bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical outcomes of patients with bone-predominant metastatic renal cell carcinoma.
Authors: Gheeya Jinesh S. , Li Mingjia , Xu Menglin , Zimmerman Danielle Elise , Collier Katharine A. , Wang Peng , Folefac Edmund , Monk Paul , Mortazavi Amir , Clinton Steven K. , Yin Ming , Yang Yuanquan 
Published: March 2023

703 Background: Bone-predominant metastatic renal cell carcinoma (mRCC) is associated with aggressive biology and poor prognosis. The optimal management of these patients (pts) remains not well-established. While contemporary trials showed the superiority of immune checkpoint inhibitors (ICI) compared to vascular endothelial growth factor tyrosine kinase inhibitors (TKI), these pts were often excluded due to non-measurable disease. mRCC bone metastases show an enhanced angiogenesis gene signature suggesting the potential for greater responses to TKI. We test this hypothesis in a retrospective study comparing treatment outcomes for the first line (1L) TKI versus ICI in pts with bone-predominant mRCC. Methods: Pts with mRCC who received care at the Ohio State University Comprehensive Cancer Center from 1/1/2008 to 6/1/2021 were identified through retrospective chart review. Bone-predominant metastasis was defined as the number of bone metastases > extra-osseous metastases. Pts who had ≥1 cycle of treatment and follow-up scans were evaluated for treatment responses per RECIST 1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. The comparisons were made between TKI and ICI cohorts, and the significance was determined by logrank test. Pt who received ICI-TKI in 1L were excluded from the survival analysis due to limited N. Results: A total of 335 pts with mRCC were identified, of which 45 (13.4%) had bone-predominant metastasis. Most of the pts (44/45) had clear cell histology. TKI was the 1L intervention for 21 (47%) while 20 (44%) pts received ICI, and 4 (9%) pts received TKI-ICI. TKI and ICI cohorts were similar for International Metastatic RCC Database Consortium (IMDC) Risk (Table). In the TKI cohort, 19 pts had evaluable responses with ORR of 15.7% and SD of 42%. The mPFS was 5.9 months (95% CI 2.8–9), and mOS was 30.4 months (95% CI 3.3–57.6). In the ICI cohort, 16 had evaluable responses with ORR of 6% and SD of 43.8%. The mPFS was 3.4 months (95% CI 0–8.2), and mOS was 19.3 months (95% CI 14.9–23.7). The hazard ratio was 0.58 for PFS and 0.54 for OS, favoring TKI over ICI, although statistical significance was not reached due to the small sample size (p=0.10 and 0.12, respectively). Conclusions: In this single-center retrospective study, pts with bone-predominant mRCC who received TKI compared to ICI as 1L therapy showed improved ORR, PFS, and OS. These results warrant further investigation in larger studies comparing TKI-containing regimen vs ICI doublet. [Table: see text]
Additional biological and clinical characteristics to refine International Metastatic RCC Database Consortium (IMDC) prognostic/predictive assessment in metastatic renal cell carcinoma (mRCC).
Authors: Zampiva Ilaria , Merler Sara , Inzerilli Nicola , Zacchi Francesca , Manduca Stefano , Pafumi Sarah , Piacentini Michela , Marletta Stefano , Cesta Incani Ursula , Torroni Lorena , Vesentini Roberta , Marchetti Pierpaolo , Fantinel Emanuela , Zivi Andrea , Caliò Anna , Brunelli Matteo , Verlato Giuseppe , Milella Michele 
Published: March 2023

