bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of patients (pts) with advanced renal cell carcinoma (aRCC) treated with cabozantinib (CABO) after lenvatinib plus pembrolizumab (LEN+PEM).
Authors: Haro-Silerio Jaime Ivan , Johns Andrew , Moussa Mohammad Jad , Wang Mindy , Wang Emily , Kovitz Craig A. , Campbell Matthew T , Jonasch Eric , Shah Amishi Yogesh , Tannir Nizar M. 
Published: January 2024

433 Background: LEN+PEM is an approved first-line therapy for aRCC. In the CLEAR study, it produced a 71% objective response rate (ORR), an 18% complete response rate, and improved progression-free survival (PFS) and overall survival (OS) compared to sunitinib. CABO is approved as second and later line therapy for aRCC. We explored the efficacy of CABO in pts with aRCC after treatment with LEN+PEM. Methods: This is a retrospective study of pts with aRCC who received CABO after LEN+PEM at our institution from 12/2019 to 8/2023. Demographics and clinical data were abstracted from the EMR. A blinded radiologist assessed tumor response using RECIST v1.1. We measured PFS, time on therapy (TOT) and OS from start date of CABO. Results: 22 pts were analyzed (Table 1). Median follow up was 7.7 months (mo); 11 pts received LEN+PEM on the HOPE 111 trial (NCT02501096). Among all 22 pts, 11 (50%) had a partial response (PR), 5 (22.7%) had stable disease (SD), and 6 (27.3%) had progressive disease (PD) on LEN+PEM. Median TOT with LEN+PEM was 7.4 mo (range: 1.8-29). 20 pts (90.9%) discontinued LEN+PEM due to PD, 1 pt (4.5%) due to fatigue, and 1 pt (4.5%) due to elevated liver enzymes. 17 pts received CABO right after LEN+PEM; 3 pts received 1 line and 2 pts received 2 lines of therapy before CABO after LEN+PEM. Of 19 pts with evaluable radiographic response on CABO, 1 pt had a PR (ORR 5.3%, PFS 16.1 mo) and 3 pts had SD for ≥6 mo. Median TOT with CABO was 4.3 mo (range: 0.2-18.2); 13 pts (59.1%) took CABO for ≥4 mo, 7 pts (31.8%) took it for ≥6 mo, of which 3pts receivedpalliative radiation andcontinued CABO therapy beyond PD. Median PFS and median OS with CABO were 4.1 mo (range: 1.2-16.1) and 8.1 mo (range: 0.8-22.5), respectively. At time of analysis, 4 pts were still taking CABO (3 SD, 1 not yet evaluated); 15 pts discontinued CABO: 12 for PD, 1 for Grade 3 hand-foot skin reaction, 1 per pt request, and 1 for transition to hospice; 3 pts died during CABO therapy (bowel obstruction [1], COVID-19 [1], cardiac arrest [1]). Adverse events attributed to CABO were consistent with published reports. Conclusions: In this cohort of heavily pretreated pts who received CABO after LEN+PEM, CABO demonstrated a modest clinical benefit in a minority of pts, underscoring the need to develop effective novel therapies for aRCC. [Table: see text]
Single institutional experience of neoadjuvant therapy prior to planned surgical resection for complex or locoregional renal cell carcinoma.
