bluuebunny/crossref_metadata_2025_split huggingface dataset:
An observational multicenter French study on unanswered questions in patients with advanced renal cell carcinoma (aRCC) treated with cabozantinib: OCTOPUS.
Authors: Thibault Constance , Mourey Loic , Pasquier David , Bernhard Jean-Christophe , Boissier Marion , Perrot Valérie , Albiges Laurence 
Published: January 2024

430 Background: Real-world studies with cabozantinib in aRCC have investigated its effectiveness and tolerability in routine practice, but questions remain unanswered including: Activity of systemic therapies after progression on Cabozantinib, patterns of long-responders and use in elderly patients. Methods: OCTOPUS study (NCT05444933) is a retrospective study of all consecutive patients (pts) treated with cabozantinib 2nd line (2L) for aRCC from March 2018 to March 2021 in 26 French centers. Pre-defined analysis included: descriptive analysis of Cabozantinib 2L regimen, activity of subsequent line (defined by treatment duration), patterns of long-term responders (defined as duration of cabozantinib more than 12 months in patients with complete, partial response or stable disease); and in elderly pts (>75 years). Results: In total, 252 patients were included. Median age was 63 years (20-86), 84.1% had clear-cell histology. At Cabozantinib 2L initiation, among 69 patients with available IMDC score, IMDC risk was favorable/intermediate/poor in 13.0 %, 49.3% and 37.7 % of the cases, respectively. Patients had an ECOG PS of 1 (45.8%) or 2 (25.8%). Bone, liver and brain metastasis (mets), were present in 130 (52.0%), 69 (27.6%) and 34 (13.6%) patients, respectively. 102 (40.5%) pts had 3 or more mets sites and 167 (66.3%) pts had a prior nephrectomy. 154 (61.1%) pts were pretreated with a tyrosine kinase inhibitor (TKi) based regimen and 94 (37.3%) were pretreated with an immunotherapy (IO) based regimen. Results are reported in the table. 157 patients received a 3rd line (3L) treatment after cabozantinib: nivolumab (55.4%) or a VEGFR TKI (26.1%) including axitinib (85.4%). In this subgroup, the median duration of treatment (DOT) and median progression free survival (PFS) were respectively 8.2 months and 8.0 months, with a disease control rate (DCR) of 80.3 % for Cabozantinib 2L. Conclusions: We reported the pattern of use of Cabozantinib in RWE, highlighting feasibility in elderly and long-term exposure in long responders as well as subsequent therapy activity. [Table: see text]
Pharmacodynamics and gene expression analysis of patients with renal cell carcinoma treated with combination nivolumab and TPST-1120 in a phase I clinical trial (NCT03829436).
Authors: Bastos Bruno R. , Standifer Nathan , Garje Rohan , Whiting Sam H. 
Published: January 2024

438 Background: TPST-1120 is a first-in-class, oral inhibitor of peroxisome proliferator-activated receptor (PPAR-α), a fatty-acid ligand-activated transcriptional factor that controls the expression of multiple genes involved in fatty acid oxidation (FAO), angiogenesis and inflammation. In a phase 1 open-label trial, TPST-1120 was administered as a single agent and in combination with nivolumab in multiple tumor types. Among the tumor types treated, 4 patients in the combination arm had Renal Cell Carcinoma (RCC). 2 of the patients experienced clinical and radiographic response confirmed by RECIST. On this study, we plan to further study the pharmacodynamic and radiographic changes in these patients with RCC to further understand signals to identify patients who may benefit from this treatment. Methods: Mutational analysis of ctDNA was assessed using the PredicineCARE assay (Predicine Inc.), and lipid analysis was performed by tandem mass spectrometry. Gene Expression changes were quantified using the nCounter PanCancer Iune Profiling Panel (Nanostring Inc.) supplemented with 30 PPAR-α target genes. The radiographic Analysis was performed with CT chest-abdomen-pelvis and response evaluated using RECIST criteria. Results: RCC patients with PR (2/4) confirmed by RECIST exhibit greater reductions in 6 PPAR-α regulated genes. They had an early increase in thrombospondin (TSP-1) level due to PPAR-α inhibition. An increase in long-chain fatty chain fatty acids was seen including circulating FFA, lysophosphorylcholine (LPC) or lysophosphorylethanolaine (LPE). They also had great reductions in 6 PPAR-α regulated genes including ACAD8, ACSL3, CPT2, FABP1, FABP3, HADHB. Conclusions: There is a paucity of treatment options for patients with stage IV RCC post anti-PD1 and anti-VEGF therapies. Novel therapies on this clinical scenario are needed. On this abstract we showed radiographic and pharmacodynamic data on patients with RCC who achieved a clinical partial response by RECIST on the phase I clinical trial TPST1120-001. The trial explored the se of a PPAR-α inhibitor in combination with Nivolumab. The pharmacodynamic data indicates that there is fatty acid oxidation perturbation and immune gene expression changes as potential biomarkers of clinical benefit. PI3K pathway or IDH mutations may indicating a signal that RCC patients may benefit from this combination therapy. Larger studies in the future may be designed to further explore the use of this combination in patients with RCC. Clinical trial information: NCT03829436 .