705 Background: mRCC prognostic stratification is currently based on the IMDC score. However, some patients experience outcomes markedly different from those predicted by the median outcome of their risk class. Moreover, risk scores are prognostic, rather than predictive, and developing reproducible, affordable, biology-based predictive biomarkers to tailor treatment choices in individual pts remains an unmet clinical need. Methods: A retrospective cohort of 113 mRCC pts treated at the Verona University Hospital Trust between 2013 and 2021 was explored to identify additional clinical prognostic factors for OS to complement IMDC score. Outlier pts (i.e. individual pts whose clinical outcome differed significantly from the median of the IMDC group they belonged to) were further explored to find putative molecular signatures, using FISH and IHC assays. Results: At a median follow-up of 69 months (range 18-136m), novel variables impacting on OS in addition to IMDC risk group were identified: bone, central nervous system (CNS) and pancreatic mets and high neutrophil/lymphocyte ratio (N/L) with a cut-off of 3.2. We also analyzed outliers: 3 good-risk pts with lower than expected OS, 4 poor-risk pts with longer than expected OS, and two intermediate-risk pts with long treatment response. Two putative signatures were found predictive of disease behavior: a cold signature (9p loss, poor of TILs) and a hot signature (rich in CD56+, CD15+ and CD8+ infiltrating cells). The cold and hot signatures were found in good risk pts with bad OS and poor-risk pts good OS, respectively; both intermediate-risk pts had a hot signature, consistent with their disease course. Conclusions: Additional clinical and molecular factors have been identified to possibly improve IMDC prognostic performance; multivariable models including them along with standard IMDC are being developed. Molecular analysis suggests potential signatures to be applied in routine clinical practice, whose predictive performance could be validated in prospective multicentric trials. [Table: see text]
Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma.
Authors: Singla Nirmish , Nirschl Thomas , Obradovic Aleksandar , Shenderov Eugene , Lombardo Kara A. , Liu Xiaopu , Pons Alice , Zarif Jelani , Rowe Steven P. , Trock Bruce J. , Hammers Hans J. , Bivalacqua Trinity , Pierorazio Phillip , Deutsch Julie S. , Lotan Tamara L. , Taube Janis M. , Ged Yasser , Gorin Michael A. , Allaf Mohamad E. , Drake Charles G. 
Published: March 2023

708 Background: Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We sought to (1) elucidate the effects of PD-1 inhibition on primary tumor-infiltrating and circulating immune cell populations in ccRCC and (2) correlate tumor microenvironment and circulating immune cell compositions with response to anti-PD-1 therapy. Methods: We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from this cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response using fluorescence-activated cell sorting, bulk RNA sequencing with protein activity inference, and enzyme-linked immunosorbent assay for circulating cytokines. Results: We found that nivolumab durably promotes a pro-inflammatory state within the primary tumor, as evidenced by a sustained increase in the effector T cell phenotype and decreased representation of regulatory T cell subsets. Baseline immune infiltration within the primary tumor including T effector and myeloid enrichment along with angiogenic depletion correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. Conclusions: Our findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations. Clinical trial information: NCT02575222 .
Association of serum lactate dehydrogenase (LDH) isozyme with prognosis of patients with metastatic clear cell renal cell carcinoma (mCRCC).
Authors: Takeda Hayato , Kimura Go , Akatsuka Jun , Endo Yuki , Yanagi Masato , Mikami Hikaru , Hasegawa Hiroya , Katsu Akifumi , Funato Ryota , Taniuchi Mami , Toyama Yuka , Kondo Yukihiro 
Published: March 2023

709 Background: LDH isozyme is a tetramer of two subunits, H chain and M chain, and is present in all living tissue. Five types of molecular forms characterize the LDH pattern, and tumor tissues relatively consist LDH-4 and LDH-5, composed with a high ratio of the M chain, compared to normal tissues. This study analyzed the association between LDH isozyme and prognosis of mCRCC after nephrectomy. Methods: Clinical records of mCRCC patients those who were initially diagnosed M0 disease at Nippon Medical School between 2012 and 2016 were retrospectively reviewed. LDH isozyme values before operation and at time of metastasis were checked. Isozyme patterns were classified into 6 types, LDH 1-5 dominant and common type, according to the most composed molecular form. Results: Out of 38 patients, 33 patients (87%) were male, 5 patients (13%) were female. Median age was 65 years old (36-87). pT1 was seen in 3 cases, pT2 in 4, pT3 in 27, and pT4 in 4. Pathological grade 2 were 9 cases, G3 in 21, and G4 in 8. As for the IMDC risk, favourable was 2 cases (5%), intermediate in 26 (68%) and poor in 10 (26%). Median LDH was 163 IU/L (113-317), and isozyme dominant pattern were as follows: LDH-2 in 9 cases (24%), LDH-3 in 6 (16%), LDH-4 in 4, LDH-5 in 11. 8 cases were common type, and no cases showed LDH-1 dominant. Median time from surgery to recurrence was 10 months (1-104), median follow-up period after recurrence was 18 months (4-72). 16 deaths occurred. No significant correlation was seen between pre-operative LDH isozyme pattern and pathological grade or pT stage. Pre-operative LDH isozyme did not correlate with the time to recurrence (p=0.7420). The median OS for LDH-4 dominant at the time of metastasis was 10.9 months, significantly shorter than other isozyme types (P=0.0134). Conclusions: LDH-4 dominant isozyme pattern at the time of recurrence has a short OS, proposing as a prognostic predictor in mRCC.
Evaluating the clinical utility of circulating tumor cells (CTC) profiling to predict selection of preferred therapeutic regimens in newly diagnosed or pretreated refractory renal cell carcinomas (RCC).
Authors: Vaishampayan Ulka N. , Taylor Jeremy MG , Alva Ajjai Shivaram , Shah Neha , Mhalsekar Anuja , Gosavi Rahul Ashok , Apurwa Sachin , Patil Darshana 
Published: March 2023