Authors: Puri Dhruv , Yuen Kit , Wang Luke , Meagher Margaret , Afari Jonathan , Nguyen Mimi , Cortes Julian , Mahmood Mirha , Mansour Mariam , Matian Joshua , Javier-Desloges Juan , Derweesh Ithaar 
Published: January 2024

439 Background: Cytoreduction via systemic neoadjuvant therapy is an emerging investigational strategy in localized renal cell carcinoma (RCC). We analyzed our single institutional experience with neoadjuvant therapy. Methods: ingle institutional retrospective analysis of patients with T2-T3N0M0 RCC. Patients received confirmatory biopsy for clear cell histology prior to receipt of systemic therapy and underwent radical (RN) or partial nephrectomy (RN). Neoadjuvant therapy consisted of tyrosine kinase inhibitor (TKI) or Immuno-oncology (IO) therapy and/or combination (TKI-IO). Neoadjuvant therapy was given prior to planned partial nephrectomy for complex renal mass with imperative indications for nephron preservation and prior to planned radical nephrectomy in setting of locoregional disease with possible adjacent organ or great vessel involvement where multiorgan system resection was risked. Primary outcome was percentage cytoreduction comparing pre-treatment and post treatment mass size. Secondary outcome included partial response (PR) rate as per RECIST criteria, negative surgical margins, and lack of major 30-day complications (Clavien ≥3). Comparative analysis was conducted for outcomes between groups for overall survival (OS), cancer specific survival (CSS), and progression free survival utilizing Kaplan Meier Analyses (KMA). Results: A total of 50 patients (33 TKI, 17 IO + TKI-IO) were analyzed (median follow up 31.1 months). Overall PR and cytoreduction rates were 18.0% and 4.2%. No differences in tumor size were noted (7.7 vs. 10.4 cm, p= 0.08). There were no differences in % cytoreduction (12.2 vs. 11.8, p=0.13) and % PR (17.8% vs. 30.7%, p=0.73) between the groups. Overall, 18 patients and 30 patients underwent PN and RN, respectively. 30-day major complication rate was 28.0% and 20.5% was PSM rate. KMA revealed 3-year OS, CSS and PFS of 74%, 75%, and 14%. No differences were noted between TKI and IO/IO-combination groups for PFS (16.7% vs. 10.0%, p=0.45), CSS (70.9% vs. 93.3%, p=0.20), and OS (68.3% vs. 93.3%, p=0.06). Conclusions: Neoadjuvant therapy prior to surgery for complex and locoregional disease resulted in cytoreduction and was associated with acceptable safety, surgical quality, and short term oncological outcomes. Further investigation is requisite to delineate role of neoadjuvant therapy in localized RCC.
Serum IgG: A potential biomarker for predicting the efficacy of systemic therapy in metastatic renal cell carcinoma.
Authors: Cui Honglei , Wu Jie , Xie Rui-Yang , Du Gan , Shang Bing-Qing , Dong Xin , Song Yan , Qu Wang , Bai Hongsong , Guan Youyan , Shi Hongzhe , Bi Xin-Gang , Zhou Ai-Ping , Shou Jianzhong 
Published: January 2024

442 Background: Immunotherapy-tyrosine kinase inhibitor (IO-TKI) and tyrosine kinase inhibitor (TKI) are the main treatment strategies that have significantly improved outcomes of metastatic renal cell carcinoma (mRCC) patients. However, there are no effective biomarkers available to predict the efficacy of these regimens. We aim to explore the predictive value of serum immunoglobulin G (IgG) in systemic treatment. Methods: The study consisted of 292 mRCC patients who received TKI or IO-TKI therapy. Serum IgG in the pre-treatment baseline, 1 month, and 3 months after systemic treatment were measured using the immunoturbidimetric method. The Wilcox test was used to compare baseline serum IgG levels and paired t-test was utilized to compare serum IgG levels between baseline and 3 months after treatment. Kaplan-Meier curve were used to evaluate the PFS and Cox proportional hazard regression analysis was conducted to identify independent determinant factors for PFS. Results: The baseline level of IgG was not associated with objective response rate (ORR) in the overall patient cohort. However, there was a significant decrease in IgG in patients achieving CR/PR and an increase in patients with SD/PD after 3 months of treatment (p<0.05). In the TKI cohort, the estimated 9-month PFS was significantly higher in the IgG-decrease group versus the IgG-increase group (HR 2.5, 95%CI 1.8-3.4, p<0.001). The results were similar in the IO-TKI cohort. The predictive value of alteration of IgG after 1-month treatment was demonstrated in terms of the estimated 9-month PFS (HR 1.5, 95%CI 1.0-2.3, p=0·048). The ROC curve showed outstanding performance of alteration of serum IgG in predicting PFS. Conclusions: Alteration of serum IgG after systemic treatment is a reliable biomarker to predict the efficacy in mRCC patients. The change of IgG after 1-month treatment could serve as indicator of treatment efficacy and improve individualized drug selection. Further validation is warranted.