Low- and high-volume disease in mHSPC, from CHAARTED to PSMA-PET: An international multicenter retrospective study.
Authors: Unterrainer Lena , Hope Thomas A. , Fendler Wolfgang P. , Ndlovu Honest , Barbato Francesco , Sathekge Mike , Herrmann Ken , Czernin Johannes , Calais Jeremie 
Published: January 2024

44 Background: High-volume disease (HVD) and low-volume disease (LVD) definitions are based on conventional imaging (CI = CT + bone scan (BS)) according to CHAARTED. Volume of disease is associated with overall survival and used for treatment decisions in mHSPC patients. It remains unknown how these definitions transfer to PSMA-PET. Methods: mHSPC patients from 4 international sites who underwent PSMA-PET+BS within a maximum time interval of 100 days and without any new treatment in between were retrospectively included. CHAARTED stratification into HVD/LVD was applied to BS, CT, MRI and PSMA-PET. HVD was defined by the presence of visceral metastases and/or ≥ 4 bone metastases (with ≥ 1 beyond spine / pelvis). EXINIbone 3.4 (EXINI Diagnostics) was used for the automated bone scan index (aBSI) and the number/localization of lesions on BS. The whole-body (WB) PSMA-PET positive tumor volume (PSMA-TV) was obtained using a semi-automatic thresholding method on Affinity 3.0.2 (Hermes Medical Solutions). Results: Fifty-sevenpairs of PSMA-PET/CT+BS were included (median PSA 226.0 (0.2–2840.0 ng/ml). Based on CI, 16/57 patients had CI-HVD (28.1%) and 41/57 CI-LVD (71.9%). Based on PSMA-PET, 25/57 patients had PSMA-HVD (43.9%) and 19/57 PSMA-LVD (33.3%), 13/57 (22.8%) patients had on PSMA-PET no PSMA-positive or only local / N1-disease. Upshift and downshift from CI to PSMA-PET occurred in 22/57 (38.6%): 9/57 (22.0%) patients were upstaged and 13/57 (22.8%) were downstaged by PSMA-PET. The downshifted patients had no PSMA-PET-positive lesion or only in the prostate fossa while CI was M1 disease. The mean WB-PSMA-TV and aBSI were for CI-HVD was 778.2 ml (0.3–3734.0) and 3.8% (0–11.7), for CI-LVD 51.6 ml (0–228.0) and 0.1% (0–0.6), for PSMA-HVD 573.7 ml (7.9–3734.0) and 2.6% (0–11.7) and for PSMA-LVD, 49.4 ml (1.6–228.0) and 0.1% (0–0.6), respectively. Conclusions: Stage migration between LVD and HVD from CI to PSMA-PET occurs both by up- and downstaging. HVD/LVD based on PSMA PET/CT should be redefined based on patients’ outcome.
High expression of sialylated cancer-derived IgG and survival in metastatic clear cell renal cell carcinoma.