717 Background: There is an unmet need for biomarkers enabling therapeutic selection and prediction of clinical outcomes in kidney cancer . We evaluated the feasibility and utility of profiling of circulating tumor cells (CTCs) via multiplexed fluorescence immunocytochemistry (ICC) to identify liquid biopsy biomarkers linked to treatment response (or resistance) in advanced RCC patients. In addition, transcriptome analysis for 20802 genes from exosomal RNA is planned to evaluate novel prognostic and predictive signatures. Methods: Patients with either untreated or pretreated advanced RCC were eligible prior to starting a new systemic therapy regimen. IRB approved written informed consent was obtained. Serial blood samples were collected at baseline, and at 3, 6, 12 and 24 months. Primary endpoint of the study was to detect the proportion of patients with RCC in whom CTCs can be detected and profiled. Secondary endpoints are to correlate the profiling and changes in CTC with response and clinical outcomes. The study will meet its primary endpoint if the assay provides adequate detection and profiling for at least 12 patients. With an overall sample size of 50 the width of a 95% confidence interval for the rate of providing a therapeutic intervention is guaranteed to be less than 26%. Results: 44 evaluable patients have been enrolled; 11 females, 33 males. Median age was 64 years (range 40-85 years). 38 white patients, 2 black patients and 4 of other ethnicity have been enrolled.16 patients were untreated, 22 were pretreated and 6 were undergoing adjuvant therapy post nephrectomy. 37 patients had clear cell histology, 4 non clear cell and 3 unclassified histology. 42 of the 44 (95.5%) patients had detectable CTCs in the baseline sample. 21 on treatment samples have been collected to date, with detectable CTCs in all except one sample. 53 of 65 samples (81.5%) demonstrated detection of at least one biomarker by ICC. VEGFA expression was the most commonly detected biomarker on ICC (detected in 28 of 63 samples). Conclusions: The primary endpoint was met, and feasibility of the test was demonstrated with 95% of the baseline samples showing CTC detection and 81.5% showing biomarker expression. This blood-based, non-invasive liquid biopsy demonstrated high sensitivity for detection of cancer cells, and presents a potential opportunity for biomarker profiling to predict therapeutic efficacy of conventional RCC therapeutic agents. Correlation of longitudinal CTC with clinical outcomes will be reported. Transcriptome analysis is under evaluation for novel prognostic and predictive signatures and will be reported.
Nivoswitch trial: Predictive value of PD-L1 in plasma and extracellular vesicles.
Authors: Sonnleithner JAdzia , Himbert Dirk , Zeuschner Philip , Hartmann Arndt , Grüllich Carsten , Ivanyi Philipp , Wirth Manfred , Staib Peter , Schostak Martin , Dargatz Philip , Müller Lothar , Grünwald Viktor , Junker Kerstin 
Published: March 2023