Monocyte to lymphocyte ratios and cancer-specific mortality for patients with renal cell carcinoma and inferior vena cava tumor thrombus.
Authors: Sandberg Maxwell , Ritts Rory , Namugosa Mary , Temple Davis , Whitman Wyatt , Costa Claudia Marie , Refugia Justin , Eilender Benjamin , Mehrazin Reza , Zanotti Rafael Ribiero , Garcia Marchiñena Patricio , Zequi Stenio Cassio , Rodriguez Alejandro 
Published: January 2024

444 Background: Renal cell carcinoma (RCC) with inferior vena cava (IVC) tumor thrombus carries a poor prognosis and presents complex medical management to urologists. Long-term data examining RCC with IVC tumor thrombus is sparse. Specifically, markers predicting cancer-specific survival are lacking. Recently, immune cell markers in cancer, such as neutrophils, lymphocytes, and monocytes, have come into focus. These cell counts and/or ratios may provide a window into cancer-specific outcomes. The purpose of this study was to examine the use of immune cell ratios in patients with RCC and IVC tumor thrombus to predict survival outcomes through a collaboration project across North and South America. Methods: Patients were included in this study if they had a diagnosis of RCC with IVC tumor thrombus and underwent nephrectomy with IVC thrombectomy for their RCC. Data was reviewed and entered into a multi-institutional/continental database. Complete blood counts taken as close to the date prior to/date of surgery were used to calculate immune cell ratios. Neutrophil to (/) lymphocyte ratios were done by dividing patients’ neutrophil cell count by their lymphocyte count. Monocyte/lymphocyte ratios were calculated in the same manner. Independent samples t-test was used to test for significance in cause of death post-operatively (RCC versus non-RCC cause) based on immune cell ratio. Results: There were 107 patients included in the study with long-term follow-up data (Mean: 2.6 years; Range: 0-16-years). Of all patients, 43/107 died by the end of the study, with 31/43 (72.1%) dying due to RCC and 12/43 (27.9%) from other causes. No difference existed in neutrophil/lymphocyte ratios based on cause of death (p=0.260). Monocyte/lymphocyte ratios were significantly lower in those who died from RCC relative to another cause (p=0.035). Conclusions: Immune cell ratios may have a role in predicting death from RCC. In our study, monocyte/lymphocyte ratios were significantly lower in patients who died from RCC compared to death from other reasons. Our results stem from a multi-continental/institutional study, and thus hold clinical utility as an increased focus is turned towards including diverse populations in research. Urologists may consider monocyte/lymphocyte ratios in the future when managing patients with RCC and an IVC thrombus. [Table: see text]
Significance of CD73/adenosine receptor 2 (A2aR) and immune microenvironmental status in renal cell carcinoma with sarcomatoid changes and rhabdoid features.