Authors: Wu Jie , Cui Hong-Lei , Shi Hongzhe , Zhou Ai-Ping , Shou Jianzhong 
Published: January 2024

443 Background: The treatment landscape of metastatic clear cell renal cell carcinoma (mccRCC) has evolved from cytokine regimens to targeted therapy, and now immunotherapy-based drug combinations over the past two decades. However, there is a lack of confirmed prognosis biomarkers for mccRCC patients. The International mRCC Database Consortium (IMDC) risk model is the most widely used effective biomarker for prognostication in mccRCC. Immunoglobulin G (IgG), well known as immune molecule secreted by B cells, has recently been detected in various types of cancer cells, named as cancer-derived IgG. Notably, it has been demonstrated that IgG derived from epithelial cancer cells displays unique N-glycosylation, which is highly sialylated (SIgG). In this study, we aimed to explore the expression of SIgG in mccRCC tissues using the monoclonal antibody RP215, and evaluated the correlation of SIgG expression level with clinicopathological factors and prognosis of mccRCC patients. Methods: A total of 179 mccRCC patients with complete clinicopathological information and survival data were enrolled. Tumor tissues were collected during surgery and fixed in 10% buffered formalin, embedded in paraffin. Tissue microarray slides were then constructed for immunohistochemistry (IHC). The primary end point was overall survival (OS), defined as the time from initiation of systemic treatment to death from any cause or last follow-up. Results: The results of IHC showed that SIgG was mainly expressed in the cell membrane and cytoplasm, and the high expression of SIgG was significant correlated with poor OS in mccRCC patients (HR = 2.281, P < 0.001). Moreover, based on multivariate Cox regression analysis, high SIgG expression was identified as an independent prognostic variable for OS in mccRCC patients (HR = 2.110, P < 0.001), as well as poor IMDC risk group (HR = 2.123, P = 0.018). The time-dependent ROC curve also suggested the promising prognostic value of SIgG expression, with a 5-year AUC of 0.679 for SIgG alone and 0.742 for SIgG combined with IMDC risk model. In addition, subgroup analyses were performed to further assess prognostic value of SIgG for mccRCC patients among groups based on IMDC risk group, metastatic site, and metastatic time. The prognostic value of SIgG was more marked in patients with intermediate (HR = 2.191, P = 0.019) and poor (HR = 2.111, P = 0.058) IMDC risk group, and lung metastasis (HR =1.970, P = 0.009). Notably, the prognostic value of SIgG was significant in both synchronous and metachronous metastasis patients. Conclusions: SIgG appears to be a reliable predictor for the outcome of mccRCC patients, and SIgG combined with IMDC risk model was a more effective prognostic model than IMDC risk group alone.
Peripheral blood cell counts as biomarkers of clinical benefit in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) receiving immune checkpoint inhibitor (ICI) combination (combo) therapies.
Authors: Feinaj Ardit , Nathani Kaizen , Touma Amina , Elias Roy , Pallauf Maximilian , Markowski Mark Christopher , Carducci Michael Anthony , Singla Nirmish , Ged Yasser 
Published: January 2024

446 Background: Numerous combos of ICIs and Tyrosine Kinase Inhibitors (TKIs) have received approval for the management of mccRCC. Specific peripheral blood cell counts reflect inflammation and impact anti-tumor immunity, and here we investigated their role as biomarkers of clinical benefit to ICI combos in RCC. Methods: We performed a retrospective study of 179 mccRCC patients treated with ICI combos ≥ 4 weeks (2013-2023), where we examined baseline and 6-week post-treatment Neutrophil to Lymphocyte ratio (NLR), Red cell Distribution Width (RDW), and eosinophil values. We categorized these values as High (H) or Low (L) based on baseline medians. Our analysis included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to next treatment (TNT). Kaplan-Meier methods and the log-rank test were used to evaluate time from start of ICI combos to the event of interest. Results: Our analysis included 111 eligible ICI-naïve mccRCC patients median age 63, 76% male. IMDC risk scores categorized 22% as favorable, 53% intermediate, and 25% poor risk. Treatment included 50 (45%) patients on ICI+ICI combos with a median therapy duration of 6.3 months, and 61 (55%) on ICI+TKI with a median duration of 8.8 months. In the ICI+ICI group, median OS was 28.2 months (95% CI 20.7-38.4), PFS 5.5 months (95% CI 3.7-7.8), and TNT 12.7 months (95% CI 7.4-20.4). In the ICI+TKI group, median OS was 21.7 months (95% CI 17.1-25.4), PFS 7.4 months (95% CI 5.6-11.1), and TNT 12.5 months (95% CI 9.7-16.4). The ORR was 38% in the ICI+ICI group, and 56% in the ICI+TKI group (p=0.062). No differences were seen with NLR. In the ICI+ICI group, higher baseline RDW levels were correlated with a shorter TNT, while higher eosinophil levels at week 6 were correlated with longer PFS and TNT (significant results highlighted in the table below). Conclusions: Eosinophil levels and RDW are potentially readily available biomarkers in the clinic for predicting and monitoring ICI combo treatment outcomes in mccRCC patients. Validation of these results in larger cohorts is warranted. [Table: see text]
Tumor-infiltrating CD163-positive macrophages and clinical outcomes to first-line nivolumab therapy in patients with advanced clear cell renal cell carcinoma (ccRCC) enrolled in the HCRN GU16-260 trial.
