, 1 (7.4%) had favorable-risk disease, while 10 (71.4%) and 3 (21.4%) had intermediate- and poor-risk disease, respectively. Tumors at diagnosis were stage III (n = 6, 33.3%), and IV (n = 12, 66.7%). Median time from diagnosis to the start of systemic therapy was 2.8 months. Six types of regimens were given as first-line therapy (Table). Fourteen patients (78%) developed disease progression on frontline therapy and received subsequent therapy; two patients, initially treated with an mTOR inhibitor and combined vascular endothelial growth factor (VEGF) inhibitor and immune checkpoint inhibitor (ICI), are off therapy and still under surveillance with no recurrence to date; one patient passed away while on frontline therapy; and one patient has limited follow-up. For a median follow-up of 22 months (IQR:6.4-49), the 18-month-overall survival estimate was 81% (95% confidence interval [CI]: 53%-94%) and median progression-free survival (PFS) was 6.7 months (95%CI: 5.0-17.0). Conclusions: This study shows considerable heterogeneity in the treatment for FH deficient-RCC, with disparate clinical outcomes. Dedicated trials and guidelines on the management of FH-deficient RCC are needed.[Table: see text]
Clinical effectiveness of second-line TKI plus PD-1 following targeted therapy in patients with metastatic non-clear cell renal cell carcinoma: A real-world study.
Authors: Wang Jun , Zhang Zhiling , Wei Wensu , Li Zhiyong , Han Hui , Guo Shengjie , Li Zhiyong , Dong Pei 
Published: June 2022

e16523 Background: Non-clear cell renal carcinoma (nccRCC) usually had a poorer response to tyrosine kinase inhibitors (TKIs) due to its heterogeneity and rarity. The combination of immunotherapy with TKIs has shown promising efficacy in ccRCC. However, for nccRCC failed standard first-line TKI therapy, the second-line option is still limited. This real-world study aimed to evaluate the efficacy of immune-targeted combination therapy versus TKI monotherapy as the second-line regimen in patients with metastatic nccRCC who failed first-line TKI therapy. Methods: Demographic and clinicopathological data of patients with metastatic nccRCC who were admitted into the Sun Yat-sen University Cancer Center between October, 2011 and September, 2020 were retrospectively collected. All patients failed in first-line TKI therapy and received second-line TKI alone (TKI group) or TKI plus PD-1 therapy (combination group). Efficacy including the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) was calculated. The differences on baseline characteristics and efficacy between the two groups were compared. Results: Totally 67 patients were included, with a median age of 50 (interquartile 37-60) years. The median follow-up time was 32.7 (interquartile 21.6-53.0) months. The overall ORR, DCR was 37.3% and 56.7%, respectively. The overall second-line PFS was 7.2 (95% CI: 5.8-8.5) months and OS was 53.2 (18.4-88.0) months. Baseline characteristics between the combination group (n = 45) and the TKI group (n = 22) did not differ significantly except that the combination group had more proportion of liver metastasis (20.9% vs 4.5%, P = 0.025). The combination group had a significantly longer PFS compared with the TKI group [median PFS (95% CI): 9.2 (6.4-12.0) vs 5.2 (2.9-7.5) months, P = 0.001]. Similarly, ORR (48.9% vs 13.6, P = 0.005) and DCR (71.1% vs 27.3%, P = 0.001) was remarkably improved in the combination group. The superior efficacy over TKI monotherapy was more prominent in the younger (< 60 years), male, and patients with lower KPS, IMDC intermediate/poor-risk, non-hereditary RCC and multiple metastatic sites. Conclusions: Immune-targeted combination therapy was effective in the treatment of metastatic nccRCC who failed first-line TKIs.[Table: see text]
Exploratory analysis on crosstalk between intra-tumor immunity and FGF/FGFR pathway in clear cell renal cell carcinoma.