718 Background: Predictive markers for immune checkpoint inhibition (ICI) in renal cell carcinoma patients are still missing. Until now, mainly primary tumor tissues have been analyzed to identify reliable markers including PD-L1, although distant metastases represent the therapy targets. Taking into account putative heterogeneity between primary tumors and metastases as well as dynamic changes during tumor progression and treatment, markers from liquid biopsies seem to be more suitable. The aim of this study was to investigate the predictive value of PD-L1 in plasma and on extracellular vesicles (EV) from plasma in the Nivoswitch trial. Methods: Plasma samples at randomization were obtained from 39 patients who received 3 months of tyrosine kinase inhibitor (TKI) therapy followed by random allocation to Nivolumab (“switch arm”) or continued TKI therapy (control arm) and during treatment (day 30). PD-L1 concentration was quantified by ELISA. EVs were isolated by ultracentrifugation or by using a commercial kit. They were characterized by Western blotting using cell specific, EV-specific markers as well as PD-L1 antibody. The data was analyzed by Mann Whitney and Kruskal Wallis tests as well as Kaplan Meier estimates. Results: PD-L1 was detected in plasma and EVs in all patients. PD-L1 plasma concentration was similar between response categories both in the overall cohort and the control (TKI) arm. In contrast, PD-L1 concentration in the “switch arm” was significantly lower in patients with objective response compared to patients with stable (p=0.028) or progressive disease (p=0.008) at day 0, whereas no significant difference occurred at day 30. Plasma PD-L1 levels during treatment (day 30 compared to day 0) did not show an association with therapy response in both arms. A trend towards better OS was found in patients with lower PD-L1 irrespective of treatment arm, but not for PFS. PD-L1 was detected on plasma EVs both by Western blotting as well as by ELISA, although the concentrations were too low for statistical analysis. Conclusions: In this study, plasma PD-L1 concentration did not show strong associations with clinical outcomes which might be caused by the rather small sample size and inherent heterogeneity of treatment. However, PD-L1 concentrations may have prognostic value confirming published data on tumor tissues. PD-L1 is detectable on EVs from plasma. Further studies should investigate the potential of EVs as biomarkers as well as their functional role in therapy response, especially in ICI. Clinical trial information: NCT02959554 .
Outcomes of first subsequent taxane (FST) therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who previously received docetaxel intensification (DI) for metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Robin Gabrielle , Basappa Naveen S. , North Scott A. , Ghosh Sunita , Kolinsky Michael Paul 
Published: March 2023

72 Background: The management of advanced prostate cancer continues to rapidly evolve, particularly with earlier use of survival prolonging therapies in mCSPC. Though approved prior to the use of intensification therapy in mCSPC, taxane-based chemotherapies remain a relevant option for pts with mCRPC. However, there is little evidence determining outcomes of taxane chemotherapies as FST in mCRPC pts who received DI in mCSPC. The purpose of this study is to compare outcomes between the survival prolonging taxanes, docetaxel (D) and cabazitaxel (C), as FST after DI. Methods: New patient consults seen at the Cross Cancer Institute from 1 July 2014 to 31 Dec 2020 were reviewed. Pts were considered eligible if they received DI for mCSPC and then received either D or C in mCRPC. Variables of interest were collected from the electronic medical record. The primary endpoint was ≥50% PSA response at 12 weeks relative to baseline for FST. Secondary endpoints included OS from mCSPC diagnosis, as well as PFS and OS from FST start date. PSA responses were compared using chi-squared test and time-based endpoints were compared using the Kaplan-Meier method. Results: 34 pts were identified: D = 22, C = 12 as FST. 91.2% of pts (D 95.5% vs C 83.3%) received FST in 2nd line mCRPC. Median age at diagnosis (63.1 vs 67.1 yrs, p = 0.236) and median time to CRPC (18.6 vs 14.2 mos, p = 0.079) were similar for D and C, respectively. Median time to FST (24.1 vs 34.6 mos, p = 0.036) and OS from mCSPC diagnosis (30.9 vs 52.7 mos, p = 0.002) were significantly shorter for pts receiving C vs D. PSA responses occurred in 40.9% of pts treated with D compared to 25.0% treated with C (p = 0.645). There was no significant difference in median PFS (2.7 vs 3.5 mos, p = 0.727) or median OS (11.4 vs 8.1 mos, p = 0.132) from time of FST for pts treated with D vs C, respectively. Conclusions: Both D and C demonstrated activity as FST after DI in mCSPC. Pts who received C had shorter time to FST and OS from mCSPC. The reasons for this may reflect clinician preference for C in pts with aggressive or rapidly progressing disease. No difference was found in PSA response, PFS, or OS from FST with D compared to C. While limited by its retrospective nature and small sample size, this study suggests that D is active as FST despite treatment with DI in mCSPC.
Clinical characteristics, tumor genomic and transcriptomic profiles of patients (pts) with metastatic renal cell carcinoma (mRCC) who developed venous thromboembolism (VTE).
Authors: Li Haoran , Sahu Kamal Kant Kant , Gebrael Georges , Chigarira Beverly , Mathew Thomas Vinay , Jo Yeonjung , Kumar Shruti Adidam , Nordblad Blake , Brundage James , Tripathi Nishita , Sayegh Nicolas , Swami Umang , Agarwal Neeraj , Maughan Benjamin L. 
Published: March 2023