Authors: El Ahmar Nourhan , Matar Sayed , Jegede Opeyemi , Nabil Laimon Yasmin , Savla Varunika , Bagheri Sheshdeh Aseman , Denize Thomas , Mohanna Razan Assaad , Choueiri Toni K. , Catalano Paul J. , Braun David A. , Haas Naomi B. , Hammers Hans J. , Bilen Mehmet Asim , Stein Mark N. , Sosman Jeffrey A. , Wu Catherine J. , McDermott David F. , Atkins Michael B. , Signoretti Sabina 
Published: January 2024

448 Background: There is evidence that intratumoral myeloid cell infiltration can modulate response to immune checkpoint inhibitors in some tumor types, but its role in ccRCC remains unclear. Here, we investigated the role of tumor-infiltrating CD163-positive macrophages as a determinant of clinical outcome to anti-PD-1 therapy in patients (pts) with advanced ccRCC treated with first-line nivolumab therapy as part of the HCRN GU16-260 clinical trial. Methods: Primary tumor tissues from pts with ccRCC (n= 67) were analyzed by multiparametric immunofluorescence (IF). Image analysis algorithms were used to assess the density of CD163-positive cells (dCD163) in tumor areas with high CD8+ T cell-infiltrates. In addition, dCD163 was also assessed in randomly selected tumor areas. Log-transformed densities were correlated with objective response rate (ORR) and progression-free survival (PFS) using Cox proportional hazards and binary logistic (modeling odds of attaining objective response) regression analysis, respectively. Alpha level was set a priori at 5% (2-sided). The functional form of CD163 for the PFS endpoint was obtained using a smoothed martingale residual plot. Results: Analysis of dCD163, assessed in high-CD8+ cell tumor areas and measured as a continuous variable, showed a positive association with ORR (OR= 2.21, p= 0.002) and PFS (HR= 0.77, p= 0.028). However, visual inspection of the dCD163 functional form plot for PFS revealed a threshold effect at the raw (log-transformed) value of 262.5 (5.6) cell/mm2. Similar to the entire cohort, in patients with dCD163 below this threshold (n= 54), dCD163 was positively associated with PFS (HR= 0.61, p<.001). In contrast, in patients with dCD163 above this threshold (n=13), results suggested the presence of a negative association between dCD163 and PFS (HR= 1.36, p= 0.726). Of note, similar findings were obtained by analyzing dCD163 assessed in random tumor areas. Conclusions: Levels of tumor-infiltrating CD163-positive macrophages are associated with improved clinical outcomes to first-line nivolumab in pts with advanced ccRCC up to a density threshold, above which an association with poor outcomes is noted. Further investigations into the role of tumor-infiltrating myeloid cells in predicting outcomes to anti-PD-1-based therapies are ongoing. Clinical trial information: NCT05403541 .
Prognostic value of circulating tumor DNA fraction (TF) for patients with metastatic renal cell carcinoma (mRCC).