Authors: Takamatsu Dai , Eto Masatoshi 
Published: January 2024

447 Background: One of the most aggressive forms among the kidney cancer is sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC). There is still no effective treatment, and new therapies are needed. In this study, we focused on CD73 and A2aR, which regulate Treg involved in immune escape, and examined them clinicopathologically. Methods: We reviewed a total 1390 formalin-fixed, paraffin-embedded specimens of surgically resected RCC between 1989 and 2016. We detected 60 cases of RCC with sarcomatoid changes and rhabdoid features. We performed immunohistochemistry of CD73, A2aR, PD-L1, and CD8. We attempted to examine clinicopathological significance of CD73- and A2aR- positive RCC with S/R RCCs. The relationship between clinical and pathological features was evaluated using Wilcoxon’s rank sum and Fisher’s exact tests. A Cox proportional hazards regression model was used for multivariate analysis. Both PFS and OS were analyzed by using the Kaplan-Meier method and compared by the Wilcoxon’s rank test. All statistically signiﬁcances were defined as P<0.05. Results: High-grade components were sarcomatoid changes (31 cases, 51.7%), rhabdoid features (16 cases, 21.7%), and both sarcomatoid and rhabdoid (13 cases, 21.7%). CD73 expression in the high-grade component was observed in 41 cases (68.3%), and A2aR expression was observed in 27 cases (45%). Significant differences among cMstage and high-grade components, sarcomatoid and rhabdoid, are detected in A2aR positive cases, respectively (p=0.0368, 0.0396, 0.0187). The univariate analysis showed a significantly poorer OS for patients whose tumors expressed CD73 and A2aR ( P = 0.0109 and P < .0001). To validate this finding further, a multivariate analysis was performed using the Cox proportional hazards model). The results indicated that A2aR expression ( P = 0.0206) and pTstage ( P = 0.0433) were independent markers for unfavorable prognosis in S/R RCCs. CD73 and A2aR expressions were significantly related to poor PFS ( P = 0.0395, P = 0.0043, respectively). CD73 and A2aR expressions were significantly related to poor OS ( P = 0.0188, P < .0001, respectively). Conclusions: CD73 and A2aR expression correlated with the poorest prognosis group among S/R RCCs, indicating that the use of inhibitors against them in combination with conventional therapies may improve prognosis.
Detection of sarcomatoid renal cell carcinoma using plasma cell-free DNA methylation.
Authors: Semaan Karl , El Zarif Talal , Seo Ji-Heui , Eid Marc , Canniff John , Fortunato Brad , Savignano Hunter , Davidsohn Matthew P. , Lakshminarayanan Gitanjali , Saad Eddy , Saliby Renee Maria , Bakouny Ziad , Matar Sayed , Nuzzo Pier Vitale , Berchuck Jacob E , Signoretti Sabina , Braun David A. , Freedman Matthew , Baca Sylvan , Choueiri Toni K. 
Published: January 2024

449 Background: Sarcomatoid differentiation (SD) in renal cell carcinoma (RCC) is associated with poor survival and heightened response to immune checkpoint blockade. Detection of SD can be challenging due to spatial heterogeneity and sampling error. Herein, we introduce a novel tissue–informed epigenomic approach to noninvasively identify sarcomatoid differentiation in patients with RCC from cell-free DNA (cfDNA) using <1mL of plasma. Methods: Methylated immunoprecipitation and high-throughput sequencing (MeDIP-seq) was performed on pathologically reviewed clear cell RCC frozen tissue samples with and without SD (sarcomatoid-RCC and epithelioid-RCC, resp.) collected at the Dana-Farber Cancer Institute. Differentially methylated regions (DMRs) between sarcomatoid and epithelioid subtypes were identified using DESeq2 (false discovery rate of q < 0.01). Then, MeDIP-seq was performed on cell-free DNA (cfMeDIP-seq) from patients with sarc-RCC and epi-RCC. A Sarcomatoid Methylation Score (SMS) was derived for each sample by aggregating the methylated cfDNA signal at tissue-derived sarcomatoid-enriched DMRs (sarc-DMRs), while normalizing to signal at epithelioid-enriched DMRs (epi-DMRs). Scores were compared between the two groups using a Wilcoxon rank-sum test. A classifier was built to distinguish sarc-RCC from epi-RCC based on SMS and its performance was evaluated using the area under the receiver operating characteristic (AUROC) curve. Results: We identified 32,086 DMRs between 9 sarc-RCC and 10 epi-RCC tissue samples at a false discovery rate of q < 0.01, among which We selected 16,083 DMRs that are enriched in sarcomatoid vs. epithelioid. We generated high-quality cfMeDIP-seq profiles from plasma of 46 patients, 13 with sarc-RCC and 33 with epi-RCC. SMS were significantly higher in sarc-RCC vs. epi-RCC plasma samples (p = 6.7×10-8). These scores achieved an AUROC curve of 0.95 for classifying patients with sarc-RCC from patients with epi-RCC. Conclusions: We present the first proof of concept study for the detection of sarcomatoid differentiation in RCC based on tissue-informed assessment of DNA methylation signals in cfDNA using <1mL of plasma. This approach could overcome the challenges of spatial heterogeneity and sampling error that make identification of sarc-RCC difficult. More generally, it establishes a paradigm for identifying histologic subtypes of cancer based on their epigenomic correlates from cfDNA, with possible therapeutic implications in real-time.