Authors: Narisawa Takafumi , Naito Sei , Mitsuda Yoshihide , Oe Rintaro , Sato Hidenori , Kobayashi Chizuru , Fukuda Mizuki , Kitaoka Takumi , Miyano Yuki , Ito Hiromi , Kimura Mizuki , Hamaguchi Makoto , Aoshima Ken , Futakuchi Mitsuru , Tsuchiya Norihiko 
Published: June 2022

e16525 Background: Clear cell renal cell carcinoma (ccRCC) patients classically show good response to VEGFR inhibitors; however, the biological basis by which FGFR inhibition provides tumor response was not well understood. Here, we performed an exploratory analysis of the relationship between the FGF/FGFR pathway and intra-tumor immunity to support the effectiveness of FGFR inhibitors for ccRCC. Methods: We used whole transcriptome data and immunohistochemistry with metastatic clear cell RCC specimens from patients who were treated at the Yamagata University Hospital (n = 57). FFPE samples were prepared from the primary lesions of treatment-naive metastatic ccRCC patients. FFPE was sliced by a pathologist to evaluate the immunological microenvironment. RNA extraction and immunostaining were performed at the same site. Immuno-histological quantification was performed by automatically analysis system HALO in digital whole slide imaging. Hierarchical clustering was performed, and the cohort was divided based on the profile of the FGF and immune cells. We analyzed the cancer-specific survival based on the FGF cluster classification and investigated the relationship between FGF-FGFR expression and immune cell infiltration that were evaluated histologically. Results: RNA transcriptome data showed that FGF2 and FGF7 were widely expressed in ccRCC. Hierarchical cluster analysis based on the FGF expression profile (intrinsic FGFs were excluded) revealed that metastatic ccRCC had three distinct patterns. Cluster1 showed low FGFs expression, except for FGF2 and 7, while Cluster2 and 3 expressed multiple FGFs. Survival analysis showed Cluster2and 3 had a poor cancer-specific survival rate than Cluster1 (Logrank test, p = 0.05). However, no association was detected between the FGF cluster classification and the infiltration of immune cell count in immunohistological analysis. In comparison of the expression of each FGF subfamily and the positive cells of CD4, CD8, CD68 and CD31 (Mann–Whitney U test, p < 0.05), CD4 and CD8 were higher in the cases expressing FGF20. While most FGF subfamilies have been suggested to be less associated with immune cell infiltration (excluding FGF20), further analysis among FGF receptor expression and immune signatures are ongoing. Conclusions: Our study demonstrates the possibility of intra-tumor interaction between FGF/FGFR axis and immune infiltration in ccRCC.
Toxicities of anti-VEGF therapies used in metastatic renal cell carcinoma: A real-world experience.
Authors: Master Samip R. , Findakly Dawood 
Published: June 2022

e16533 Background: Tumor endothelial proliferation inhibition using vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) have revolutionized metastatic renal cell carcinoma (mRCC) therapy. We retrospectively analyzed data on various anti-VEGF adverse events (AEs) utilizing the FDA Adverse Events Reports System (FAERS). Methods: We examined the FAERS public dashboard data on VEGF inhibitors’ reported AEs for the years 2019-2021. Data analyzed using descriptive statistics. Results: A total of 34,651 AEs were identified for anti-VEGF therapies, of which 29,328 (84.6%) were serious and 5,830 (16.82%) reported deaths (Table). Lenvatinib has most reported serious hemorrhagic events and thyroid impairment in 5.5% and 1.2%, respectively, and least (3.4%) reported dermatologic toxicity (including Hand-foot skin reaction, depigmentation, and rash. Cabozantinib has most (2.8%) reported gastrointestinal (GI) perforation and fistula. Pazopanib has most bone marrow suppression (BMS)—neutropenia, leukopenia, thrombocytopenia, and anemia (43.3%), dermatologic toxicity (25.8%), hepatotoxicity—jaundice, elevated transaminases, hyperbilirubinemia, hepatic encephalopathy, coagulopathy, ascites, and/or hepatorenal syndrome (23.9%), arterial thromboembolic events (ATE)—comprising cerebral infarction, ischemic stroke, transient ischemic attack, myocardial infarction, angina (19.8%), proteinuria and nephrotic syndrome (NS; 10.4%), pulmonary toxicity—interstitial lung disease, and pneumonitis (7.2%), posterior reversible encephalopathy syndrome (PRES; 4.9%), cardiotoxicity—cardiac failure (3.1%), and tumor lysis syndrome (TLS; 0.9%). Sunitinib has most reported osteonecrosis of the jaw AEs (ONJ; 37.3%), QT Prolongation and various arrhythmias (11.9%), severe hypertension (SHTN—including accelerated, urgency, and emergency; 10.0%), and aortic complications—including aortic aneurysm, dissection, and rupture (3.1%). Conclusions: Pazopanib has most while axitinib has least reported BMS, ATE, and pulmonary AEs. Cabozantinib has most reported GI AEs and sunitinib has most reported ONJ, SHTN, QT prolongation, arrhythmias, and aortic complications. With expanding treatment landscape for mRCC, this study helps shed light on the different anti-VEGF toxicity profiles and would therefore support treatment decision making.