Authors: Zurita Amado J. , Danziger Natalie , Scott Takara , Gjoerup Ole , Zhong Lei , Tukachinsky Hanna , Ross Jeffrey S. , Graf Ryon 
Published: January 2024

455 Background: Risk stratification, based on the IMDC classification, is central to treatment decisions for patients with mRCC. The strongest prognostic feature in the original validation was the clinical assessment of patient frailty through performance status (PS). Although inexpensive and ubiquitous, clinical features such as PS are prone to degrees of subjectivity and considerable variation in assessment from practitioner to practitioner. Recent work (Reichert et al. 2022, Annals of Oncology) observed that TF levels around the initiation of new treatment were prognostic independently of standard clinical features including ECOG PS, in advanced/metastatic lung, breast, prostate, and colorectal cancers, but has not yet been investigated in mRCC. Methods: This study used a cohort of patients in the de-identified nationwide, U.S. based Flatiron Health-Foundation Medicine renal cell clinico-genomic database, which originated from approximately 280 US cancer clinics (~800 sites of care), who underwent genomic testing as part of routine care. TF estimation on FoundationOne Liquid CDx was based on a composite algorithm incorporating multiple factors including aneuploidy and variant allele frequency of canonical alterations. Clinical characteristics, laboratory and treatment data were captured from the electronic health record. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by TF level. Results: 45 patients with mRCC and liquid biopsy testing had TF assessments within 90 days of start of new treatment. Patients with TF≥1% (15 of 45) had younger median age (58y vs. 66y, p = 0.041) and higher prevalence of calcium levels above upper limit of normal (46% vs. 4%, p < 0.001). Higher TF (≥1%) was associated with less favorable rwPFS (hazard ratio (HR) 1.41, 0.70-2.82, p=0.34) and rwOS (HR 2.54, 1.08-5.96, p=0.033). In the 15 patients with TF ≥1%, we observed detection of known pathogenic genomic alterations in VHL (7/15, 47%), SETD2 (4/15, 27%), PBRM1 (4/15, 27%), BAP1 (3/15, 20%). Conclusions: In this initial cohort study, ctDNA TF shows prognostic significance in mRCC with potential to inform expected longevity of patients. Liquid biopsy detects alterations characteristic of mRCC genomics, supporting its utility to identify drivers and potential targetable alterations. Risk stratification based entirely upon algorithmic determination independent of human interpretation has the potential to improve risk stratification in mRCC and improve treatment decisions. Expansion of our cohort and survival data maturation will allow for evaluation of whether TF may be a useful addition to the established IMDC clinical classification and improve risk stratification and treatment assignment.
A convolutional neural network model using intraprostatic patterns of [F18]DCFPyL uptake in PSMA PET images to predict synchronous metastases.
Authors: Juarez Jesus Eduardo , Benitez Cecil Mayra , Rzechowski Kamil , Sjöstrand Karl , Anand Aseem , Sonni Ida , Berenji Gholam Reza , Duriseti Sai , Rettig Matthew , Nickols Nicholas George 
Published: January 2024

46 Background: [F18]DCFPyL (PyL) is a PSMA targeted imaging agent that provides whole-body staging of prostate cancer. Image analysis of the primary tumor using deep learning algorithms might offer additional insight into disease biology, including co-existing metastatic disease. We developed convolutional neural network (CNN) models using inputs from the entire prostate on PyL images along with auto-segmented hot spots within the of primary prostate cancer tumor to predict synchronous metastases and compared the models against established models built from clinico-pathologic data. Methods: 91 Veterans with de novo prostate cancer were imaged with PyL PSMA PET/CT for initial staging (46% with metastatic disease). The PyL images of the prostate were analyzed using aPROMISE, which autosegments, localizes, and quantifies disease on PSMA PET. The segmentations of the prostate were used to map the PyL PET image of the prostate. Both the entire prostate, as well as aPROMISE defined hot spots were used as inputs for the CNN, where, according to attention map analysis, the hotspot information helps the network understand the location and extent of tumors. The CNN model architecture was based on SqueezeNet v2. The dataset was split into training, validation and test sets using stratified random sampling. The area under ROC curve (AUC) was computed to determine the performance of the model in predicting the presence of metastases and the test predictions were compared with ground truth (M1). Training was repeated 50 times and the best performing experiment was identified. Prediction scores from UCSF-CAPRA and UCLA PSMA risk calculator were used as comparators. Results: The best CNN model had an AUC of 0.89 for prediction of metastatic disease (median 0.72, ICR 0.64 and 0.8). For comparison, the AUC from the UCSF-CAPRA score and UCLA-PSMA risk calculator (any upstaging on PET), which rely on clinicopathologic information, had AUCs of 0.729 and 0.754 in this dataset, respectively. Conclusions: The CNN based model using PyL imaging demonstrates that synchronous metastases can be predicted from intraprostatic PyL uptake patterns alone with a predictive accuracy in this dataset that is at least comparable to published prediction models based on clinicopathologic features. This study raises the hypothesis that PyL CNN-based models could be developed to prognosticate metastatic progression.