726 Background: VTE is a common complication in pts with mRCC. Identifying pts with mRCC at the highest risk of developing VTE may provide the rationale for initiating prophylactic anticoagulation. Methods: In this IRB-approved retrospective study, pts diagnosed with mRCC between 7/2012 and 7/2022 at Huntsman Cancer Institute at University of Utah were included. Variables evaluated were pts' clinical characteristics, treatment, and anticoagulation therapy. Pts with mRCC with VTE within 12 months after diagnosis were used as cases and those without VTE during the same period were used as control. The multivariable logistic model was used to assess risk factors of VTE. DeSeq2 analysis was implemented in Bioconductor Software to analyze differentially expressed genes based on the VTE. These results were subjected to gene ontology analysis in the TopGO software. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. Results: Among 355 pts with mRCC, 53 pts developed VTE within 12 months after diagnosis (incidence rate: 14.9%). Pts of the two groups (with or without VTE) did not differ significantly when compared for age, gender, race, cytoreductive nephrectomy rate, clear cell histology, grade of tumor, IMDC risk factors (table). Pts who developed VTE had a higher BMI at diagnosis (31.7 vs. 29.1 kg/m2, p=0.03). In multivariate analysis, obesity (OR=1.06, [1.01-1.12], p=0.028) was associated with increased VTE risk. There was no significant difference of mutation rates in genomic panel. Transcriptomic analysis showed hormone metabolic, organic acid transport, extracellular matrix and structure organization (all p<0.0001) are among the most significantly elevated pathways associated with VTE. Correlation of genomic and transcriptomic data with occurrence of VTE will be presented in the meeting. Conclusions: In this real-world population of pts with mRCC, VTE is more commonly associated with mRCC than what was previously reported in clinical trials. These hypothesis generating data, upon external validation, may provide guidance for clinical use of prophylactic anticoagulation therapy in pts with mRCC.[Table: see text]
Mapping distribution of brain metastases in renal cell carcinoma (RCC) and association with clinical features.
Authors: Ged Yasser , Feinaj Ardit , Markowski Mark Christopher , Yerrapragada Anirudh , Elias Roy , Bettegowda Chetan , Singla Nirmish , Kamson David 
Published: March 2023

727 Background: Brain metastases (BM) are frequently observed in metastatic RCC (mRCC) with a tendency to present with hemorrhagic BM. Distribution patterns of BM in RCC and associations with clinical outcomes are not well understood. Here we present a detailed distribution analysis in a surgically resected BM RCC cohort with a focus on clinically relevant associations. Methods: A retrospective analysis was performed on patients (pts) with mRCC who underwent craniotomy for BM at our institution. We reviewed gadolinium-enhanced MRI brain and CT head (if available) at the time of BM diagnosis. We assessed the presence of hemosiderin on MRI or hemorrhage on CT in the BM lesion and marked each at their corresponding anatomic location. Public brain atlases were used for distribution analysis. Overall survival (OS) from the date of BM diagnosis and CNS progression free survival (CNS-PFS) from the date of craniotomy were calculated. Results: A total of 67 BM were analyzed from 46 pts. 23 with synchronous BM, 9 with two and 6 with 3 concurrent BM. Most patients were male (n=35, 76%) with a median age at diagnosis of 63 years. Primary histology was clear cell in 42 pts (91%) and 10 pts (22%) had renal vein thrombosis (RVT) at primary diagnosis. IMDC scores at time of BM diagnosis were favorable in 20%, intermediate in 60% and poor in 20%. Hemosiderin (MRI) or hemorrhage (CT) was seen in 82% and 80% of BM, respectively. 55% of lesions were left sided, 45% frontal, 21% parietal, 18% occipital, 7% temporal and 6% cerebellar. Posterior circulation and posterior cerebral artery territories contained 42% and 34% of BM despite supplying only 30% and 16% of the brain volume, respectively. Patients with solitary BM had higher Karnofsky performance status (p=0.006) and lower disease burden (p=0.004) than those with multiple BM. Shorter CNS-PFS was seen in association with hemosiderin on MRI (log-rank p=0.04) and RVT in primary specimen (log-rank p=0.002). IMDC risk scores (log-rank p<0.001) predicted OS. On multivariable OS analysis, BM lateralized to the right (HR 2.6, p=0.06), hemosiderin in BM (HR 6.5, p=0.02) and IMDC risk groups (intermediate HR 2.9, poor risk HR 25.6, p<0.04) were independent prognostic factors for shorter OS. Conclusions: The above-presented lesion mapping method shows clinically relevant findings in RCC BM. Tumoral hemosiderin deposits appear a potential parameter to predict outcomes in RCC BM which deserve further study and validation.