Single-nucleus RNA-sequencing analysis reveals transcriptome differences in TIGIT+ exhausted T-cell associated with poor prognosis in muscle-invasive bladder cancer (MIBC).
Authors: Xiao Shanshan , Wang QI , Zheng Liuqing , Wang Qian , Wang Tao ,   Hangzhou Repugene Technology Co,.Ltd
Published: June 2022

e16544 Background: Compared with single-cell RNA-sequencing (scRNA-seq), Single-nuclei RNA-sequencing(snRNA-seq) can detect more genes with higher sensitivity, and it is more robust in identifying cellular markers. TIGIT+ exhausted T cells were reported significantly associated with poor prognosis in muscle invasive bladder cancer(MIBC) by flow cytometry. We aimed to evaluate unique markers of TIGIT+ exhausted T cells in MIBC via snRNA-seq and to construct a potential prognostic survival model. Methods: We collected snRNA-seq data from 25 MIBC and 4 non-MIBC patients in GSE169379, including 57 cancer tissues and 4 distant normal tissues. Meanwhile, expression profiling data and clinical information of 402 Bladder Urothelial Carcinoma(BLCA) patients were collected in The Cancer Genome Atlas (TCGA). Firstly, the snRNA-seq data was preprocessed and filtered. Next, We re-clustered T-cell subsets and abstracted TIGIT+ exhausted T cells (TIGIT+Tex), then screened out the genes uniquely expressed in TIGIT+Tex subsets by differential expression analysis. We further evaluate the correlations between uniquely expressed genes and the exhausted T cell markers, identified significantly correlated differential expressed genes, constructed a prognostic model based on multivariate cox regression analysis and exploited the patient's overall survival and disease-free survival to confirm our findings. Results: Top 10 genes (CNTN1, CTPS1, EYA1, GRIK2, FOXP2, YBX1, DACH1, SYT1, NOL4, TRIT1) of unparalleled differential up-regulation were identified from TIGIT+ exhausted T cells via snRNA-seq data. Based on the correlation analysis of TCGA expression profile data, six genes (CNTN1, CTPS1, EYA1, GRIK2, FOXP2, YBX1) that were significantly positively correlated with exhausted T cells were obtained. Next, we constructed a regression prediction model consisting of 5 genes (CNTN1, CTPS1, EYA1, GRIK2, FOXP2) through multivariate cox regression analysis based on patients’ clinical information. The model was associated with significantly poor prognosis overall survival (OS) (P < 0.01,HR = 2) and disease-free survival (DFS) (P < 0.01,HR = 1.6) in BLCA patients. Conclusions: In our study, Single-nuclei RNA expression profiling data revealed transcriptome differences between TIGIT+ exhausted T cells and other types of T cells. The regression model for potential prognostic survival was constructed using TCGA expression profiling data. These results demonstrated that distinctive differentially high expressed genes associated with TIGIT+ exhausted T cells may act as potential markers for predicting prognosis outcomes in bladder cancer patients.
Assessment of changes in the international prostate symptom score for patients enrolled in a phase I trial of intravesical bacillus Calmette-Guérin combined with intravenous pembrolizumab for recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous bacillus Calmette-Guérin treatment.