Topological heterogeneity of genomic and immunologic effects from combination immunotherapy treatment in the neoadjuvant setting for renal cell carcinoma (RCC).
Authors: Alban Tyler , Singh Salendra , Pavicic Paul G. , Rayman Patricia A. , Bangalore Prerana Parthasarathy , Rupani Amit , Makarov Vladimir , Przybycin Christopher , Ko Jennifer S. , Krishnamurthi Venkatesh , Campbell Steven , Chan Timothy An-thy , Rini Brian I. , Diaz-Montero C. Marcela , Ornstein Moshe Chaim 
Published: January 2024

454 Background: We present a multi-regional genomic analysis of tumor from a phase 1b clinical trial of perioperative durvalumab (D) and tremelimumab (T) in patients (pts) with high-risk RCC. Genomic & transcriptomic analyses were performed on nephrectomy samples post neoadjuvant therapy to assess genomic/immunologic impact of combinatorial D+T therapy compared to D alone. Methods: Post-treatment nephrectomy samples were regionally sampled at 4 locations: non-tumor, tumor distant, tumor near, and tumor center. RNA-sequencing was performed on all 4 regions and utilized on a per patient basis to identify regional tumor microenvironment alterations compared to normal kidney. Whole exome sequencing was performed on tumor center. Results: 29 pts enrolled in the trial. 15 were included in the analysis; 5 received neoadjuvant D and 10 received D+T. 60 multi-regional specimens were analyzed; each patient's own normal kidney tissue served as their baseline. There were significant transcriptional differences in D+T compared to D alone (Table). While many of these genes overlapped between treatment arms, the amplitude of differentially expressed genes (i.e., differences between normal and tumor tissue) were greater in the D+T arm, particularly among immune related genes, such as CD8A, CXCL9, CXCL13 and PRAME. Enhanced immune activity was confirmed by immune deconvolution analyses showing broad regional immune infiltration of lymphocytes, including CD8+ T cells, in D+T, which was not detected in D alone. Further comparison of mutational profiles within this cohort showed that D+T treatment resulted in increased clonality compared to D. Conclusions: These data highlight the potential differential genomic/immunologic impact of combination immunotherapy vs single agent across tumor topology. It also demonstrates the utility of pt specific comparisons and a multiregional sampling approach. D+T treatment resulted in enhanced immune activity in RCC tumors and activation of anti-tumor processes above and beyond D alone. This design increases power & biological interpretation of small pt cohorts and allows additional insight into enhanced activation of the immune system with D+T. Summary of transcriptomic comparisons within D & D+T cohorts per region where p <0.05 was used as selection criteria along with positive & negative log fold change. Pathway analysis performed using Hallmarked pathways based on differentially expressed genes, and Celltype deconvolution via ssGSEA (p<0.05). [Table: see text]
Association between β3-adrenergic receptor agonist use and risk of kidney cancer among patients with overactive bladder.