Authors: Montgomery Jazzmyne T. , Sana Sherjeel , El-Zawahry Ahmed , Peabody James O. , Pearce Tiffany , Adams Nicole , Deebajah Mustafa , Dynda Danuta , Babaian Kara N. , Crabtree Jane , Delfino Kristin , McVary Kevin , Robinson Kathy , Rao Krishna A. , Alanee Shaheen Riadh 
Published: June 2022

e16553 Background: We conducted the first phase I dose-escalation trial (NCT02324582) of intravesical Bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab in patients with high-grade non-muscle-invasive bladder cancer who had persistent or recurrent disease after prior intravesical therapy with BCG. The International Prostate Symptom Score (IPSS) were administered to assess subjects’ urinary bother during the trial. Methods: Eighteen subjects were consented for the study, 13 were treated. The study population was comprised of 11 males, 2 females, with age range 42 - 92 years. The IPSS was assessed at pre-treatment, Week 10 (during combined BCG and pembrolizumab treatment), and at 3 and 6 months from treatment completion. IPSS outcomes were analyzed using a mixed-model repeated measures analysis with p-value < 0.05 considered statically significant. Results: For each time point, there was no significant change in any of the component variables of the IPSS. There was no increase in reported bother symptoms over the course of treatment, given median IPSS scores of 9, 11, 7, and 8 (IQR 1.75) for each time point, respectively. Furthermore, quality of life measurements demonstrated no significant change in subjective burden with 75% of subjects reporting that they were “mostly satisfied” with treatment outcomes, followed by 13% reporting “delighted” or “pleased” at 6 month follow-up. Conclusions: There is no significant change in quality of life or the perceived bother of symptoms indicated in the component variables of the IPSS for our study population before, during or after treatment.
Blood-based miRNA, exosomal PD-L1, and immune profiling analysis as predictive biomarkers for immune checkpoint inhibitor treatment response in urothelial cancer.
Authors: Kim Joori , Kim In-Ho , Shin Sun , Kim Ok Ran , Park Juyeon , Kang Nahyeon , Shin Kabsoo 
Published: June 2022

e16559 Background: Predicting response to immune checkpoint inhibitor (ICI) is difficult and adequate biomarkers are lacking. PD-L1 expression of tumor cells (TC) and tumor-infiltrating immune cells (IC) has limitations. We hypothesized that peripheral blood analysis would provide systemic insights about the immune responses induced by therapies blocking the PD-1/PD-L1 pathway. Methods: First, plasma samples from urothelial cancers (N = 30) with matched paired samples (N = 27) at baseline, after 1 week of PD-L1 inhibitor administration, and at response evaluation were analyzed. Exosomes were extracted and the expression of plasma-derived exosomal PD-L1 (exo PD-L1) and cytokine levels (IFN-γ, IL-10, TGF-ß, granzyme B) were determined with ELISA. Peripheral blood mononuclear cells (PBMCs) were analyzed with FACS. Samples were stained with anti-CD3, CD8, CD69, and PD1. Secondly, small RNA-sequencing was done using plasma samples from 8 patients and samples from 4 normal ones to identify differentially expressed miRNAs (DE-miRNAs) between treatment responders and non-responders. Expressions of selected DE-miRNAs were validated in a separate patient cohort of 54 patients. Results: In all of patients’ samples tested, exoPD-L1 was detected. Pretreatment level of exoPD-L1 was significantly higher in patients with objective tumor response (P = 0.010). For both clinical responders and non-responders, the level of exoPD-L1 expression increased at treatment day 8. A lower fold change (< 18) in plasma exoPD-L1 was associated with a better rate of response to the anti-PD-L1 therapy (P = 0.032). Compared to non-responder group, the PD1+CD8+T-cell fraction was significantly lower at baseline (p = 0.005) and increased at treatment day 8 in the responder group (p = 0.018). At baseline, the IL-10 level was significantly higher in the responder group (p = 0.005). Decreased levels of immune-suppressive cytokines, TGF-beta1/2 and IL-10, at post-treatment day 8 indicated better response (p = 0.005 and 0.020, respectively). From small RNA sequencing analysis, two upregulated (miR-451a and let-7i-5p) and eight downregulated (miR-1290, miR-151a-3p, miR-10b-5p, miR-148a-3p, miR-10a-5p, miR-1246, miR-34c-3p, let-7b-3p) differentially expressed miRNA in responders were identified. Conclusions: Our findings suggested that the higher expression of exoPD-L1, early peripheral PD1+CD8+T-cell response, and decrease of immunosuppressive cytokines could serve as blood-based predictive biomarkers for responses to ICI treatment and that miRNAs could act as regulators in these processes.