Authors: Park Jee Soo , Lee Myung Eun , Jang Won Sik , Kim Jongchan , Shin Gwangmo , Ham Won Sik 
Published: January 2024

456 Background: New aspects of β3-AR have been recently described with overexpression in cancers. Although post-authorization safety study of mirabegron, the first approved β3-AR agonist for overactive bladder (OAB), found no association between mirabegron use and risk of overall cancer, subgroup analysis revealed that some malignancies were significantly associated with β3-AR agonist use. This study aimed to examine whether cumulative β3-AR agonist use is associated with a higher risk of kidney cancer and demonstrate underlying mechanisms of β3-AR agonist through murine model. Methods: This nationwide population cohort study included newly diagnosed OAB patients who initiated their OAB medications between 2015 and 2020. In pulmonary metastatic orthotopic murine mRCC model, primary tumor weight and number of lung nodules were measured and evaluation of browning of perinephric fat (PF) and tumor immune microenvironment (TIME) was performed and compared between β3-AR agonist and vehicle treatment groups. Results: Among a total of 3,728,929 patients, 7,437 (0.2%) developed kidney cancer after starting OAB medications. There was an increased risk of kidney cancer among β3-AR agonist users (hazard ratio (HR)=1.514, 95% confidence interval (CI) 1.418–1.615) compared to anticholinergic users. The incidence of kidney cancer was also significantly increased with an increase in the cumulative dose of mirabegron (adjusted HR (aHR)=1.221 (1.104-1.351) for 30-180 cDDDs (cumulative defined daily doses), aHR=1.413 (1.281-1.558) for >181 cDDDs) compared to low-dose cDDDs (<30 cDDDs)). The β3-AR agonist treated mice demonstrated significantly higher primary tumor burden and lung metastasis with increased mitosis in cancer cells and browning of PF. Immunofluorescence analysis demonstrated that β3-AR agonist modulate TIME by increasing both myeloid-derived suppressor cells and regulatory T cells. Conclusions: This is the first study to demonstrate the association of kidney cancer and β3-AR agonist both in murine and human studies. By showing that the β3-AR agonist not only increases PF browning but also induces immune tolerance which eventually increases the initiation and progression of kidney cancer, we suggest β3-AR as the potential therapeutic target for novel anti-neoplastic approaches.
Effect of cytoreductive nephrectomy on the efficacy of immunotherapy in metastatic renal cell carcinoma by decreasing IL-6 to modulate tumor-associated macrophage and myeloid-derived suppressor cell.
Authors: Park Jee Soo , Lee Myung Eun , Jang Won Sik , Kim Jongchan , Shin Gwangmo , Ham Won Sik 
Published: January 2024

457 Background: Although the contemporary role of cytoreductive nephrectomy (CN) has been significantly downsized, the role of CN in immuno-oncology era still remains. Since the efficacy of immune checkpoint inhibitor (ICI) is limited, the role of CN in combination with ICI from the perspective tumor immune microenvironment (TIME) was evaluated using murine models and hypothesized that interleukin 6 (IL-6) blockade would enhance the efficacy of ICI therapy. Methods: Low- and high-tumor burden pulmonary metastatic orthotopic murine mRCC models have been developed. Antibodies targeting PD-1, CTLA-4, and IL-6 were systemically injected through the peritoneum. Renca implanted kidney was removed in the CN performed group and the timing of CN was differentiated according to the upfront and deferred CN group. The remodeling of the TIME was analyzed by flow cytometry, immunofluorescence analysis, and measurement of cytokines. Results: Upfront CN group demonstrated significantly better survival outcomes compared to deferred CN group in low-tumor burden models, while significantly longer survival was reported in deferred CN group compared to upfront CN group in high-tumor burden models. CN modulate IL-6 levels which act as a negative regulator of myeloid-derived stem cells (MDSCs) and M2 tumor-associated macrophage (TAM). The blockade of IL-6 activated CD8+ T-cell accumulation and led to decreased expression of MDSCs and M2 TAM, which is similar to the effects on TIME by CN combined with ICI therapy. Conclusions: This study is the first animal study to demonstrate the role of CN in combination with ICI. CN decreases the production of the cytokine IL-6, increasing the anti-cancer immunity TIME through modulation of MDSC and M2 TAM. Our study provides a research basis for the significant role of IL-6 in tumor regression and highlights a novel target to improve the efficacy of immunotherapy.